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Scoping Review of Symptoms in Children with Rare, Progressive, Life-Threatening Disorders Pawliuk, Colleen; Widger, Kimberley; Dewan, Tammie Joanne; Brander, Gina; Brown, Helen; Hermansen, Anne-Mette; Grégoire, Marie-Claude; Steele, Rose; Siden, Harold (Hal) 2019

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Scoping Review of Symptoms in Children with Rare, Progressive, Life-Threatening Disorders  Colleen Pawliuk, MLIS BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada   Kim Widger, RN, PhD, CHPCN(C)  Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada   Tammie Dewan, BSc, MD, MSc Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada   Gina Brander, MLIS Saskatchewan Polytechnic, Regina, Saskatchewan, Canada  Helen Brown, MLIS University of British Columbia, Vancouver, British Columbia, Canada   Anne-Mette Hermansen, MA BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada (  Marie-Claude Grégoire, MD, MSc, FRCPC Department of Paediatrics, Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada   Rose Steele, RN, PhD 2  School of Nursing, York University, Toronto, Ontario, Canada   Harold (Hal) Siden, MD, MHSc, FRCPC Department of Pediatrics, University of British Columbia BC Children's Hospital, Vancouver, British Columbia, Canada   Corresponding Author: Harold (Hal) Siden, MD, MHSc, FRCPC Department of Pediatrics, University of British Columbia; BC Children's Hospital Research Institute, 4480 Oak Street, Room F612A Vancouver, BC V6H 3V4 Canada  Email: hsiden@bcchr.ca    This article has been accepted for publication in BMJ Supportive and Palliative Care, 2019 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/bmjspcare-2019-001943.  © the Authors   3  ABSTRACT  Background: Q3 conditions are progressive, metabolic, neurological, or chromosomal childhood conditions without a cure. Children with these conditions face an unknown lifespan as well as unstable and uncomfortable symptoms. Clinicians and other health care professionals are challenged by a lack of evidence for symptom management for these conditions. Aims: In this scoping review we systematically identified and mapped the existing literature on symptom management for children with Q3 conditions. We focussed on the most common and distressing symptoms, namely alertness, behavioral problems, bowel incontinence, breathing difficulties, constipation, feeding difficulties, sleep disturbance, temperature regulation, tone and motor problems and urinary incontinence. For children with complex health conditions, good symptom management is pertinent to ensure the highest possible quality of life.  Methods: Scoping Review. Electronic database searches in Ovid MEDLINE, Embase and CINAHL and a comprehensive grey literature search. Results: We included 292 studies in our final synthesis. The most commonly reported conditions in the studies were Rett syndrome (n=69), followed by De Lange syndrome (n=25) and tuberous sclerosis (n=16). Tone and motor problems was the most commonly investigated symptom (n=141), followed by behavioral problems (n=82) and sleep disturbance (n=71). Conclusion: The evidence for symptom management in Q3 conditions is concentrated around a few conditions and these studies may not be applicable to other conditions. The evidence is dispersed in the literature and difficult to access, which further challenges health care providers. More research needs to be done in these conditions to provide high quality evidence for the care of these children.    Running head: Scoping Review to Examine Symptoms  4  BACKGROUND Quadrant 3 (Q3) conditions are progressive, metabolic, neurological, or chromosomal childhood conditions for which there currently exists no curative treatment. They are also known as Category 3 conditions in the report by the UK-based charity, Together for Short Lives.1 Children with these conditions face an unknown lifespan and symptoms that are both unstable and uncomfortable. Although the individual diagnoses are rare, Q3 conditions are a significant cause of disability and death in childhood. These conditions are numerous and varied, however, collectively they share many features in symptoms and burden of care. Children with Q3 conditions are living longer due to medical advances, but extending the duration of life does not necessarily mean improving a child’s quality of life. Until cures are found, a clinician’s obligation is to maximize comfort and quality of life. There is a lack of research on these conditions and, particularly, their associated symptoms. Clinicians, health professionals and families caring for children with Q3 conditions are challenged by this lack of research, which limits their ability to make evidence-based care decisions. Our aim in this scoping review was to systematically identify and map the literature regarding the assessment and management of the most common symptoms in Q3 conditions. With better evidence, clinicians and families will be able to make informed decisions about care and ensure better health outcomes for children living with distressing symptoms of complex conditions.     METHODS Search Methods Our comprehensive search strategy combined 181 Q3 conditions and 10 symptoms. Q3 conditions were identified through an initial pilot literature search, our previous work in this 5  area2,3 and 2 lists of Q3 conditions written by experts in the field.4,5 When creating the search strategy for the Q3 conditions we were challenged by the lack of controlled vocabulary for many of these conditions in the databases we searched. To ensure complete retrieval of all relevant studies we included broader controlled vocabulary terms when a specific condition term was not available or had only been recently added to the database. For example, “Farber Lipogranulomatosis” was introduced as a MeSH term in 2009, so to ensure coverage to database inception we also included the broader MeSH terms “Lipidoses” and “Sphingolipidoses” that had been previously used to index this condition. See Supplementary File 1 for our full MEDLINE Search Strategy. The 10 symptoms identified in our pilot study were based on Hunt,6 Malcolm et al.7 and our Charting the Territory study.8 The investigated symptoms were alertness (fatigue, arousal, wakefulness, concentration); behavioral (agitation, irritability, aggression, self-harm, negative affect); bowel incontinence; breathing difficulties (dyspnea, cough, apnea, hypoventilation, obstruction); constipation; feeding difficulties (gastric reflux, regurgitation, emesis, retching, nausea, feeding intolerance, salivary secretions, dyspepsia, swallowing difficulty, aspiration); sleep disturbance; temperature regulation; tone and motor problems (spasticity, dystonia, ataxia); and urinary incontinence. Seizures and pain were excluded from the symptom list as seizures is a common symptom with extensive literature and pain is the subject of another scoping review by one of our investigators. “Symptom management” search terms based on the clinical experience of the investigators were added to increase the specificity of the search.  We searched MEDLINE (Ovid), Embase and CINAHL from inception until January 2018; we did not limit our search by publication date or by language. To locate grey literature sources we searched ClinicalTrials.gov, WHO International Clinical Trials Platform, Conference 6  Proceedings Citation Index- Science (Web of Science), TRIP, ProQuest Dissertations and Theses Global, OAIster and LILACS. Experts in the field were contacted through relevant listservs to locate unpublished studies. Palliative care conferences were identified and conference abstracts were hand-searched when not indexed in the electronic databases already searched. The references of all included studies were hand-searched and Web of Science was used to search the citing articles of each study. Study Inclusion Studies had to 1) include at least one of the 181 Q3 conditions, 2) report on at least one of the 10 symptoms and 3) be focused on assessment tools to evaluate symptoms or on interventions to relieve symptoms. We only included studies with pediatric populations (0-18 years) or studies with adults were there was more than one pediatric participant. We excluded non-studies (i.e. letters to the editor, commentaries) and case reports with a single participant. Languages other than English or French were excluded due to a lack of resources for translation. Study Selection All search results were imported into Endnote© and duplicates were removed. Due to the comprehensiveness of our search strategy, we returned a large number of results. To more efficiently filter these results, a single team member pre-screened by title and abstract to remove articles that did not include both a symptom and a Q3 condition. The titles and abstracts of the remaining articles were screened in more depth independently and in duplicate by team members using abstrackr.9 The resulting full-text of studies were then reviewed by team members independently and in duplicate using Rayyan.10 For articles where the 2 team members did not agree in both the screening and review phases, the team met to come to a consensus decision to 7  include or exclude. Data were extracted from the remaining full text articles using a database created in REDCap.11 We extracted data on study design, sample size, tools or scales, intervention, year of publication, journal, Q3 condition(s), symptom(s), study objective, and primary outcome(s). To summarize the charted data, we grouped the studies together by symptom and summarized the study design and study objective. We did not register the protocol for our review our scoping review. We used the PRISMA Extension for Scoping Reviews guidelines to report the methods of our scoping review.12 RESULTS Our database and grey literature search retrieved 46,644 results. We returned a high number of results due to the broadness of our search and the lack of controlled vocabulary for these conditions. Once duplicates were removed, we pre-screened 36,447 and excluded 35,294 for not including both a Q3 condition and a symptom from our list. For this phase, when there was ambiguity the team member always chose to include studies for the next phase. The resulting 1,153 titles and abstracts were then screened and 316 were excluded for lack of symptom focus, wrong study design or wrong population. The remaining 837 full-text articles were reviewed and 545 were excluded for lack of symptom focus (n=206), lack of assessment (n=73), publication type (reviews, letters, commentaries: n=68), ongoing studies without finalized data (n=57), wrong outcome (n=46), wrong population (n=39), not in English or French (n=24), wrong study design (n=14), background article (n=17), and full-text not available (n=1). This left 292 studies in our final synthesis. See Figure 1 for the PRISMA Flowchart of the study selection process.  8   Figure 1: PRISMA flow chart of study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Study Characteristics One of the studies was a thesis and the other 291 studies were journal articles. The 291 studies were published in 112 different journals and 70 of these journals only had a single study to contribute to this review. See Table 1 for the 10 most common journals. There was only 1 general pediatric journal, the Journal of Pediatrics, that had 3 studies to contribute to this review. The other journals are from a wide variety of disciplines, including clinical neurology, surgery, education, rehabilitation, dermatology, genetics, otorhinolaryngology, palliative care and gastroenterology. The studies were published between 1974 and 2018, with 52% (152) published 9  in 2010 or later. Fifty-nine percent of the studies used only validated tools or scales, while 27% used non-validated tools or scales, and 14% combined both validated and non-validated tools. See Supplementary File 2 for a table of the characteristics and a full bibliography of all included studies.  Table 1: 10 most common journals  Journal Name Frequency of Articles 2017 Journal Impact Factor  Developmental Medicine & Child Neurology 20 3.289 Journal of Intellectual Disability Research 16 2.026 Journal of Child Neurology 13 1.665 American Journal of Medical Genetics Part A 12 2.264 Movement Disorders 11 8.324 Pediatric Neurology 11 2.398 Brain & Development 9 1.544 European Journal of Paediatric Neurology 9 2.362 Journal of Neurodevelopmental Disorders 8 3.500 International Journal of Pediatric Otorhinolaryngology 7 1.305  Q3 Conditions Rett syndrome was the most investigated Q3 condition (n=69) followed by De Lange syndrome (n=25), tuberous sclerosis (n=16), mucopolysaccharidosis type III (n=15), spinal muscular atrophy type 1 (n=15), Cri-du-Chat (n=14), Friedrich’s ataxia (n=13), neuronal ceroid lipofuscinosis type 3 (n=13), and Lesch-Nyhan syndrome (n=12). Only 20 conditions comprised 10  80% of the studies (Table 2). One hundred and twenty-four of the 181 Q3 conditions did not appear in a single study and the remaining 36 conditions were investigated in 5 or fewer studies. See Supplementary File 1 for a heat map of all Q3 conditions and symptoms.  Table 2: 20 most common Q3 Conditions Q3 Condition Frequency of studies  Q3 Condition Frequency of studies  Rett syndrome  69 Epidermolysis bullosa 10 De Lange syndrome  25 Infantile neuroaxonal dystrophy 10 Tuberous sclerosis  16 Mucopolysaccharidosis type I 10 Mucopolysaccharidosis type III 15 Mucopolysaccharidosis type II 10 Spinal muscular atrophy 1 15 Achondroplasia 8 Cri-du-chat 14 Ataxia telangectasia 8 Friedrich’s ataxia 13 Mucopolysaccharidosis VI 8 Neuronal ceroid lipofuscinosis 3 13 Glutaric acidemia type I 6 Lesch-Nyhan syndrome 12 Mucopolysaccharidosis type IIIA 6 Jacobsen syndrome 10 West syndrome 6  Using a classification system for these conditions,3 Neurodegenerative Diseases was the most investigated condition category (n=102), followed by Multi-Organ Congenital Abnormalities (n=97), Lysosomal Storage / Peroxisomal Diseases (n=45), Small Molecule Diseases (n=20), Neuromuscular Diseases (n=14), Other Inborn Errors of Metabolism (n=8),  Severe Neurological Impairment -Not Yet Diagnosed (n=7), Structural Central Nervous System Abnormalities (n=5), Other Conditions Not Otherwise Specified (n=4), Mitochondrial Encephalo-/Myopathies (n=2), 11  and Congenital Disorders of Glycosylation (n=1). See Figure 2 for a heat map of condition categories and symptoms.   Figure 2: Heat map of Q3 condition categories and symptoms Symptoms Alertness Fourteen studies investigated alertness in Q3 conditions: 11 cross-sectional, 1 case-control, 1 open label and 1 tool/scale development study. The single open-label study investigated a psychological intervention in Rett syndrome: structured training to increase attention and reduce help needed.13 Paulsen et al. conducted an initial validation of the PedQL Fatigue Scales in Friedrich’s ataxia.14 The remaining 12 studies provided evidence of the severity of this symptom and described its trajectory. See Figure 3 for a heat map of the study objectives and symptoms and Figure 4 for a heat map of symptoms and study designs. For children who have attentional difficulties, clinical practitioners could try structured training, as this was found to be effective in one study in Rett syndrome. Rett syndrome has a distinct clinical profile, so structured training may not be effective in other Q3 conditions. No effective interventions were found for fatigue or alertness. Future studies should focus on other Q3 conditions that may be more applicable to the 12  group as a whole. A single study suggests the PedQL Fatigue Scales may be useful to measure levels of fatigue in Friedrich’s ataxia, which may be useful in other Q3 conditions.   Figure 3: Heat map of study objectives and symptoms  Figure 4: Heat map of study designs and symptoms. Behavioral Problems The majority of the 82 studies investigating behavioral problems were cross-sectional (n=47), followed by case control (n=9), case series (n=9), tool or scale development (n=9), survey (n=9), longitudinal (n=5), open-label (n=2), retrospective chart review (n=2), N of 1 trial (n=1) and RCT (n=1). Eight studies investigated an intervention: 6 were pharmacologic and 2 were psychological. Six of the studies were in Lesch-Nyhan syndrome and investigated strategies to reduce or eliminate self-injurious behavior.15–20 Nyhan et al. tested 5-hydroxytryptophan in a case-series;15 Khasnavis et al. tested Ecopipam in a RCT;16 Anderson et al. tested L-5-hydroxytryptophan in a case-series;17 Mizuno compared L-5-Hydroxytryptophan, L-tryptophan 13  or levodopa in a case-series;18 and Visser et al. investigated levodopa and carbidopa.19 Anderson et al. also investigated if electric shock, positive reinforcement, or time-out reduced self-injury.20,21 In a case-control study Sloneem et al. investigated how environmental conditions (demand, denial, attention, no contact) affected self-injurious behavior in De Lange syndrome.22 Ucar et al. investigated risperidone in children with mucopolysaccharidosis type III in an open-label trial.23 Eight studies designed and/or aimed to validate scales or tools. Darling et al. designed and pilot tested a disease rating scale for pantothenate kinase-associated neurodegeneration that included a section on psychiatric symptoms.24 In 2 studies, de Vries et al. and Lezlezio et al. designed and pilot-validated the TAND Checklist for tuberous sclerosis, which includes questions on behavioral concerns.25,26 Mount et al. developed the Rett Syndrome Behaviour Questionnaire.27 In 3 studies, Rojahn et al. developed and validated the Behavior Problems Inventory in unspecified intellectual disabilities.28–30 Shapiro et al validated the Sanfilippo Behavior Rating Scale in mucopolysaccharidosis type III.31 The remaining 66 studies provided insight into the behavioral challenges faced by caregivers of children with Q3 conditions, identified the possible mechanisms of self-injury, or described the trajectory of this symptom.  Behavioural problems was the second most studied symptom, and most of the studies that investigated interventions focused on self-injurious behaviour. None of the pharmacologic studies showed clear and lasting effects on self-injury. Clinicians could suggest positive reinforcement and/or time-outs, as this led to reductions in self-injury in one study, while punishment led to increased self-injury. Three systematic reviews and 1 RCT were found for behavioral problems, which highlights the need for more high level studies to be conducted on 14  this challenging symptom. Some condition-specific scales have been created and/or validated for behavioral problems and may be valuable for other Q3 conditions as well.  Bowel Incontinence Five studies investigated bowel incontinence: 4 cross-sectional and 1 case-control. All the studies described incidence and/or trajectory. Bowel incontinence was the second least studied symptom. Although studies included in this review found that this is a common symptom in Q3 conditions, no studies provide evidence on which to base symptom management. Breathing Difficulties Thirty-seven studies investigated breathing difficulties: 13 cross-sectional, 7 case-series, 5 retrospective chart reviews, 4 case-controls, 4 longitudinal, 4 surveys, 2 systematic reviews, 2 RCTs and 1 tool/scale development. Seven of the studies investigated an intervention; six of these examined a combination of surgical and physical interventions. Only 1 study investigated a pharmacologic intervention: testing the efficacy of oral naltrexone in children with Leigh syndrome and other children with sleep apnea in an RCT.32 In a retrospective chart review, Tenconi et al. assessed conventional treatment options (adenotonsillectomy, continuous positive airway pressure (CPAP), losing weight) for obstructive sleep apnea (OSA) in children with achondroplasia.33 Also in achondroplasia, a case-series investigated surgery, CPAP, bilevel positive airway pressure, cervical decompression for OSA.34 In a RCT, Sudarsan et al. compared adenotonsillectomy and CPAP in children with mucopolysaccharidosis types I, II, III, VI and VII.35 Another retrospective chart review of children with mucolipidosis types II and III and mucopolysaccharidosis types I, II and III, recorded interventions used for respiratory complications, including surgery (adenotonsillectomy, tracheostomy); low flow oxygen; 15  medications (diuretics, theophylline, digoxin, beta adrenergic blockers, calcium antagonists).36 Nabatame et al. and Mellies et al. investigated the efficacy of non-invasive positive pressure ventilation for sleep disordered breathing in glycogen storage disease type II and spinal muscular atrophy type 1 respectively.37,38 Mount et al. developed the Rett Syndrome Behavior Questionnaire that includes questions on breathing problems including air swallowing, breath holding and hyperventilation.27 The remaining 29 studies described breathing difficulties in this population and provided insight into its trajectory.  Many of the studies confirm the prevalence of both sleep apnea and other breathing problems in Q3 conditions. Sleep apnea studies in achondroplasia suggest surgical intervention may be necessary, while for other Q3 conditions CPAP appears to be effective. Medications, such as naltrexone, could also be effective for sleep apnea. For other breathing problems, 1 study suggested a combination of surgical and pharmacological interventions may be effective, but a systematic review on treatments for dyspnea found the evidence to be of low quality. Our review also shows that overall there is a lack of high level evidence breathing difficulties and more research is needed. One of the studies created a Rett syndrome specific tool that includes a section on breathing problems, which may not be relevant to other Q3 conditions. Constipation Ten studies investigated constipation: 5 cross-sectional, 3 retrospective chart reviews, 2 surveys, 1 case-series and 1 open-label study. Three of the studies tested a pharmacological or dietary intervention to reduce constipation. In retrospective chart review, Mordekar et al. investigated parenteral nutrition in Rett syndrome, mucopolysaccharidosis type III and West syndrome39 and Murata et al. investigated supplementary carnitine in neuronal ceroid lipofuscinosis type 3, 16  Pelizaeus-Merzbacher disease, tuberous sclerosis and West syndrome.40 In an open-label study Haynes et al. investigated fiber-containing formula in epidermolysis bullosa.41 No studies developed or validated a tool or scale and the remaining 7 studies described the features or trajectory of this symptom.41 To help manage constipation in Q3 conditions, clinical practitioners can try parenteral nutrition, fiber-enriched formula, or supplementation with carnitine. In our Charting the Territory study we found constipation to be the fourth most commonly reported symptom by caregivers, yet only 3 studies investigate symptom management in this population.8 More studies are needed for this symptom. Feeding Difficulties Forty-five studies investigated feeding difficulties: 15 cross sectional, 12 retrospective chart reviews, 11 case series, 3 scale/tool development, 3 surveys, 2 longitudinal and 2 open-label. Thirteen studies investigated an intervention and 10 of these were surgical interventions. Seven of the surgical studies investigated balloon dilation of esophageal strictures in epidermolysis bullosa.42–48 Stehr et al. and Seguy et al. performed retrospective chart reviews of percutaneous gastrostomy placement in epidermolysis bullosa,49 spinal muscular atrophy type 1 and other congenital muscular dystrophies and congenital myopathies.50 Blommaert et al. reported a case series of bilateral submandibular gland excision and parotid duct ligation for drooling in children with MEGDEL syndrome.51 Two of the studies investigated a pharmacological intervention. Kawai et al. performed an open-label study of baclofen for emesis and gastroesophageal reflux disease in children with De Lange and West syndromes.52 Kawahara et al. reported the effects of rikkushito on gastroesophageal reflux in children with profound neurological impairment.53  17  Three studies examined physical interventions. In a longitudinal open-label study Munakata et al. investigated the effects of black pepper oil at stimulating oral feeding in Costello syndrome and lissencephaly type 1.54 Mordekar reported treating feed-induced dystonia with parenteral nutrition in Rett syndrome, mucopolysaccharidosis type III and West syndrome.39 In Rett syndrome, Morton et al. tried a variety of physical interventions to reduce air bloating and apneas at rest, including a large, flattened dummy with a hollow tube to allow the flow of air, gum shield, and palatal training devices.55 Two of the studies examined psychological interventions. Hyman et al. reported the use of positive reinforcement and guidance techniques in argininosuccinate lyase deficiency, methylmalonyl-CoA mutase deficiency, ornithine carbamoyltransferase deficiency disease and propionic acidemia.56 Piazza et al. provided training to girls with Rett syndrome in scooping food, bringing food to mouth and placing spoon in mouth by a trainer.57 Four of the studies developed or validated tools or scales. Fyfe et al. developed and validated a parent-report checklist and video-based evaluation tool for eating and drinking in Rett syndrome.58 Iturriaga el al. developed a disability scale for Niemann–Pick type C, which included scoring for feeding difficulties.59 In 2 studies, de Vries et al. and Lezlezio et al. developed and pilot-validated the TAND Checklist for tuberous sclerosis, which includes a question on feeding difficulties.25,26 The remaining 24 studies reported the trajectory, incidence and characteristics of the feeding difficulties in this population.  Several studies showed that balloon dilation can be effective for esophageal strictures in epidermolysis bullosa. Percutaneous gastrostomy placement or parenteral nutrition may also reduce feeding difficulties. For drooling, 1 study found that bilateral submandibular gland excision and/or parotid duct ligation may be helpful, but that each patient needed personalized 18  treatment for it to be effective. For gastroesophageal reflux and emesis, baclofen and rikkushito were found to reduce these symptoms. For oral feeding, black pepper oil may help stimulate appetite and positive reinforcement and training with guidance techniques may be helpful for teaching children with Q3 conditions to feed themselves. One study investigated a flattened dummy with a hollow tube to allow the flow of air, gum shield, and palatal training devices to help reduce air swallowing during feeding in Rett syndrome. None of the studies investigating feeding difficulties are RCTs or systematic reviews, highlighting that higher levels of evidence are needed for this symptom. Some condition-specific tools or scales have been developed and/or validated and may be useful to assess feeding difficulties.  Sleep Disturbance Sixty-two of the studies investigated sleep disturbance: 38 cross-sectional, 8 RCT, 6 tool/scale development, 5 case-control, 5 case series, 5 surveys, 3 open-label studies, 1 retrospective chart review and 1 systematic review. Sixteen of the studies investigated an intervention, 13 of which were pharmacologic. Twelve studies, including all 8 of the RCTs, investigated melatonin in Rett syndrome,60–63 18q deletion syndrome and mucopolysaccharidosis Type III,64 neuronal ceroid lipofuscinosis type 3,65 tuberous sclerosis66,67 and unspecified Q3 Conditions.68–72 In an open-label study, Ucar et al. investigated risperidone in mucopolysaccharidosis type III.23 The remaining 2 studies investigated psychological interventions. Piazza et al. reported a case series using a fading procedure in Rett syndrome.73 In an open-label study, Colville et al. tried a personalized sleep plan developed by a clinical psychologist for children with mucopolysaccharidosis type III.74 Seven studies developed and/or validated a tool or a scale. De Vries et al. and Lezlezio et al. designed and pilot-validated the TAND Checklist for tuberous sclerosis with a question about sleep disturbance.25,26 Two studies developed scales with 19  questions about sleep disturbance in Rett syndrome27 and Niemann–Pick type C.59 In unspecified Q3 conditions, Blankenburg et al. and Tietze et al. developed and validated and Maas et al. validated questionnaires on sleep disturbance.75–77 The remaining 44 studies described the characteristics, trajectory, mechanism and challenges of sleep disturbance.  Clinical practitioners can suggest several interventions that may be effective for sleep problems in Q3 conditions. Melatonin may slightly increase sleep duration and decrease sleep latency, but studies are mixed on its efficacy. Another study shows risperidone prescribed for behavioral problems may also increase sleep. Other non-pharmaceutical interventions, including fading procedures and personalized sleep plans, can also help to decrease sleep disturbances. Sleep problems had the highest number of RCTs of all symptoms but all of them investigated melatonin. Other high-level studies investigating other interventions are necessary. Several studies developed and validated SNAKE for diagnosing sleep disturbances in Q3 conditions, while other condition-specific tools may also be useful for measuring sleep disturbances.     Temperature Regulation Only 2 studies investigated temperature regulation. In a case-control Svedberg et al. recorded differences in hand temperatures between children with Jacobsen syndrome, spinal muscular atrophy type 1 and other central nervous system damage and healthy controls.78 In a further case-series, Svedberg et al. tested the efficacy of acupuncture in children with Smith-Lemli-Opitz syndrome and other neurological disorders.79 Temperature regulation was the least studied symptom. Clinical practitioners could suggest trying acupuncture to caregivers, as 1 study suggests it can raise skin temperature through a cumulative effect. More research is needed for this symptom.  20  Tone and Motor Problems Tone and motor problems was the most investigated symptom with 141 studies: 27 case series, 26 tool/scale development, 26 cross-sectional studies, 15 longitudinal, 11 retrospective chart reviews, 7 open-label, 5 surveys, 3 systematic reviews, 3 cohort studies, 3 N-of-1 studies and 2 RCTs. Forty-one of the 141 studies investigated an intervention, 12 of which were pharmacologic. In case-series of Lesch-Nyhan syndrome, Visser et al investigated levodopa or carbidopa19 and Mizuno et al. compared L-5-Hydroxytryptophan, L-tryptophan and levodopa. Aberg et al. compared levodopa and selegiline in neuronal ceroid lipofuscinosis types 3 and 6 in an open-label trial.80 Cak et al. investigated how tricyclic antidepressants affect cataplexy in Niemann–Pick type C.81 In x-linked adrenoleukodystrophy, Hjartarson et al. reported the use of intrathecal baclofen for spasticity and dystonia.82 Both in ataxia-telangectasia, Zannolli et al. investigated betamethasone in a RCT83and Nissenkorn et al. investigated amantadine sulfate in an longitudinal open-label study.84 In a RCT, Zweije-Horman et al. compared amantadine, fenadrine, madopar and placebo in neuronal ceroid lipofuscinosis type 3.85 In 18q Deletion syndrome, lissencephaly type 1, metachromatic leukodystrophy and neuronal ceroid lipofuscinosis type 3, Kuhlen et al. reported on the use of dronabinol for spasticity.86 Liow et al. investigated gabapentin in a cohort study in infantile neuroaxonal dystrophy and dystonia of varying aetiologies.87 Nava et al. reported the combination of both pharmacologic (botulinum toxin type A) and a physical interventions (serial casting and intensified physical therapy) for equinus deformity in mucopolysaccharidosis type II.88  Including Nava et al., 11 studies examined a physical intervention and 9 of these were in Rett syndrome. In case series of Rett syndrome for stereotypic hand movements, Bumin et al. tried hand splints or elbow restraints,89 Naganuma et al. tried thumb abduction splints,90 Sharpe et al. 21  tried elbow orthosis or thumb abduction splints,91 and Tuten et al. tried hand splints.92 Also in Rett syndrome, Stasolla et al. used assistive technologies in three studies to increase purposeful hand movements, including picture exchange communication systems compared to vocal output communication aid,93 wobble microswitch and optic sensors,94 and photocells, interface and personal computer.95 Lotan et al. investigated how a daily training treadmill program improved functional skills in Rett syndrome.96 Mordekar et al reported how switching to parenteral nutrition can improve feed-induced dystonia in Rett syndrome.39 In Friedrich’s ataxia, Ilg examined how video game-based coordinative training can improve coordination.97  Fourteen studies investigated a surgical intervention. Eleven of these studies investigated deep brain stimulation in glutaric acidemia type I,98–100 Lesch-Nyhan syndrome,98 ataxia-telangectasia,101 methylmalonyl-CoA mutase deficiency,101 nemaline myopathy,101 infantile neuroaxonal dystrophy,98,100,102–106 and other non-specified Q3 condtions.107,108 In a retrospective chart review, Buizer reported the used of selective dorsal rhizotomy in lipidoses.109 In mucolipidosis type II and mucopolysaccharidosis types I, II, III and VI, Haddad et al. investigated the effect of surgery for carpal tunnel syndrome.110 Van Heest et al. reported on the use of surgery for children with, mucopolysaccharidosis types I, III and VI and carpal tunnel syndrome and trigger digits.111 Five studies examined at psychological interventions for tone and motor problems and all were in Rett syndrome. In an open-label study, Fabio et al. investigated how selective attention training could reduce stereotypies.13 In case series, Piazza et al. examined hand function with training in scooping food, bringing food to mouth, and placing spoon in mouth by a trainer57 and Qvardfordt et al. compared hand function in guided eating to being fed.112 In case series, Lotan et al. examined daily conductive educational program113 and Wales et al. tested how different stimulation or attention conditions affected hand stereotypies.114  22  Twenty-six studies developed and/or validated a tool or scale for tone and motor problems. Nine of the studies included tools or scales for neuromuscular diseases that included spinal muscular atrophy type 1. Glanzman et al. developed and validated the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders in 2 studies.115,116 Krosschell et al. modified and validated the Hammersmith functional motor scale117 and validated the Test of Infant Motor Performance Screening Items specifically for spinal muscular atrophy type 1. Mazzone et al. compared the reliability of the Hammersmith Functional Motor Scale and the Motor Function Measure-20.118 Nelson et al. validated the Gross Motor Function Measure119 and de Lattre et al. and Vuillerot validated the Motor Function Measure.120,121 Finkel et al. tested the validity of the Test of Infant Motor Performance in children with spinal muscular atrophy type 1.122 Seven of the studies examined Rett syndrome. Downs et al. tested the use of accelerometers in 2 studies123,124 and validated the Rett Syndrome Gross Motor Scale in one study.125 Stahlhut et al. compared the modified two-minute walk test and a modified Rett syndrome specific functional mobility scale.126 Dy et al. and Fyfe et al. both developed and tested coding protocols for video-taped evaluation of hand steroteypies.58,127 Mount et al. developed the Rett Syndrome Behaviour Questionnaire that includes questions on hand behaviors.27 Four studies validated tools or scales in Friedrich’s ataxia. Cano et al. and Bürk et al. validated scales to measure the level of impairment due to ataxia128,129 and Subramony et al. developed and validated a neurologic rating scale.130 Germanotta et al. validated the use of InMotion Arm Robot to measure upper limb function.131 Nissenkorn et al. developed a clinical global impression scale for ataxia telangiectasia, which includes sections on motor function.132 For progressive myelopathy, including mucopolysaccharidosis types I and VI, Castilhos developed and validated the Severity Score System for Progressive Myelopathy.133 Darling et al. designed and pilot-tested the PKAN-23  Disease Rating Scale, which includes a motor examination protocol for infantile neuroaxonal dystrophy.24 In Niemann–Pick type C, Iturriaga developed a disability scale that includes scoring for motor disorders.59 Ruiz-Cortes validated the Motor Function Measure in unspecified hereditary neuromuscular diseases134 and van Capelle developed and validated the Quick Motor Function Test in glycogen storage disease type II.135 The remaining 48 studies described the characteristics, trajectory and challenges of tone and motor problems in this population.  As the most well studied symptom, there are several pharmacological, physical and surgical interventions for clinical practitioners to consider for the different types of tone and motor problems. Many of the studies investigated the specific stereotypic movements found in Rett syndrome. Interventions for this population include hand or finger splints or elbow restraints, assistive technologies, exercise programs, switching to parenteral nutrition to reduce dystonia and various forms of training or environmental conditions. These studies may not be relevant to other Q3 conditions, as Rett syndrome has distinct tone and motor challenges. In other conditions, several pharmacologic interventions showed some efficacy that clinical practitioners may wish to consider, including levodopa, intrathecal baclofen, tricyclic antidepressants, betamethasone, amantadine sulfate, dronabinol, gabapentin and botulinum toxin type A. Deep brain stimulation can be considered, but the results are mixed and may depend on condition and even mutation. Other surgical interventions include surgery for carpal tunnel syndrome and selective dorsal rhizotomy to reduce spasticity. Physical interventions include serial casting and intensified physical therapy for equinus deformity and video game training to improve coordination. Only 2 of the studies were RCTs and 3 were systematic reviews, showing the need for higher levels of evidence before strong recommendations for treatment can be made by clinical practitioners. Several studies developed and/or validated scales and tools for tone and 24  motor problems. Some of the tools, for example a protocol for a video-taped evaluation of hand stereotypies in Rett syndrome, may be condition-specific. However, several tools and scales may be helpful in Q3 conditions to assess and measure tone and motor difficulties. Urinary Incontinence Nine studies assessed urinary incontinence: 6 cross-sectional, 2 case-control and 1 survey. All 9 of the studies provided insight into the trajectory or characteristics of the symptom, or compared the severity or features of urinary incontinence to other populations. No evidence on interventions or tools to assess urinary incontinence were found for Q3 conditions. More research is needed for this symptom. DISCUSSION This scoping review identified tools to best assess and interventions to best manage troubling symptoms for children living with Q3 conditions. While many of the tools and scales found in this review are condition specific and may not be useful in other Q3 conditions, we did locate some that are either intended for the larger category of Q3 conditions or may be valid in other populations. More research should be done to design tools for symptoms without any current tools and to validate existing tools in Q3 conditions as a whole. Tone and motor problems was the most investigated symptom. Many of the studies investigated the specific stereotypic movements found in Rett syndrome and these studies may not be relevant to other Q3 conditions. Studies showed some efficacy for a variety of pharmacological interventions, other surgical and physical interventions and mixed results for deep brain stimulation We can only guess as to why tone and motor problems, and specifically the ones associated with Rett syndrome, have been more thoroughly investigated that other symptoms. 25  One suggestion is that as an outwardly evident symptom, in a clearly diagnosed condition, it is seemingly easier for researchers to investigate. Behavioural problems were the second most studied symptom, and most of the studies that investigated interventions focused on self-injurious behaviour, particularly in Lesch-Nyhan syndrome. Again, we can only guess as to why self-injury is so well-studied in comparison to other symptoms, but it may be due to the disturbing nature of the symptom for caregivers and the ease at which an investigator can measure changes. No pharmacologic studies showed clear and lasting effects on self-injury, but some behavioral studies provided effective strategies.  Sleep difficulties was the third most studied symptom. Melatonin was overwhelmingly the most studied intervention, but studies were mixed on the efficacy of melatonin in Q3 conditions. Other interventions studies included risperidone prescribed for behavioral problems, fading procedures and personalized sleep plans. Sleep problems had the highest number of RCTs of all symptoms, all of which investigated melatonin.  As the fourth most studied symptom, studies about feeding difficulties investigated a variety of interventions, but several of the studies may only be relevant in epidermolysis bullosa and Rett syndrome. Studies that may be more generalizable to Q3 conditions include, percutaneous gastrostomy placement, parenteral nutrition, bilateral submandibular gland excision and/or parotid duct ligation, baclofen, rikkushito, black pepper oil and behavioral strategies.  Breathing problems were the fifth mostly commonly investigated symptom. Sleep apnea studies in achondroplasia suggest surgical intervention may be necessary, while for other Q3 conditions CPAP or medications, such as naltrexone, appear to be effective. The evidence for other breathing difficulties is mixed and of low quality. 26  Alertness, constipation, urinary and bowel incontinence and were the fifth, fourth, third and second least studied symptom respectively. For alertness, structured training to increase attention in Rett syndrome was the only intervention studied. For constipation some studies suggest parenteral nutrition, fiber-enriched formula, or supplementation with carnitine. For urinary and bowel incontinence no interventions were studied. The least studied symptom was temperature regulation. Only acupuncture was studied which may increase skin temperature over time.  Overall this scoping review found that very little evidence exists for symptom management in Q3 Conditions. Given the absence of cures for these conditions, the clinical focus should be on symptom management and its contribution to quality of life. We found that most of the studies are concentrated on a handful of diseases, particularly Rett syndrome. Rett syndrome has a distinct clinical profile and interventions used for this condition may not be generalizable to other conditions. Additionally, no condition has a consistent evidence base for all 10 symptoms, and most have only limited evidence for a single symptom. Furthermore, some symptoms, such as temperature regulation problems that have been identified as important to parents, have received little attention in the published clinical research. With the exception of melatonin for sleeping difficulties, there is also a lack of high-level evidence for all symptoms. In conclusion, there is an urgent need for higher levels of evidence for reliable assessment tools and effective interventions for managing prevalent symptoms in Q3 conditions. Implications for Practice The studies found in this scoping review are dispersed across multiple disciplines and major general pediatric journals are not represented, except for the Journal of Pediatrics. As a result, general pediatricians or even specialists are unlikely to see most of the articles that would 27  provide valuable evidence to ensure optimal symptom management in this population. Retrieval of this evidence is further complicated by the lack of an accepted and widely used term for this group of progressive, life-threatening conditions. “Q3” is a term used amongst clinicians working with this specific population, but not a term that is reflected in scientific literature and thus a disconnect happens when care providers are looking for evidence of best practices. It is unlikely that a clinician would find these studies through a quick online search. This situation ultimately leaves clinicians with little to no evidence of effective symptoms management for their patients and a distressing inability to improve health outcomes informed by research rather than anecdotal evidence or individual experience.  Limitations and Future Directions This scoping review is limited by our last search date of January 2018, as more recent studies may have been published within the past year. Additionally, we were not able to translate studies that were not in English or French due to a lack of resources and we were not able to locate the full-text of some studies. This may introduce bias into our results as some studies were excluded before our team had the opportunity to review the full-text. Despite these limitations, it is clear that there needs to be more research done on these symptoms to have a strong evidence base on which to base treatment. For clinical practitioners who must manage the symptoms of child with a Q3 condition with little or no evidence, studies from other conditions may provide the only guidance available for measurement tools and interventions. This scoping review highlights gaps in our knowledge regarding the management of common symptoms in children with neurological, genetic, or chromosome-based conditions that impair quality of life.  Researchers and clinicians can use this information to develop broader programs of research to develop 28  assessment tools and then test interventions that will have a meaningful impact on these children and their families.  Abbreviations CPAP – Continuous positive airway pressure  OSA – Obstructive sleep apnea  RCT – Randomized controlled trial Q3 – Quadrant 3   Authorship:  C. Pawliuk developed and implemented the search strategy, reviewed abstracts, titles and full articles, and contributed to the writing of the manuscript and revised it for important intellectual content. K. Widger participated in planning the study, reviewed abstracts, titles and full articles, and revised the manuscript for important intellectual content. T. Dewan participated in planning the study, reviewed abstracts, titles and full articles, and revised the manuscript for important intellectual content. G. Brander implemented the search strategy and revised the manuscript for important intellectual content. H. Brown provided methodological guidance and revised the manuscript for important intellectual content. A.-M. Hermansen reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. M.-C. Grégoire participated in planning the study, reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. R. Steele participated in planning the study, reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. H. Siden conceptualized the study, participated in planning the study, reviewed abstracts, titles and full articles, contributed to the writing and revised it for important intellectual content.  29  Funding: This work was supported by the Canadian Institutes of Health Research (CIHR) Knowledge Synthesis Grant #328968.  Declaration of conflicts of interest: None declared.  Acknowledgements: The authors would like to thank Charlotte Beck for her methodological guidance in the early stage of the review   Data management and sharing: All available data has been included in this publication and supplementary materials.  Licence for Publication: The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ Supportive and Palliative Care and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructions-for-authors/licence-forms).  30  REFERENCES 1.  Association for Children’s Palliative Care. A Guide to the Development of Children’s Palliative Care Services. 3rd ed. Report, Bristol, UK. 2009. 2.  Siden H, Steele R, Brant R, et al. 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Surgical treatment of carpal tunnel syndrome and trigger digits in children with mucopolysaccharide storage disorders. J Hand Surg Am 1998;23A:236–243. 112.  Qvarfordt I, Engerstrom IW and Eliasson AC. Guided eating or feeding: three girls with Rett syndrome. Scand J Occup Ther 2009;16:33–39. 113.  Lotan M, Schenker R, Wine J, et al. The conductive environment enhances gross motor function of girls with Rett syndrome. A pilot study. Dev Neurorehabil 2012;15:19–25. 38  114.  Wales L, Charman T and Mount RH. An analogue assessment of repetitive hand behaviours in girls and young women with Rett syndrome. J Intellect Disabil Res 2004;48:672–8. 115.  Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): Test development and reliability. Neuromuscul Disord 2010;20:155–161. 116.  Glanzman AM, McDermott MP, Montes J, et al. Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther 2011;23:322–326. 117.  Krosschell KJ, Maczulski JA, Crawford TO, et al. A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy. Neuromuscul Disord 2006;16:417–26. 118.  Mazzone E, De Sanctis R, Fanelli L, et al. Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients. Neuromusc Disord 2014;24:347–352. 119.  Nelson L, Owens H, Hynan LS, et al. The gross motor function measure is a valid and sensitive outcome measure for spinal muscular atrophy. Neuromusc Disord 2006;16:374–80. 120.  de Lattre C, Payan C, Vuillerot C, et al. Motor Function Measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil 2013;94:2218–2226. 121.  Vuillerot C, Payan C, Girardot F, et al. Responsiveness of the Motor Function Measure in neuromuscular diseases. Arch Phys Med Rehabil 2012;93:2251–6.e1. 122.  Finkel RS, Hyman LS, Glanzman AM, et al. The test of infant motor performance: reliability in spinal muscular atrophy type I. Pediatr 2008;20:242–6. 123.  Downs J, Leonard H, Hill K. Initial assessment of the StepWatch Activity MonitorTM to measure walking activity in Rett syndrome. Disabil Rehabil 2012; 34: 1010–1015. 124.  Downs J, Leonard H, Jacoby P, et al. Rett syndrome: establishing a novel outcome measure for walking activity in an era of clinical trials for rare disorders. Disabil Rehabil 2015; 37: 1992–1996. 125.  Downs J, Stahlhut M, Wong K, et al. Validating the Rett Syndrome Gross Motor Scale. PLoS One 2016;11:e0147555 126.  Stahlhut M, Downs J, Leonard H, et al. Building the repertoire of measures of walking in Rett syndrome. Disabil Rehabil 2017;39:1926–1931. 127.  Dy ME, Waugh JL, Sharma N, et al. Defining hand stereotypies in Rett syndrome: a movement disorders perspective. Pediatr Neurol 2017;75:91–95. 39  128.  Cano SJ, Hobart JC, Hart PE, et al. International Cooperative Ataxia Rating Scale (ICARS): appropriate for studies of Friedreich’s ataxia? Mov Disord 2005;20:1585–1591. 129.  Bürk K, Mälzig U, Wolf S, et al. Comparison of three clinical rating scales in Friedreich ataxia (FRDA). Mov Disord 2009;24:1779-1784 6p. 130.  Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: Interrater reliability of a neurologic rating scale. Neurology 2005;64:1261–2. 131.  Germanotta M, Vasco G, Petrarca M, et al. Robotic and clinical evaluation of upper limb motor performance in patients with Friedreich’s Ataxia: an observational study. J Neuro Eng Rehabil 2015;12:13. 132.  Nissenkorn A, Borgohain R, Micheli R, et al. Development of global rating instruments for pediatric patients with ataxia telangiectasia. Europ J Paediatr Neurol 2016;20:140–6. 133.  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Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada   Tammie Dewan, BSc, MD, MSc Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada   Gina Brander, MLIS Saskatchewan Polytechnic, Regina, Saskatchewan, Canada  Helen Brown, MLIS University of British Columbia, Vancouver, British Columbia, Canada   Anne-Mette Hermansen, MA BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada (  Marie-Claude Grégoire, MD, MSc, FRCPC Department of Paediatrics, Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada   Rose Steele, RN, PhD 2  School of Nursing, York University, Toronto, Ontario, Canada   Harold (Hal) Siden, MD, MHSc, FRCPC Department of Pediatrics, University of British Columbia BC Children's Hospital, Vancouver, British Columbia, Canada   Corresponding Author: Harold (Hal) Siden, MD, MHSc, FRCPC Department of Pediatrics, University of British Columbia; BC Children's Hospital Research Institute, 4480 Oak Street, Room F612A Vancouver, BC V6H 3V4 Canada  Email: hsiden@bcchr.ca    This article has been accepted for publication in BMJ Supportive and Palliative Care, 2019 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/bmjspcare-2019-001943.  © the Authors   3  ABSTRACT  Background: Q3 conditions are progressive, metabolic, neurological, or chromosomal childhood conditions without a cure. Children with these conditions face an unknown lifespan as well as unstable and uncomfortable symptoms. Clinicians and other health care professionals are challenged by a lack of evidence for symptom management for these conditions. Aims: In this scoping review we systematically identified and mapped the existing literature on symptom management for children with Q3 conditions. We focussed on the most common and distressing symptoms, namely alertness, behavioral problems, bowel incontinence, breathing difficulties, constipation, feeding difficulties, sleep disturbance, temperature regulation, tone and motor problems and urinary incontinence. For children with complex health conditions, good symptom management is pertinent to ensure the highest possible quality of life.  Methods: Scoping Review. Electronic database searches in Ovid MEDLINE, Embase and CINAHL and a comprehensive grey literature search. Results: We included 292 studies in our final synthesis. The most commonly reported conditions in the studies were Rett syndrome (n=69), followed by De Lange syndrome (n=25) and tuberous sclerosis (n=16). Tone and motor problems was the most commonly investigated symptom (n=141), followed by behavioral problems (n=82) and sleep disturbance (n=71). Conclusion: The evidence for symptom management in Q3 conditions is concentrated around a few conditions and these studies may not be applicable to other conditions. The evidence is dispersed in the literature and difficult to access, which further challenges health care providers. More research needs to be done in these conditions to provide high quality evidence for the care of these children.    Running head: Scoping Review to Examine Symptoms  4  BACKGROUND Quadrant 3 (Q3) conditions are progressive, metabolic, neurological, or chromosomal childhood conditions for which there currently exists no curative treatment. They are also known as Category 3 conditions in the report by the UK-based charity, Together for Short Lives.1 Children with these conditions face an unknown lifespan and symptoms that are both unstable and uncomfortable. Although the individual diagnoses are rare, Q3 conditions are a significant cause of disability and death in childhood. These conditions are numerous and varied, however, collectively they share many features in symptoms and burden of care. Children with Q3 conditions are living longer due to medical advances, but extending the duration of life does not necessarily mean improving a child’s quality of life. Until cures are found, a clinician’s obligation is to maximize comfort and quality of life. There is a lack of research on these conditions and, particularly, their associated symptoms. Clinicians, health professionals and families caring for children with Q3 conditions are challenged by this lack of research, which limits their ability to make evidence-based care decisions. Our aim in this scoping review was to systematically identify and map the literature regarding the assessment and management of the most common symptoms in Q3 conditions. With better evidence, clinicians and families will be able to make informed decisions about care and ensure better health outcomes for children living with distressing symptoms of complex conditions.     METHODS Search Methods Our comprehensive search strategy combined 181 Q3 conditions and 10 symptoms. Q3 conditions were identified through an initial pilot literature search, our previous work in this 5  area2,3 and 2 lists of Q3 conditions written by experts in the field.4,5 When creating the search strategy for the Q3 conditions we were challenged by the lack of controlled vocabulary for many of these conditions in the databases we searched. To ensure complete retrieval of all relevant studies we included broader controlled vocabulary terms when a specific condition term was not available or had only been recently added to the database. For example, “Farber Lipogranulomatosis” was introduced as a MeSH term in 2009, so to ensure coverage to database inception we also included the broader MeSH terms “Lipidoses” and “Sphingolipidoses” that had been previously used to index this condition. See Supplementary File 1 for our full MEDLINE Search Strategy. The 10 symptoms identified in our pilot study were based on Hunt,6 Malcolm et al.7 and our Charting the Territory study.8 The investigated symptoms were alertness (fatigue, arousal, wakefulness, concentration); behavioral (agitation, irritability, aggression, self-harm, negative affect); bowel incontinence; breathing difficulties (dyspnea, cough, apnea, hypoventilation, obstruction); constipation; feeding difficulties (gastric reflux, regurgitation, emesis, retching, nausea, feeding intolerance, salivary secretions, dyspepsia, swallowing difficulty, aspiration); sleep disturbance; temperature regulation; tone and motor problems (spasticity, dystonia, ataxia); and urinary incontinence. Seizures and pain were excluded from the symptom list as seizures is a common symptom with extensive literature and pain is the subject of another scoping review by one of our investigators. “Symptom management” search terms based on the clinical experience of the investigators were added to increase the specificity of the search.  We searched MEDLINE (Ovid), Embase and CINAHL from inception until January 2018; we did not limit our search by publication date or by language. To locate grey literature sources we searched ClinicalTrials.gov, WHO International Clinical Trials Platform, Conference 6  Proceedings Citation Index- Science (Web of Science), TRIP, ProQuest Dissertations and Theses Global, OAIster and LILACS. Experts in the field were contacted through relevant listservs to locate unpublished studies. Palliative care conferences were identified and conference abstracts were hand-searched when not indexed in the electronic databases already searched. The references of all included studies were hand-searched and Web of Science was used to search the citing articles of each study. Study Inclusion Studies had to 1) include at least one of the 181 Q3 conditions, 2) report on at least one of the 10 symptoms and 3) be focused on assessment tools to evaluate symptoms or on interventions to relieve symptoms. We only included studies with pediatric populations (0-18 years) or studies with adults were there was more than one pediatric participant. We excluded non-studies (i.e. letters to the editor, commentaries) and case reports with a single participant. Languages other than English or French were excluded due to a lack of resources for translation. Study Selection All search results were imported into Endnote© and duplicates were removed. Due to the comprehensiveness of our search strategy, we returned a large number of results. To more efficiently filter these results, a single team member pre-screened by title and abstract to remove articles that did not include both a symptom and a Q3 condition. The titles and abstracts of the remaining articles were screened in more depth independently and in duplicate by team members using abstrackr.9 The resulting full-text of studies were then reviewed by team members independently and in duplicate using Rayyan.10 For articles where the 2 team members did not agree in both the screening and review phases, the team met to come to a consensus decision to 7  include or exclude. Data were extracted from the remaining full text articles using a database created in REDCap.11 We extracted data on study design, sample size, tools or scales, intervention, year of publication, journal, Q3 condition(s), symptom(s), study objective, and primary outcome(s). To summarize the charted data, we grouped the studies together by symptom and summarized the study design and study objective. We did not register the protocol for our review our scoping review. We used the PRISMA Extension for Scoping Reviews guidelines to report the methods of our scoping review.12 RESULTS Our database and grey literature search retrieved 46,644 results. We returned a high number of results due to the broadness of our search and the lack of controlled vocabulary for these conditions. Once duplicates were removed, we pre-screened 36,447 and excluded 35,294 for not including both a Q3 condition and a symptom from our list. For this phase, when there was ambiguity the team member always chose to include studies for the next phase. The resulting 1,153 titles and abstracts were then screened and 316 were excluded for lack of symptom focus, wrong study design or wrong population. The remaining 837 full-text articles were reviewed and 545 were excluded for lack of symptom focus (n=206), lack of assessment (n=73), publication type (reviews, letters, commentaries: n=68), ongoing studies without finalized data (n=57), wrong outcome (n=46), wrong population (n=39), not in English or French (n=24), wrong study design (n=14), background article (n=17), and full-text not available (n=1). This left 292 studies in our final synthesis. See Figure 1 for the PRISMA Flowchart of the study selection process.  8   Figure 1: PRISMA flow chart of study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Study Characteristics One of the studies was a thesis and the other 291 studies were journal articles. The 291 studies were published in 112 different journals and 70 of these journals only had a single study to contribute to this review. See Table 1 for the 10 most common journals. There was only 1 general pediatric journal, the Journal of Pediatrics, that had 3 studies to contribute to this review. The other journals are from a wide variety of disciplines, including clinical neurology, surgery, education, rehabilitation, dermatology, genetics, otorhinolaryngology, palliative care and gastroenterology. The studies were published between 1974 and 2018, with 52% (152) published 9  in 2010 or later. Fifty-nine percent of the studies used only validated tools or scales, while 27% used non-validated tools or scales, and 14% combined both validated and non-validated tools. See Supplementary File 2 for a table of the characteristics and a full bibliography of all included studies.  Table 1: 10 most common journals  Journal Name Frequency of Articles 2017 Journal Impact Factor  Developmental Medicine & Child Neurology 20 3.289 Journal of Intellectual Disability Research 16 2.026 Journal of Child Neurology 13 1.665 American Journal of Medical Genetics Part A 12 2.264 Movement Disorders 11 8.324 Pediatric Neurology 11 2.398 Brain & Development 9 1.544 European Journal of Paediatric Neurology 9 2.362 Journal of Neurodevelopmental Disorders 8 3.500 International Journal of Pediatric Otorhinolaryngology 7 1.305  Q3 Conditions Rett syndrome was the most investigated Q3 condition (n=69) followed by De Lange syndrome (n=25), tuberous sclerosis (n=16), mucopolysaccharidosis type III (n=15), spinal muscular atrophy type 1 (n=15), Cri-du-Chat (n=14), Friedrich’s ataxia (n=13), neuronal ceroid lipofuscinosis type 3 (n=13), and Lesch-Nyhan syndrome (n=12). Only 20 conditions comprised 10  80% of the studies (Table 2). One hundred and twenty-four of the 181 Q3 conditions did not appear in a single study and the remaining 36 conditions were investigated in 5 or fewer studies. See Supplementary File 1 for a heat map of all Q3 conditions and symptoms.  Table 2: 20 most common Q3 Conditions Q3 Condition Frequency of studies  Q3 Condition Frequency of studies  Rett syndrome  69 Epidermolysis bullosa 10 De Lange syndrome  25 Infantile neuroaxonal dystrophy 10 Tuberous sclerosis  16 Mucopolysaccharidosis type I 10 Mucopolysaccharidosis type III 15 Mucopolysaccharidosis type II 10 Spinal muscular atrophy 1 15 Achondroplasia 8 Cri-du-chat 14 Ataxia telangectasia 8 Friedrich’s ataxia 13 Mucopolysaccharidosis VI 8 Neuronal ceroid lipofuscinosis 3 13 Glutaric acidemia type I 6 Lesch-Nyhan syndrome 12 Mucopolysaccharidosis type IIIA 6 Jacobsen syndrome 10 West syndrome 6  Using a classification system for these conditions,3 Neurodegenerative Diseases was the most investigated condition category (n=102), followed by Multi-Organ Congenital Abnormalities (n=97), Lysosomal Storage / Peroxisomal Diseases (n=45), Small Molecule Diseases (n=20), Neuromuscular Diseases (n=14), Other Inborn Errors of Metabolism (n=8),  Severe Neurological Impairment -Not Yet Diagnosed (n=7), Structural Central Nervous System Abnormalities (n=5), Other Conditions Not Otherwise Specified (n=4), Mitochondrial Encephalo-/Myopathies (n=2), 11  and Congenital Disorders of Glycosylation (n=1). See Figure 2 for a heat map of condition categories and symptoms.   Figure 2: Heat map of Q3 condition categories and symptoms Symptoms Alertness Fourteen studies investigated alertness in Q3 conditions: 11 cross-sectional, 1 case-control, 1 open label and 1 tool/scale development study. The single open-label study investigated a psychological intervention in Rett syndrome: structured training to increase attention and reduce help needed.13 Paulsen et al. conducted an initial validation of the PedQL Fatigue Scales in Friedrich’s ataxia.14 The remaining 12 studies provided evidence of the severity of this symptom and described its trajectory. See Figure 3 for a heat map of the study objectives and symptoms and Figure 4 for a heat map of symptoms and study designs. For children who have attentional difficulties, clinical practitioners could try structured training, as this was found to be effective in one study in Rett syndrome. Rett syndrome has a distinct clinical profile, so structured training may not be effective in other Q3 conditions. No effective interventions were found for fatigue or alertness. Future studies should focus on other Q3 conditions that may be more applicable to the 12  group as a whole. A single study suggests the PedQL Fatigue Scales may be useful to measure levels of fatigue in Friedrich’s ataxia, which may be useful in other Q3 conditions.   Figure 3: Heat map of study objectives and symptoms  Figure 4: Heat map of study designs and symptoms. Behavioral Problems The majority of the 82 studies investigating behavioral problems were cross-sectional (n=47), followed by case control (n=9), case series (n=9), tool or scale development (n=9), survey (n=9), longitudinal (n=5), open-label (n=2), retrospective chart review (n=2), N of 1 trial (n=1) and RCT (n=1). Eight studies investigated an intervention: 6 were pharmacologic and 2 were psychological. Six of the studies were in Lesch-Nyhan syndrome and investigated strategies to reduce or eliminate self-injurious behavior.15–20 Nyhan et al. tested 5-hydroxytryptophan in a case-series;15 Khasnavis et al. tested Ecopipam in a RCT;16 Anderson et al. tested L-5-hydroxytryptophan in a case-series;17 Mizuno compared L-5-Hydroxytryptophan, L-tryptophan 13  or levodopa in a case-series;18 and Visser et al. investigated levodopa and carbidopa.19 Anderson et al. also investigated if electric shock, positive reinforcement, or time-out reduced self-injury.20,21 In a case-control study Sloneem et al. investigated how environmental conditions (demand, denial, attention, no contact) affected self-injurious behavior in De Lange syndrome.22 Ucar et al. investigated risperidone in children with mucopolysaccharidosis type III in an open-label trial.23 Eight studies designed and/or aimed to validate scales or tools. Darling et al. designed and pilot tested a disease rating scale for pantothenate kinase-associated neurodegeneration that included a section on psychiatric symptoms.24 In 2 studies, de Vries et al. and Lezlezio et al. designed and pilot-validated the TAND Checklist for tuberous sclerosis, which includes questions on behavioral concerns.25,26 Mount et al. developed the Rett Syndrome Behaviour Questionnaire.27 In 3 studies, Rojahn et al. developed and validated the Behavior Problems Inventory in unspecified intellectual disabilities.28–30 Shapiro et al validated the Sanfilippo Behavior Rating Scale in mucopolysaccharidosis type III.31 The remaining 66 studies provided insight into the behavioral challenges faced by caregivers of children with Q3 conditions, identified the possible mechanisms of self-injury, or described the trajectory of this symptom.  Behavioural problems was the second most studied symptom, and most of the studies that investigated interventions focused on self-injurious behaviour. None of the pharmacologic studies showed clear and lasting effects on self-injury. Clinicians could suggest positive reinforcement and/or time-outs, as this led to reductions in self-injury in one study, while punishment led to increased self-injury. Three systematic reviews and 1 RCT were found for behavioral problems, which highlights the need for more high level studies to be conducted on 14  this challenging symptom. Some condition-specific scales have been created and/or validated for behavioral problems and may be valuable for other Q3 conditions as well.  Bowel Incontinence Five studies investigated bowel incontinence: 4 cross-sectional and 1 case-control. All the studies described incidence and/or trajectory. Bowel incontinence was the second least studied symptom. Although studies included in this review found that this is a common symptom in Q3 conditions, no studies provide evidence on which to base symptom management. Breathing Difficulties Thirty-seven studies investigated breathing difficulties: 13 cross-sectional, 7 case-series, 5 retrospective chart reviews, 4 case-controls, 4 longitudinal, 4 surveys, 2 systematic reviews, 2 RCTs and 1 tool/scale development. Seven of the studies investigated an intervention; six of these examined a combination of surgical and physical interventions. Only 1 study investigated a pharmacologic intervention: testing the efficacy of oral naltrexone in children with Leigh syndrome and other children with sleep apnea in an RCT.32 In a retrospective chart review, Tenconi et al. assessed conventional treatment options (adenotonsillectomy, continuous positive airway pressure (CPAP), losing weight) for obstructive sleep apnea (OSA) in children with achondroplasia.33 Also in achondroplasia, a case-series investigated surgery, CPAP, bilevel positive airway pressure, cervical decompression for OSA.34 In a RCT, Sudarsan et al. compared adenotonsillectomy and CPAP in children with mucopolysaccharidosis types I, II, III, VI and VII.35 Another retrospective chart review of children with mucolipidosis types II and III and mucopolysaccharidosis types I, II and III, recorded interventions used for respiratory complications, including surgery (adenotonsillectomy, tracheostomy); low flow oxygen; 15  medications (diuretics, theophylline, digoxin, beta adrenergic blockers, calcium antagonists).36 Nabatame et al. and Mellies et al. investigated the efficacy of non-invasive positive pressure ventilation for sleep disordered breathing in glycogen storage disease type II and spinal muscular atrophy type 1 respectively.37,38 Mount et al. developed the Rett Syndrome Behavior Questionnaire that includes questions on breathing problems including air swallowing, breath holding and hyperventilation.27 The remaining 29 studies described breathing difficulties in this population and provided insight into its trajectory.  Many of the studies confirm the prevalence of both sleep apnea and other breathing problems in Q3 conditions. Sleep apnea studies in achondroplasia suggest surgical intervention may be necessary, while for other Q3 conditions CPAP appears to be effective. Medications, such as naltrexone, could also be effective for sleep apnea. For other breathing problems, 1 study suggested a combination of surgical and pharmacological interventions may be effective, but a systematic review on treatments for dyspnea found the evidence to be of low quality. Our review also shows that overall there is a lack of high level evidence breathing difficulties and more research is needed. One of the studies created a Rett syndrome specific tool that includes a section on breathing problems, which may not be relevant to other Q3 conditions. Constipation Ten studies investigated constipation: 5 cross-sectional, 3 retrospective chart reviews, 2 surveys, 1 case-series and 1 open-label study. Three of the studies tested a pharmacological or dietary intervention to reduce constipation. In retrospective chart review, Mordekar et al. investigated parenteral nutrition in Rett syndrome, mucopolysaccharidosis type III and West syndrome39 and Murata et al. investigated supplementary carnitine in neuronal ceroid lipofuscinosis type 3, 16  Pelizaeus-Merzbacher disease, tuberous sclerosis and West syndrome.40 In an open-label study Haynes et al. investigated fiber-containing formula in epidermolysis bullosa.41 No studies developed or validated a tool or scale and the remaining 7 studies described the features or trajectory of this symptom.41 To help manage constipation in Q3 conditions, clinical practitioners can try parenteral nutrition, fiber-enriched formula, or supplementation with carnitine. In our Charting the Territory study we found constipation to be the fourth most commonly reported symptom by caregivers, yet only 3 studies investigate symptom management in this population.8 More studies are needed for this symptom. Feeding Difficulties Forty-five studies investigated feeding difficulties: 15 cross sectional, 12 retrospective chart reviews, 11 case series, 3 scale/tool development, 3 surveys, 2 longitudinal and 2 open-label. Thirteen studies investigated an intervention and 10 of these were surgical interventions. Seven of the surgical studies investigated balloon dilation of esophageal strictures in epidermolysis bullosa.42–48 Stehr et al. and Seguy et al. performed retrospective chart reviews of percutaneous gastrostomy placement in epidermolysis bullosa,49 spinal muscular atrophy type 1 and other congenital muscular dystrophies and congenital myopathies.50 Blommaert et al. reported a case series of bilateral submandibular gland excision and parotid duct ligation for drooling in children with MEGDEL syndrome.51 Two of the studies investigated a pharmacological intervention. Kawai et al. performed an open-label study of baclofen for emesis and gastroesophageal reflux disease in children with De Lange and West syndromes.52 Kawahara et al. reported the effects of rikkushito on gastroesophageal reflux in children with profound neurological impairment.53  17  Three studies examined physical interventions. In a longitudinal open-label study Munakata et al. investigated the effects of black pepper oil at stimulating oral feeding in Costello syndrome and lissencephaly type 1.54 Mordekar reported treating feed-induced dystonia with parenteral nutrition in Rett syndrome, mucopolysaccharidosis type III and West syndrome.39 In Rett syndrome, Morton et al. tried a variety of physical interventions to reduce air bloating and apneas at rest, including a large, flattened dummy with a hollow tube to allow the flow of air, gum shield, and palatal training devices.55 Two of the studies examined psychological interventions. Hyman et al. reported the use of positive reinforcement and guidance techniques in argininosuccinate lyase deficiency, methylmalonyl-CoA mutase deficiency, ornithine carbamoyltransferase deficiency disease and propionic acidemia.56 Piazza et al. provided training to girls with Rett syndrome in scooping food, bringing food to mouth and placing spoon in mouth by a trainer.57 Four of the studies developed or validated tools or scales. Fyfe et al. developed and validated a parent-report checklist and video-based evaluation tool for eating and drinking in Rett syndrome.58 Iturriaga el al. developed a disability scale for Niemann–Pick type C, which included scoring for feeding difficulties.59 In 2 studies, de Vries et al. and Lezlezio et al. developed and pilot-validated the TAND Checklist for tuberous sclerosis, which includes a question on feeding difficulties.25,26 The remaining 24 studies reported the trajectory, incidence and characteristics of the feeding difficulties in this population.  Several studies showed that balloon dilation can be effective for esophageal strictures in epidermolysis bullosa. Percutaneous gastrostomy placement or parenteral nutrition may also reduce feeding difficulties. For drooling, 1 study found that bilateral submandibular gland excision and/or parotid duct ligation may be helpful, but that each patient needed personalized 18  treatment for it to be effective. For gastroesophageal reflux and emesis, baclofen and rikkushito were found to reduce these symptoms. For oral feeding, black pepper oil may help stimulate appetite and positive reinforcement and training with guidance techniques may be helpful for teaching children with Q3 conditions to feed themselves. One study investigated a flattened dummy with a hollow tube to allow the flow of air, gum shield, and palatal training devices to help reduce air swallowing during feeding in Rett syndrome. None of the studies investigating feeding difficulties are RCTs or systematic reviews, highlighting that higher levels of evidence are needed for this symptom. Some condition-specific tools or scales have been developed and/or validated and may be useful to assess feeding difficulties.  Sleep Disturbance Sixty-two of the studies investigated sleep disturbance: 38 cross-sectional, 8 RCT, 6 tool/scale development, 5 case-control, 5 case series, 5 surveys, 3 open-label studies, 1 retrospective chart review and 1 systematic review. Sixteen of the studies investigated an intervention, 13 of which were pharmacologic. Twelve studies, including all 8 of the RCTs, investigated melatonin in Rett syndrome,60–63 18q deletion syndrome and mucopolysaccharidosis Type III,64 neuronal ceroid lipofuscinosis type 3,65 tuberous sclerosis66,67 and unspecified Q3 Conditions.68–72 In an open-label study, Ucar et al. investigated risperidone in mucopolysaccharidosis type III.23 The remaining 2 studies investigated psychological interventions. Piazza et al. reported a case series using a fading procedure in Rett syndrome.73 In an open-label study, Colville et al. tried a personalized sleep plan developed by a clinical psychologist for children with mucopolysaccharidosis type III.74 Seven studies developed and/or validated a tool or a scale. De Vries et al. and Lezlezio et al. designed and pilot-validated the TAND Checklist for tuberous sclerosis with a question about sleep disturbance.25,26 Two studies developed scales with 19  questions about sleep disturbance in Rett syndrome27 and Niemann–Pick type C.59 In unspecified Q3 conditions, Blankenburg et al. and Tietze et al. developed and validated and Maas et al. validated questionnaires on sleep disturbance.75–77 The remaining 44 studies described the characteristics, trajectory, mechanism and challenges of sleep disturbance.  Clinical practitioners can suggest several interventions that may be effective for sleep problems in Q3 conditions. Melatonin may slightly increase sleep duration and decrease sleep latency, but studies are mixed on its efficacy. Another study shows risperidone prescribed for behavioral problems may also increase sleep. Other non-pharmaceutical interventions, including fading procedures and personalized sleep plans, can also help to decrease sleep disturbances. Sleep problems had the highest number of RCTs of all symptoms but all of them investigated melatonin. Other high-level studies investigating other interventions are necessary. Several studies developed and validated SNAKE for diagnosing sleep disturbances in Q3 conditions, while other condition-specific tools may also be useful for measuring sleep disturbances.     Temperature Regulation Only 2 studies investigated temperature regulation. In a case-control Svedberg et al. recorded differences in hand temperatures between children with Jacobsen syndrome, spinal muscular atrophy type 1 and other central nervous system damage and healthy controls.78 In a further case-series, Svedberg et al. tested the efficacy of acupuncture in children with Smith-Lemli-Opitz syndrome and other neurological disorders.79 Temperature regulation was the least studied symptom. Clinical practitioners could suggest trying acupuncture to caregivers, as 1 study suggests it can raise skin temperature through a cumulative effect. More research is needed for this symptom.  20  Tone and Motor Problems Tone and motor problems was the most investigated symptom with 141 studies: 27 case series, 26 tool/scale development, 26 cross-sectional studies, 15 longitudinal, 11 retrospective chart reviews, 7 open-label, 5 surveys, 3 systematic reviews, 3 cohort studies, 3 N-of-1 studies and 2 RCTs. Forty-one of the 141 studies investigated an intervention, 12 of which were pharmacologic. In case-series of Lesch-Nyhan syndrome, Visser et al investigated levodopa or carbidopa19 and Mizuno et al. compared L-5-Hydroxytryptophan, L-tryptophan and levodopa. Aberg et al. compared levodopa and selegiline in neuronal ceroid lipofuscinosis types 3 and 6 in an open-label trial.80 Cak et al. investigated how tricyclic antidepressants affect cataplexy in Niemann–Pick type C.81 In x-linked adrenoleukodystrophy, Hjartarson et al. reported the use of intrathecal baclofen for spasticity and dystonia.82 Both in ataxia-telangectasia, Zannolli et al. investigated betamethasone in a RCT83and Nissenkorn et al. investigated amantadine sulfate in an longitudinal open-label study.84 In a RCT, Zweije-Horman et al. compared amantadine, fenadrine, madopar and placebo in neuronal ceroid lipofuscinosis type 3.85 In 18q Deletion syndrome, lissencephaly type 1, metachromatic leukodystrophy and neuronal ceroid lipofuscinosis type 3, Kuhlen et al. reported on the use of dronabinol for spasticity.86 Liow et al. investigated gabapentin in a cohort study in infantile neuroaxonal dystrophy and dystonia of varying aetiologies.87 Nava et al. reported the combination of both pharmacologic (botulinum toxin type A) and a physical interventions (serial casting and intensified physical therapy) for equinus deformity in mucopolysaccharidosis type II.88  Including Nava et al., 11 studies examined a physical intervention and 9 of these were in Rett syndrome. In case series of Rett syndrome for stereotypic hand movements, Bumin et al. tried hand splints or elbow restraints,89 Naganuma et al. tried thumb abduction splints,90 Sharpe et al. 21  tried elbow orthosis or thumb abduction splints,91 and Tuten et al. tried hand splints.92 Also in Rett syndrome, Stasolla et al. used assistive technologies in three studies to increase purposeful hand movements, including picture exchange communication systems compared to vocal output communication aid,93 wobble microswitch and optic sensors,94 and photocells, interface and personal computer.95 Lotan et al. investigated how a daily training treadmill program improved functional skills in Rett syndrome.96 Mordekar et al reported how switching to parenteral nutrition can improve feed-induced dystonia in Rett syndrome.39 In Friedrich’s ataxia, Ilg examined how video game-based coordinative training can improve coordination.97  Fourteen studies investigated a surgical intervention. Eleven of these studies investigated deep brain stimulation in glutaric acidemia type I,98–100 Lesch-Nyhan syndrome,98 ataxia-telangectasia,101 methylmalonyl-CoA mutase deficiency,101 nemaline myopathy,101 infantile neuroaxonal dystrophy,98,100,102–106 and other non-specified Q3 condtions.107,108 In a retrospective chart review, Buizer reported the used of selective dorsal rhizotomy in lipidoses.109 In mucolipidosis type II and mucopolysaccharidosis types I, II, III and VI, Haddad et al. investigated the effect of surgery for carpal tunnel syndrome.110 Van Heest et al. reported on the use of surgery for children with, mucopolysaccharidosis types I, III and VI and carpal tunnel syndrome and trigger digits.111 Five studies examined at psychological interventions for tone and motor problems and all were in Rett syndrome. In an open-label study, Fabio et al. investigated how selective attention training could reduce stereotypies.13 In case series, Piazza et al. examined hand function with training in scooping food, bringing food to mouth, and placing spoon in mouth by a trainer57 and Qvardfordt et al. compared hand function in guided eating to being fed.112 In case series, Lotan et al. examined daily conductive educational program113 and Wales et al. tested how different stimulation or attention conditions affected hand stereotypies.114  22  Twenty-six studies developed and/or validated a tool or scale for tone and motor problems. Nine of the studies included tools or scales for neuromuscular diseases that included spinal muscular atrophy type 1. Glanzman et al. developed and validated the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders in 2 studies.115,116 Krosschell et al. modified and validated the Hammersmith functional motor scale117 and validated the Test of Infant Motor Performance Screening Items specifically for spinal muscular atrophy type 1. Mazzone et al. compared the reliability of the Hammersmith Functional Motor Scale and the Motor Function Measure-20.118 Nelson et al. validated the Gross Motor Function Measure119 and de Lattre et al. and Vuillerot validated the Motor Function Measure.120,121 Finkel et al. tested the validity of the Test of Infant Motor Performance in children with spinal muscular atrophy type 1.122 Seven of the studies examined Rett syndrome. Downs et al. tested the use of accelerometers in 2 studies123,124 and validated the Rett Syndrome Gross Motor Scale in one study.125 Stahlhut et al. compared the modified two-minute walk test and a modified Rett syndrome specific functional mobility scale.126 Dy et al. and Fyfe et al. both developed and tested coding protocols for video-taped evaluation of hand steroteypies.58,127 Mount et al. developed the Rett Syndrome Behaviour Questionnaire that includes questions on hand behaviors.27 Four studies validated tools or scales in Friedrich’s ataxia. Cano et al. and Bürk et al. validated scales to measure the level of impairment due to ataxia128,129 and Subramony et al. developed and validated a neurologic rating scale.130 Germanotta et al. validated the use of InMotion Arm Robot to measure upper limb function.131 Nissenkorn et al. developed a clinical global impression scale for ataxia telangiectasia, which includes sections on motor function.132 For progressive myelopathy, including mucopolysaccharidosis types I and VI, Castilhos developed and validated the Severity Score System for Progressive Myelopathy.133 Darling et al. designed and pilot-tested the PKAN-23  Disease Rating Scale, which includes a motor examination protocol for infantile neuroaxonal dystrophy.24 In Niemann–Pick type C, Iturriaga developed a disability scale that includes scoring for motor disorders.59 Ruiz-Cortes validated the Motor Function Measure in unspecified hereditary neuromuscular diseases134 and van Capelle developed and validated the Quick Motor Function Test in glycogen storage disease type II.135 The remaining 48 studies described the characteristics, trajectory and challenges of tone and motor problems in this population.  As the most well studied symptom, there are several pharmacological, physical and surgical interventions for clinical practitioners to consider for the different types of tone and motor problems. Many of the studies investigated the specific stereotypic movements found in Rett syndrome. Interventions for this population include hand or finger splints or elbow restraints, assistive technologies, exercise programs, switching to parenteral nutrition to reduce dystonia and various forms of training or environmental conditions. These studies may not be relevant to other Q3 conditions, as Rett syndrome has distinct tone and motor challenges. In other conditions, several pharmacologic interventions showed some efficacy that clinical practitioners may wish to consider, including levodopa, intrathecal baclofen, tricyclic antidepressants, betamethasone, amantadine sulfate, dronabinol, gabapentin and botulinum toxin type A. Deep brain stimulation can be considered, but the results are mixed and may depend on condition and even mutation. Other surgical interventions include surgery for carpal tunnel syndrome and selective dorsal rhizotomy to reduce spasticity. Physical interventions include serial casting and intensified physical therapy for equinus deformity and video game training to improve coordination. Only 2 of the studies were RCTs and 3 were systematic reviews, showing the need for higher levels of evidence before strong recommendations for treatment can be made by clinical practitioners. Several studies developed and/or validated scales and tools for tone and 24  motor problems. Some of the tools, for example a protocol for a video-taped evaluation of hand stereotypies in Rett syndrome, may be condition-specific. However, several tools and scales may be helpful in Q3 conditions to assess and measure tone and motor difficulties. Urinary Incontinence Nine studies assessed urinary incontinence: 6 cross-sectional, 2 case-control and 1 survey. All 9 of the studies provided insight into the trajectory or characteristics of the symptom, or compared the severity or features of urinary incontinence to other populations. No evidence on interventions or tools to assess urinary incontinence were found for Q3 conditions. More research is needed for this symptom. DISCUSSION This scoping review identified tools to best assess and interventions to best manage troubling symptoms for children living with Q3 conditions. While many of the tools and scales found in this review are condition specific and may not be useful in other Q3 conditions, we did locate some that are either intended for the larger category of Q3 conditions or may be valid in other populations. More research should be done to design tools for symptoms without any current tools and to validate existing tools in Q3 conditions as a whole. Tone and motor problems was the most investigated symptom. Many of the studies investigated the specific stereotypic movements found in Rett syndrome and these studies may not be relevant to other Q3 conditions. Studies showed some efficacy for a variety of pharmacological interventions, other surgical and physical interventions and mixed results for deep brain stimulation We can only guess as to why tone and motor problems, and specifically the ones associated with Rett syndrome, have been more thoroughly investigated that other symptoms. 25  One suggestion is that as an outwardly evident symptom, in a clearly diagnosed condition, it is seemingly easier for researchers to investigate. Behavioural problems were the second most studied symptom, and most of the studies that investigated interventions focused on self-injurious behaviour, particularly in Lesch-Nyhan syndrome. Again, we can only guess as to why self-injury is so well-studied in comparison to other symptoms, but it may be due to the disturbing nature of the symptom for caregivers and the ease at which an investigator can measure changes. No pharmacologic studies showed clear and lasting effects on self-injury, but some behavioral studies provided effective strategies.  Sleep difficulties was the third most studied symptom. Melatonin was overwhelmingly the most studied intervention, but studies were mixed on the efficacy of melatonin in Q3 conditions. Other interventions studies included risperidone prescribed for behavioral problems, fading procedures and personalized sleep plans. Sleep problems had the highest number of RCTs of all symptoms, all of which investigated melatonin.  As the fourth most studied symptom, studies about feeding difficulties investigated a variety of interventions, but several of the studies may only be relevant in epidermolysis bullosa and Rett syndrome. Studies that may be more generalizable to Q3 conditions include, percutaneous gastrostomy placement, parenteral nutrition, bilateral submandibular gland excision and/or parotid duct ligation, baclofen, rikkushito, black pepper oil and behavioral strategies.  Breathing problems were the fifth mostly commonly investigated symptom. Sleep apnea studies in achondroplasia suggest surgical intervention may be necessary, while for other Q3 conditions CPAP or medications, such as naltrexone, appear to be effective. The evidence for other breathing difficulties is mixed and of low quality. 26  Alertness, constipation, urinary and bowel incontinence and were the fifth, fourth, third and second least studied symptom respectively. For alertness, structured training to increase attention in Rett syndrome was the only intervention studied. For constipation some studies suggest parenteral nutrition, fiber-enriched formula, or supplementation with carnitine. For urinary and bowel incontinence no interventions were studied. The least studied symptom was temperature regulation. Only acupuncture was studied which may increase skin temperature over time.  Overall this scoping review found that very little evidence exists for symptom management in Q3 Conditions. Given the absence of cures for these conditions, the clinical focus should be on symptom management and its contribution to quality of life. We found that most of the studies are concentrated on a handful of diseases, particularly Rett syndrome. Rett syndrome has a distinct clinical profile and interventions used for this condition may not be generalizable to other conditions. Additionally, no condition has a consistent evidence base for all 10 symptoms, and most have only limited evidence for a single symptom. Furthermore, some symptoms, such as temperature regulation problems that have been identified as important to parents, have received little attention in the published clinical research. With the exception of melatonin for sleeping difficulties, there is also a lack of high-level evidence for all symptoms. In conclusion, there is an urgent need for higher levels of evidence for reliable assessment tools and effective interventions for managing prevalent symptoms in Q3 conditions. Implications for Practice The studies found in this scoping review are dispersed across multiple disciplines and major general pediatric journals are not represented, except for the Journal of Pediatrics. As a result, general pediatricians or even specialists are unlikely to see most of the articles that would 27  provide valuable evidence to ensure optimal symptom management in this population. Retrieval of this evidence is further complicated by the lack of an accepted and widely used term for this group of progressive, life-threatening conditions. “Q3” is a term used amongst clinicians working with this specific population, but not a term that is reflected in scientific literature and thus a disconnect happens when care providers are looking for evidence of best practices. It is unlikely that a clinician would find these studies through a quick online search. This situation ultimately leaves clinicians with little to no evidence of effective symptoms management for their patients and a distressing inability to improve health outcomes informed by research rather than anecdotal evidence or individual experience.  Limitations and Future Directions This scoping review is limited by our last search date of January 2018, as more recent studies may have been published within the past year. Additionally, we were not able to translate studies that were not in English or French due to a lack of resources and we were not able to locate the full-text of some studies. This may introduce bias into our results as some studies were excluded before our team had the opportunity to review the full-text. Despite these limitations, it is clear that there needs to be more research done on these symptoms to have a strong evidence base on which to base treatment. For clinical practitioners who must manage the symptoms of child with a Q3 condition with little or no evidence, studies from other conditions may provide the only guidance available for measurement tools and interventions. This scoping review highlights gaps in our knowledge regarding the management of common symptoms in children with neurological, genetic, or chromosome-based conditions that impair quality of life.  Researchers and clinicians can use this information to develop broader programs of research to develop 28  assessment tools and then test interventions that will have a meaningful impact on these children and their families.  Abbreviations CPAP – Continuous positive airway pressure  OSA – Obstructive sleep apnea  RCT – Randomized controlled trial Q3 – Quadrant 3   Authorship:  C. Pawliuk developed and implemented the search strategy, reviewed abstracts, titles and full articles, and contributed to the writing of the manuscript and revised it for important intellectual content. K. Widger participated in planning the study, reviewed abstracts, titles and full articles, and revised the manuscript for important intellectual content. T. Dewan participated in planning the study, reviewed abstracts, titles and full articles, and revised the manuscript for important intellectual content. G. Brander implemented the search strategy and revised the manuscript for important intellectual content. H. Brown provided methodological guidance and revised the manuscript for important intellectual content. A.-M. Hermansen reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. M.-C. Grégoire participated in planning the study, reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. R. Steele participated in planning the study, reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. H. Siden conceptualized the study, participated in planning the study, reviewed abstracts, titles and full articles, contributed to the writing and revised it for important intellectual content.  29  Funding: This work was supported by the Canadian Institutes of Health Research (CIHR) Knowledge Synthesis Grant #328968.  Declaration of conflicts of interest: None declared.  Acknowledgements: The authors would like to thank Charlotte Beck for her methodological guidance in the early stage of the review   Data management and sharing: All available data has been included in this publication and supplementary materials.  Licence for Publication: The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ Supportive and Palliative Care and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructions-for-authors/licence-forms).  30  REFERENCES 1.  Association for Children’s Palliative Care. A Guide to the Development of Children’s Palliative Care Services. 3rd ed. Report, Bristol, UK. 2009. 2.  Siden H, Steele R, Brant R, et al. 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Liu Z, Liu Y, Yang Y, et al. Subthalamic Nuclei Stimulation in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN). Neuromodulation 2017;20:484–491. 107.  Park HR, Lee JM, Ehm G, et al. Long-term clinical outcome of internal globus pallidus deep brain stimulation for dystonia. PLoS ONE 2016;11:e0146644 108.  Susatia F, Malaty IA, Foote KD, et al. An evaluation of rating scales utilized for deep brain stimulation for dystonia. J Neurol 2010;257:44–58. 109.  Buizer AI, van Schie PEM, Bolster EAM, et al. Effect of selective dorsal rhizotomy on daily care and comfort in non-walking children and adolescents with severe spasticity. Eur J Paediatr Neurol 2017;21:350–357. 110.  Haddad FS, Jones DH, Vellodi A, et al. Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses. J Bone Joint Surg Br 1997;79:576–582. 111.  Van Heest AE, House J, Krivit W, et al. 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(2860) 7     (((3-Methylcrotonyl-CoA Carboxylase or 3MCC or BMCC) adj3 Deficiency) or 3-Methylcrotonylglycinuria).mp. (93) 8     Encephalomyelitis, Acute Disseminated/ (1708) 9     (((post or acute) adj3 vaccina* encephalitis*) or ((post or acute) adj3 infection* encephalitis*)).mp. (72) 10     "Agenesis of Corpus Callosum"/ (1967) 11     ((Agenesis adj2 Corpus Callosum) or ((hypogenes* or dysgenes* or absence*) adj2 corpus Callosum)).mp. (2300) 12     Aicardi Goutieres.mp. (289) 13     Alagille Syndrome/ (525) 14     (watson miller or alagille* or cadiovertebral or hepatofacioneurocardiovertebral or arteriohepatic displasia or (hepatic ductular adj2 hypoplasia)).mp. (835) 15     Holoprosencephaly/ (1046) 16     (Holoprosencephal* or arhinencephal*).mp. (2002) 17     Aspartylglucosaminuria/ (111) 18     ((Aspartylglucosaminuria* or glycoasparaginase* or aspartylglucosamidase) adj3 deficienc*).mp. (4) 19     ((Asphyxiating Thoracic adj3 dystroph*) or (short rib thoratic adj1 dysplasia*) or (jeune adj3 syndrome)).mp. (235) 20     Ataxia Telangiectasia/ (3029) 21     ((Ataxia adj3 Telangiectasia) or (Louis adj2 Bar)).mp. (8344) 22     Rett Syndrome/ (2049) 23     ((Rett adj3 (Syndrome or morbus)) or (cerebroatrophic adj3 hyperammonemia*)).mp. (2858) 24     Bartter Syndrome/ (1300) 25     Bartter.mp.  (1626) 26     ((Bowen adj3 Conradi) or (Bowen adj3 Hutterite)).mp. (26) 27     Carbamoyl-Phosphate Synthase I Deficiency Disease/ (100) 28     ("Carbamoyl-Phosphate Synthase I Deficiency Disease" or "Carbamoyl Phosphate Synthase I Deficiency Disease").mp. (100) 29     Carbohydrate-Deficient Glycoprotein Syndrome/ (498) 30     ("Carbohydrate-Deficient Glycoprotein Syndrome" or "Carbohydrate Deficient Glycoprotein Syndrome" or (congenital adj3 glycosylation) or (congenital adj3 dyserythropoietic anemia) or (fukuyama congenital adj3 dystrophy) or (hereditary multiple adj3 exostosis) or (walker adj3 Warburg)).mp. (1821) 31     Carnitine O-Palmitoyltransferase/df (397) 32     (Carnitine O-Palmitoyltransferase adj3 deficienc*).mp. (0) 33     myopathies, structural, congenital/ or myopathies, nemaline/ or myopathy, central core/  (987) 34     ((Centronuclear or myotubular) adj3 myopath*).mp. (581) 35     ((autosomal recessive or Charlevoix Saguenay) adj2 Spastic Ataxia).mp. (130) 36     Cholesterol Ester Storage Disease/ (111) 37     ("Cholester#l Ester Storage Disease" or "Cholester#lester Storage Disease").mp. (207) 38     Wolf-Hirschhorn Syndrome/ (103) 39     ((Wolf adj3 Hirschhorn) or (Pitt Rogers adj3 Danks) or (Chromosome 4p adj2 (Deletion or syndrome* or monosomy))).mp. (436) 40     Cri-du-Chat Syndrome/ (623) 41     Crying Cat Syndrome/ (623) 42     limit 41 to yr="1964 - 1976" (298) 43     ((Chromosome 5p adj3 Deletion) or Cri-du-Chat or (Crying adj3 Cat) or (cat adj3 cry)).mp. (706) 44     Chromosomes, Human, Pair 5/ and (Tetrasomy/ or Mosaicism/) (37) 45     (Tetrasomy 5p adj3 Mosaicism).mp. (4) 46     Chromosomes, Human, Pair 9/ and (Trisomy/ or Mosaicism/) (405) 47     (Mosaic adj3 Trisomy 9).mp. (48) 48     (Chromosomes, Human, Pair 18/ and Trisomy/) or (Chromosomes, Human, Pair 11/ and Trisomy/) (1659) 49     (Trisomy 11 or Trisomy 18).mp. (2224) 50     Chromosomes, Human, Pair 12/ and (Tetrasomy/ or Mosaicism/) (141) 51     ((Pallister adj3 Killian) or (isochromosome adj2 12p) or (Chromosome 12p adj2 (Mosaicism or Tetrasomy))).mp. (279) 52     Chromosomes, Human, Pair 13/ and Trisomy/ (928) 53     (Patau or Trisomy 13 or Trisomy d).mp. (1447) 54     Chromosomes, Human, Pair 18/ and Trisomy/ (1400) 55     ((Edward* adj3 Syndrome) or trisomy 18 or trisomy e).mp. (2249) 56     Down Syndrome/ (21870) 57     Down's Syndrome/ (21870) 58     limit 57 to yr="1975 - 1992" (5759) 59     Mongolism/ (21870) 60     limit 59 to yr="1966 - 1974" (2473) 61     (Trisomy 21 or (Down* adj2 Syndrome) or mongolism or mongoloid*).mp. (28715) 62     Chromosomes, Human, Pair 22/ and (Trisomy/ or Mosaic/) (265) 63     ((Whole chromosome adj3 trisomy) or (Meiotic adj3 Nondisjuntion) or Trisomy 22).mp. (274) 64     DiGeorge Syndrome/ (1677) 65     (DiGeorge or "Chromosome 22q11.2 Deletion").mp. (2345) 66     Common Variable Immunodeficiency/ (1718) 67     ("Common Variable Immunodeficiency" or (hypogammaglobulin?emia* adj3 (acquired or common variable)) or (agammaglobulin?emia* adj3 (acquired or common variable))).mp. (2753) 68     "Congenital Disorders of Glycosylation"/ (498) 69     ((Congenital Disorder* adj3 Glycosylation) or (carbohydrate deficient adj2 glycoprotein)).mp. (953) 70     Hydrocephalus/cn (215) 71     (Congenital adj3 Hydrocephal*).mp. (962) 72     (Congenital Myopathies and fib?r* type disproportion).mp. (51) 73     ((Congenital or Fetal) adj3 Varicella).mp. (235) 74     Costello Syndrome/ (89) 75     (Costello or faciocutaneoskeletal).mp. (472) 76     Creutzfeldt-Jakob Syndrome/ (5925) 77     Jakob-Creutzfeldt Syndrome/ (5925) 78     limit 77 to yr="1981 - 1990" (686) 79     Creutzfeldt-Jakob Disease/ (5925) 80     limit 79 to yr="1969 - 1980" (467) 81     ((Creutzfeldt adj3 Jakob) or (spongiform encephalopathy adj3 subacute) or (corticostriatospinal adj3 degeneration) or (spastic adj3 pseudosclerosis)).mp. (7453) 82     De Lange Syndrome/ (680) 83     (De Lange* or "Bushy Syndrome" or "Amsterdam dwarfism").mp. (1290) 84     "Diffuse Cerebral Sclerosis of Schilder"/ (2317) 85     (Alper#s or (myelinoclastic adj3 diffuse sclerosis) or (diffuse cerebral adj3 sclerosis) or (balo* adj3 concentric sclerosis) or (progressive adj3 sclerosing poliodystroph*) or schilder*).mp. (2479) 86     Epidermolysis Bullosa, Junctional/ or Epidermolysis Bullosa/ (2829) 87     ((Epidermolysis adj3 Bullosa) or Herlitzs).mp. (5195) 88     Farber Lipogranulomatosis/ (25) 89     Lipidoses/ (3927) 90     limit 89 to yr="1976 - 2008" (974) 91     Sphingolipidoses/ (343) 92     limit 91 to yr="1992 - 2008" (108) 93     (Farber* or ((ceramidase or n-laurylsphingosine deacylase) adj3 deficienc*)).mp. (942) 94     Friedreich Ataxia/ (2270) 95     ((Friedreich* adj3 (Ataxia or disease or syndrome)) or (hereditary adj3 (spinal scleroses or spinal staxia)) or (spinal adj3 heredoataxia)).mp. (3007) 96     Fucosidosis/ (138 97     (Fucosidosis or (alpha fucosidase adj3 deficienc*)).mp. (309) 98     Gangliosidoses/ [Lysosomal Storage Diseases, Nervous System] (567) 99     (Gangliosidos* or (ganglioside adj3 (storage or lipidosis))).mp (1761) 100     alpha-N-Acetylgalactosaminidase/df [Deficiency] (5) 101     (((alpha-N-Acetylgalactosaminidase or alpha-NAGA) adj3 Deficienc*) or Schindler or Kanzaki).mp. (171) 102     Argininosuccinic Aciduria/  (139) 103     ((Argininosuccinic adj3 Aciduria*) or ((Argininosuccinate Lyase or argininosuccinase or ALS) adj3 deficienc*) or (arginino adj3 succinic) or mckusick 20790 or argininosuccinicaciduria).mp. (311) 104     Chromosomes, Human, Pair 1/ and monosomy/ (103) 105     (Chromosome 1p36 adj3 (Monosomy or deletion)).mp. (49) 106     Chromosomes, Human, Pair 3/ and Chromosome Inversion/  (111) 107     (Chromosome 3 adj3 Inversion).mp.   (42) 108     Chromosomes, Human, Pair 3/ and Monosomy/ and (Chromosomes, Human, Pair 5/ and Trisomy/)  (2) 109     (Chromosome adj3 (3p25 Partial Monosomy or 5p15* Trisomy)).mp. (0) 110     Chromosomes, Human, Pair 5/ and Trisomy/ (206) 111     (Chromosome 5 adj3 Trisomy).mp.   (42) 112     Chromosomes, Human, Pair 5/ and Chromosome Deletion/ (861) 113     (Chromosome 5q14* adj5 Deletion).mp. (0) 114     (Chromosomes, Human, Pair 6/ and Translocation, Genetic/) or (Chromosomes, Human, Pair 4/ and Translocation, Genetic/)  (1445) 115     ((Chromosome 6 or Chromosome 4) and Unbalanced Translocation).mp.   (32) 116     (Chromosomes, Human, Pair 7/ and Trisomy/) or (Chromosomes, Human, Pair 6/ and Monosomy/)   (426) 117     ((Chromosome adj3 Unbalanced Rearrangement) or Partial Trisomy 7 or Monosomy 6).mp.   (46) 118     Chromosomes, Human, Pair 14/ and Chromosome Deletion/   (303) 119     (Chromosome 14 adj3 Deletion).mp.   (42) 120     Chromosomes, Human, Pair 18/ and Chromosome Deletion/   (447) 121     (Chromosome 18q adj3 Deletion).mp.   (38) 122     Chromosomes, Human, Pair 18/ and Chromosomes, Human, Pair 5/ and Chromosome Deletion/   (35) 123     (Chromosome 18 and Chromosome 5 and Deletion).mp.   (14) 124     Triploidy/   (226) 125     (Chromosome 69 adj3 Triploidy).mp. (0) 126     (Desminopath* or (Myopath* adj3 Myofibrillar) or (Desmin adj3 Related)).mp.   (441) 127     ((Dilated Cardiomyopathy adj3 Ataxia) or (3 Methylglutaconic adj3 Aciduria)).mp.   (159) 128     Epilepsies, Myoclonic/ [Epilepsy] (2619) 129     ((Infantile Myoclonic adj3 Epilepsy) or Dravet*).mp. (544) 130     (Early adj3 Myoclonic Encephalopathy).mp. (77) 131     Gangliosidoses, GM2/ or Tay-Sachs Disease/ or Tay-Sachs Disease, AB Variant/ (1303) 132     ((GM2 adj3 Gangliosidos*) or (Tay adj2 Sach*) or (hexosaminidase adj3 deficiency)).mp. (2215) 133     (Gangliosidos* adj4 GM3).mp. (5) 134     Glucosephosphate Dehydrogenase Deficiency/ (4294) 135     ((Glucosephosphate Dehydrogenase or g6pd or Glucose-6-Phosphate Dehydrogenase) adj3 Deficiency).mp. (5089) 136     Glutaryl-CoA Dehydrogenase/df [Deficiency] (120) 137     ((Glutaric adj3 Acidemia Type I) or (Glutaric adj3 Aciduria 1) or (Glutaryl-CoA dehydrogenase adj3 deficienc*)).mp.   (210) 138     Multiple Acyl Coenzyme A Dehydrogenase Deficiency/  (90) 139     ((Glutaric Aciduria adj3 (Type 2 or Type II)) or ((Multiple Acyl Coenzyme A Dehydrogenase or Electron transfer flavoprotein or oxidoreductase) adj3 deficienc*)).mp (340) 140     Glycogen Storage Disease Type II/ [Lysosomal Storage Diseases, Nervous System] (1323) 141     ((Glycogen Storage Disease adj3 Type II) or Pompe* or ((acid maltase or alpha-glucosidase) adj3 deficienc*)).mp. [Lysosomal Storage Diseases, Nervous System] (2342) 142     Glycogen Storage Disease Type IIb/ (98) 143     (Danon or antopol or (glycogen storage adj3 cardiomyopath*) or pseudoglycogenosis 2 or ((LAMP-2 or LAMP2 or lysosome associated membrane protein 2) adj3 deficenc*)).mp. (190) 144     Glycogen Storage Disease Type IV/ (176) 145     ((Glycogen Storage adj3 (Type IV or type 4)) or brancher or (andersen* adj3 disease) or glycogenos*).mp. (1783) 146     Hereditary Central Nervous System Demyelinating Diseases/ (282) 147     (Hereditary Central Nervous System adj3 Demyelinat*).mp. (282) 148     Histiocytosis, Langerhans-Cell/ (5024) 149     (((Histiocytos* or granulomatos*) adj3 Langerhans Cell) or (hand schu#ller adj3 Christian) or (aleukemic adj3 reticuloendotheliosis) or (histiocytos* adj3 x)).mp. (7973) 150     Hyperargininemia/ (166) 151     (Hyperargininemia* or (arginase adj3 deficienc*) or argininemia*).mp. (272) 152     Incontinentia Pigmenti/ (628) 153     (Incontinentia Pigmenti or (bloc* adj3 sulzberger) or (hypomelanosis adj3 ito) or (neonatal pigment adj3 incontinence)).mp. (1272) 154     Pantothenate Kinase-Associated Neurodegeneration/ (430) 155     ((Infantile Neuroaxonal adj3 Dystrophy) or (Pantothenate Kinase-Associated adj3 Neurodegeneration) or (Pigmentary Pallidal adj3 Degeneration) or hallervorden spatz).mp. (787) 156     Refsum Disease, Infantile/ (8) 157     ((Infantile adj3 Refsum) or (infantile adj3 phytanic acid storage disease)).mp. (135) 158     ((Joubert or Boltshauser) adj3 syndrome).mp.   (557) 159     Huntington Disease/ (10175) 160     (huntington* adj5 juvenile).mp. (126) 161     Kearns-Sayre Syndrome/ (606) 162     ((Kearns adj3 Sayre) or (cpeo adj3 myopathy) or oculocraniosomatic or ophthalmoplegia).mp. (10663) 163     Klippel-Trenaunay-Weber Syndrome/ (1083) 164     (Klippel Trenaunay or angioosteohypertrophy or angio osteohypertrophy or (dysplastic adj3 angiopathy congenital) or congenital angiodysplasisa or (osteohypertrophic varicose adj3 naevus) or (parkes adj3 weber)).mp. (1525) 165     Leukodystrophy, Globoid Cell/ (860) 166     (Krabbe or (Leukodystrophy adj3 Globoid Cell) or (galactosylceramide beta galactosidase adj3 deficienc*)).mp. (1191) 167     Lafora Disease/ (222) 168     (Lafora or (progressive myoclonic epilepsy adj3 (type 2 or type II))).mp. (525) 169     Leigh Disease/ (864) 170     ((Leigh adj3 (syndrome or disease)) or (necrotizing encephalomyelopath* adj3 subacute)).mp. (1237) 171     Lennox Gastaut Syndrome/ (192) 172     Spasms, Infantile/ (3025) 173     limit 172 to yr="1988 - 2014" (2109) 174     ((Lennox adj4 Gastaut) or (childhood epileptic adj3 encephalopathy)).mp. (1139) 175     Lesch-Nyhan Syndrome/ (1160) 176     (Lesch Nyhan or (juvenile adj3 hyperuricemia) or (guanine phosphoribosyltransferase adj3 deficienc*) or (hypoxanthine phosphoribosyltransferase adj3 deficienc*) or (choreoathetosis adj3 self mutilation)).mp. (1485) 177     Alexander Disease/ or Leukodystrophy, Metachromatic/ or Adrenoleukodystrophy/ or Pelizaeus-Merzbacher Disease/ or Hereditary Central Nervous System Demyelinating Diseases/ (3349) 178     ((Alexander adj3 Disease) or Leukodystrophy or Adrenoleukodystrophy or (Pelizaeus adj3 Merzbacher)).mp. (5722) 179     Lipidoses/ or Cholesterol Ester Storage Disease/ or Sjogren-Larsson Syndrome/ or Gaucher Disease/ (8094) 180     (Lipidos* or (lipid storage adj3 disorder*) or (cerebroside adj3 lipidosis) or Sphingolipidoses or (glucocerebrosidase adj3 deficienc*) or (Sjogren adj3 Larsson) or Gaucher or Ichthyosis).mp. (14996) 181     "Classical Lissencephalies and Subcortical Band Heterotopias"/ (107) 182     (Lissencephal* or (Miller adj3 Dieker) or (agyria pachygyria adj3 band spectrum)).mp. (1397) 183     Infant/ and Osteopetrosis/ (443) 184     (Malignant Infantile adj3 Osteopetrosis).mp. (58) 185     alpha-Mannosidosis/ (236) 186     Mannosidosis/ (5) 187     limit 186 to yr="1985 - 2003" (1) 188     beta-Mannosidosis/ (9) 189     Mannosidase Deficiency Diseases/ (5) 190     limit 189 to yr="1984 - 2003" (1) 191     ((alpha or beta) adj3 Mannosidos*).mp. (361) 192     ((Marshall adj3 Smith) or (Greig* adj3 syndrome) or (Polysyndactyly adj3 cephalopolysyndactyly)).mp. (194) 193     (Meckel or Gruver or (Dysencephalia adj3 Splanchnocystica)).mp. (4100) 194     (Menkes or (copper transport adj3 disease) or ((steely or kinky) adj3 hair) or (dystrophy adj3 trichopolio) or trichopoliodystrophy).mp. (1425) 195     MERRF Syndrome/ (321) 196     (MERRF or ((myoclon* adj3 epilepsy) and ragged red fibers) or fukuhara).mp. (629) 197     Leukodystrophy, Metachromatic/ (1139) 198     ((Metachromic Leukodystroph* adj3 Juvenile) or ((arylsulfatase or sulfatid*) adj3 deficienc*) or (sulfatid* adj3 lipidosis)).mp. (235) 199     ((Methylcrotonyl-CoA Carboxylase adj3 Deficienc*) or 3 Methylcrotonygycinuria or (Methylcrotonygycinuria adj3 type 1)).mp. (87) 200     Methylmalonyl-CoA Mutase/df [Deficiency] (105) 201     ((Methylmalonyl CoA Mutase adj3 deficienc*) or (methylmalonic adj3 acidemia)).mp. (565) 202     Mevalonate Kinase Deficiency/ (135) 203     ((Mevalonate Kinase adj3 Deficienc*) or mevalonicacidurias or (hyper igd adj3 syndrome*) or hyperimmunoglobulinemia d).mp. (366) 204     Mitochondrial Diseases/ (3856) 205     (((Mitochondrial adj3 (Disorder* or Disease*)) or (phosphorylation oxidative mitochondrial or electron transport chain or mitochondrial respiratory chain)) adj3 deficienc*).mp. (232) 206     MELAS Syndrome/ (1079) 207     ((MELAS adj3 Syndrome*) or ((mitochondrial myopathy adj3 encephalopathy) and lactic acidosis)).mp. (1377) 208     mitochondrial encephalomyopathies/ (939) 209     (Mitochondria* adj3 Encephalomyopath*).mp. (1683) 210     Mitochondrial Myopathies/ (1499) 211     ((Mitochondrial adj3 Myopath*) or (luft* adj3 disease*) or (megaconial adj3 myopath*)).mp. (2907) 212     ((Mowat adj3 Wilson) or (microcephaly adj3 mental) or (hirschsprung adj3 disease)).mp. (4771) 213     Mucolipidoses/ (925) 214     ((Mucolipidos* adj3 Type III) or (Pseudo Hurler adj3 Polydystrophy)).mp. (82) 215     (Mucolipidos* adj3 Type IV).mp. (140) 216     ((Mucolipidos* adj3 Type II) or (i cell adj3 Disease) or sialolipidos* or mucolipidos* or (myoclonus adj3 cherry red spot) or (glycoprotein neuraminidase adj3 deficienc*) or (inclusion cell adj3 disease)).mp. (1330) 217     Mucopolysaccharidosis I/ (1578) 218     (Mucopolysaccharidosis I or Hurler or Scheie or (alpha l iduronidase adj3 deficienc*) or gargoylism or lipochondrodystroph*).mp. (2034) 219     Mucopolysaccharidosis II/ (820) 220     ((Mucopolysaccharidosis adj3 (II or type 2)) or (Hunter adj3 syndrome) or (iduronate sulfatase adj3 deficienc*)).mp. (1004) 221     Mucopolysaccharidosis III/ (572) 222     ((Mucopolysaccharidosis adj3 (III or type 2)) or Sanfilippo* or San filippo* or ((n-acetylglucosamine-6-sulfatase or acetyl-coa:alpha-glucosaminide n-acetyltransferase or sulfamidase) adj3 deficienc*) or oligophrenia polydystrophic).mp. (781) 223     (((Mucopolysaccharidosis adj3 (IIIa or type 3a)) or (Heperan sulfate or sulfamidase)) adj3 deficienc*).mp. (23) 224     (((Mucopolysaccharidosis adj3 (IIIb or type 3b)) or (n acetyl alpha d glucosaminidase or naglu)) adj3 deficienc*).mp. (11) 225     Multiple Sulfatase Deficiency Disease/ (24) 226     SPHINGOLIPIDOSES/ (343) 227     limit 226 to yr="2000 - 2006" (63) 228     Sulfatases/ (3289) 229     limit 228 to yr="1973 - 2006" (2109) 230     ((Multiple Sulfatase adj3 Deficienc*) or (Austin adj3 Disease) or mucosulfatidosis or (juvenile adj3 sulfatidos*)).mp. (124) 231     Myoclonic Epilepsies, Progressive/ (298) 232     ((Myoclon* Epileps* adj3 Progressive) or (haw adj3 river) or encephalopathyadj3 biotin-responsive or (naito adj2 oyanagi) or (dentatorubral-pallidoluysian adj3 atrophy) or (myoclonus adj3 nephropathy) or (atypical adj3 inclusion-body) or (may adj2 white) or (dentatorubral pallidoluysian adj3 atrophy)).mp. (1755) 233     ((myotubular or x-linked centronuclear) adj3 myopath*).mp. (348) 234     Myopathies, Nemaline/ (408) 235     ((Rod adj3 Myopath*) or (nemaline adj3 myopath*)).mp. (749) 236     Neuroaxonal Dystrophies/cn [Congenital] (1) 237     (Seitelberger*adj3 Disease or (Neuroaxonal Dystroph* adj3 Congenital) or (congenital adj3 neuroaxonal dystrophy)).mp. (1) 238     Neuronal Ceroid-Lipofuscinoses/ (1741) 239     ((Neuronal Ceroid Lipofuscinosis adj3 (Type 3 or juvenile)) or cerebroretinaladj3 degeneration* or (batten adj3 disease) or (vogt adj3 spielmeyer) or (spielmeyer adj3 sjogren) or (Janksy adj3 Bielschowsky) or (Kuf* adj3 Disease) or (Spielmeyer Vogt adj3 Sjogren Batten) or (amaurotic adj3 idocy)).mp. (852) 240     (Neuronal Ceroid Lipofuscinosis adj3 (Type 6 or late infantile)).mp. (255) 241     Niemann-Pick Disease, Type A/ (38) 242     ((Niemann Pick adj3 (Type A or classical)) or (neuronal cholesterol adj3 lipidos*) or (sphingomyelinas* adj3 deficienc*) or (sphingomyelin adj3 (lipidos* or storage disease))).mp. (319) 243     Niemann-Pick Disease, Type C/ (430) 244     (Niemann-Pick Disease adj3 (Type C or nova scotia*)).mp. (786) 245     Hyperglycinemia, Nonketotic/ (177) 246     ((Hyperglycin?emia* adj3 (Nonketotic or non ketotic)) or (glycine adj3 encephalopath*)).mp. (496) 247     Oculocerebrorenal Syndrome/ (359) 248     Olivopontocerebellar Atrophies/ (633) 249     ((Olivopontocerebellar adj3 (Atroph* or degeneration*)) or (olivo ponto cerebellar adj3 (Atroph* or degeneration*)) or (pontoolivocerebellar adj3 (Atroph* or degeneration*)) or (dejerine adj3 thomas) or (presenile adj3 ataxias) or (Lowe* adj3 syndrome)).mp. (3366) 250     Sleep Apnea, Central/ (1015) 251     ((Ondine* adj3 curse) or (congenital adj3 central hypoventilation) or (primary alveolar adj3 hypoventilation) or (central sleep breathings adj3 disorder*)).mp. (629) 252     Ophthalmoplegia, Chronic Progressive External/ (488) 253     ((Ophthalmoplegia Chronic adj3 Progressive) or (ocular myopathy adj3 von graefe fuchs) or (dystrophy ocular adj3 muscular) or (ocular myopathy adj3 mitochondrial) or (graefe* adj3 disease)).mp. (505) 254     Pelizaeus-Merzbacher Disease/ (269) 255     "Diffuse Cerebral Sclerosis of Schilder"/ (2317) 256     limit 255 to yr="1966 - 1999" (1716) 257     Multiple Sclerosis/ (43327) 258     limit 257 to yr="1966 - 1999" (17568) 259     ((Pelizaeus adj3 Merzbacher) or (leukodystrophy adj3 hypomyelinating 1) or (balo adj3 disease) or ((brain or cerebral) adj3 sclerosis) or (concentric adj3 periaxial encephalitis)).mp. (3896) 260     Peroxisomal Disorders/ (507) 261     ((Peroxisomal adj3 (Disorder* or disease)) or disfunction* or (adrenoleukodystrophy autosomal adj3 neonatal) or hyperpipecolatemia* or (acidemia* adj3 hyperpipecolic) or (neonatal adj3 adrenoleukodystroph*)).mp. (2589) 262     ((Pontocerebellar Hypoplasia adj3 (Type II or type 2)) or (volendam adj3 neurodegenerative)).mp. (21) 263     (3 Hydroxyisobutyric adj3 Aciduria).mp. (15) 264     Progeria/ (1274) 265     ((Hutchinson adj3 Gilford) or Gilford or progeria or premature senility).mp. (1739) 266     Propionic Acidemia/ (109) 267     ((Propionic* adj3 Acidemia*) or (propionyl coa carboxylase adj3 deficienc*) or (hyperglycinemia ketoacidosis adj3 leukopenia) or propionicaciduria* or (glycin?emia* adj3 ketotic)).mp. (492) 268     Pyruvate Carboxylase Deficiency Disease/ (139) 269     ((Pyruvate Carboxylase adj3 Deficienc*) or (ataxia adj3 lactic acidosis)).mp. (186) 270     Pyruvate Dehydrogenase Complex Deficiency Disease/ (366) 271     (Pyruvate Dehydrogenase Complex adj3 Deficienc*).mp. (404) 272     Pyruvate Metabolism, Inborn Errors/ (54) 273     (Pyruvate Metabolism adj3 Inborn Errors).mp. (55) 274     Refsum Disease/ (625) 275     ((Refsum adj2 (Disease or syndrome)) or ((hereditary motor adj3 sensory neuropathy) and (type iv or type 4)) or (polyneuritiformis hemeralopia adj3 heredoataxia) or (phytanic acid oxidase adj3 (deficienc* or storage disease)) or (heredopathia adj3 (atactica polyneuritiformis or atacticapolyneuritiformis))).mp. (785) 276     Rubinstein-Taybi Syndrome/ (433) 277     ((Rubinstein adj3 Taybi) or (broad thumb adj3 hallux) or (rubinstein adj3 syndrome)).mp. (640) 278     Sandhoff Disease/ (395) 279     ((Sandhoff adj3 Disease) or ((total hexosaminidase or beta hexosaminidase beta subunit) adj3 deficienc*) or ((hexosaminidases adj5 deficiency) and (a and b))).mp. (512) 280     "Malformations of Cortical Development"/ (947) 281     Cerebral Cortex/ab [Abnormalities] (1727) 282     limit 281 to yr="1995 - 2007" (1073) 283     ((Schizencephaly adj2 (Type 2 or type II)) or (cerebral cortical adj3 dysplasia*) or (cortical development adj3 malformation*) or (schizocephal* adj3 (Type 2 or type II))).mp. (1514) 284     Short Rib-Polydactyly Syndrome/ (126) 285     ((Short Rib adj3 Polydactyly) or (polydactyly adj3 neonatal chondrodystrophy) or (saldino adj3 noonan) or (majewski adj3 syndrome)).mp. (234) 286     Sialic Acid Storage Disease/ (64) 287     ((Sialic Acid adj3 Storage Disease) or (sialuria* adj3 (finnish type or french type))).mp. (121) 288     "Spinal Muscular Atrophies of Childhood"/ (1031) 289     ((Spinal Muscular Atrophy adj3 (Type 1 or type i)) or (Infantile adj3 (spinal Muscular Atrophy or muscular atrophy)) or (Werdnig adj3 Hoffmann) or (hereditary progressive spinal adj3 muscular atrophy)).mp. (585) 290     Smith-Lemli-Opitz Syndrome/ (519) 291     Abnormalities, Multiple/ (38849) 292     limit 291 to yr="1967 - 1995" (19000) 293     (((Smith Lemli Opitz or reductase deficiency 7-dehydrocholesterol or rutledge friedman harrod or lethal acrodysgenital or rutledge lethal multiple congenital anomaly) adj2 Syndrome) or (hyperotosis corticalis adj3 generalisata familiaris)).mp. (785) 294     "NAV1.1 Voltage-Gated Sodium Channel"/ (597) 295     ((Voltage-Gated Sodium Channel adj3 "NAV1.1") or (Sodium channel voltage-gated adj3 (alpha subunit and type 1))).mp. (602) 296     Sphingolipidoses/ (343) 297     (Sphingolipidoses or (sphingolipid storage adj3 diseases)).mp. (458) 298     Subacute Sclerosing Panencephalitis/ (2223) 299     ((Subacute Sclerosing adj3 Panencephalitis) or ((Dawson or Bogaert*) adj3 Disease) or (sclerosing leukoencephalitid* adj3 subacute) or (inclusion body encephalitis adj3 measles)).mp. (2649) 300     ((Systemic adj3 Juvenile Xanthogranulomato*) or JXK).mp. (4) 301     Tuberous Sclerosis/ (5188) 302     ((Tuberous adj3 Sclerosis) or (bourneville adj3 pringle*) or (bourneville adj3 (syndrome or phacomatosis or adenoma sebace*))).mp. (7889) 303     Unverricht-Lundborg Syndrome/ (118) 304     ((Unverricht adj3 Lundborg) or (mediterranean adj3 myoclonic epileps*) or (unverricht adj3 disease*) or (myoclon* adj3 baltic) or (epilepsy progressive adj3 myoclonic 1a)).mp. (297) 305     von Hippel-Lindau Disease/ (2293) 306     ((von Hippel adj3 Lindau) or (lindau adj3 disease*) or (retina* adj5 angiomatos*) or (cerebelloretinal adj3 hemangioblastomatosis)).mp. (5235)  307     Spasms, Infantile/ (3025) 308     ((West adj3 Syndrome) or ((juvenile or infantile) adj3 spasm*)).mp. (4116) 309     Wolman Disease/ (166) 310     ((Wolman* adj3 (Disease or xanthomatos*)) or (familial adj3 xanthomatos*) or (acid lipase adj3 deficienc*)).mp. (413) 311     Adrenoleukodystrophy/ (1546) 312     ((X linked adj3 Adrenoleukodystroph*) or (Addison adj3 Schilder) or (Addison adj3 disease)).mp. (5274) 313     Xeroderma Pigmentosum/ (3302) 314     (((Xeroderma or atrophoderma) adj3 Pigmentos*) or (kaposi* adj3 disease) or (melanosis lenticularis adj3 progressiva)).mp. (6076) 315     Zellweger Syndrome/ (531) 316     (((Zellweger adj3 (Syndrome or disease)) or (cerebro hepato renal or cerebrohepatorenal)) adj3 syndrome*).mp. (942) 317     Anencephaly/ (2970) 318     (Anencephal* or (congenital absence adj3 brain)).mp. (4021) 319     Lipodystrophy, Congenital Generalized/ (126) 320     DIABETES MELLITUS, LIPOATROPHIC/ (194) 321     limit 320 to yr="2005 - 2006" (30) 322     Lipodystrophy/ (3042) 323     limit 322 to yr="1968 - 2006" (1880) 324     ((LIPODYSTROPH* adj3 CONGENITAL GENERALIZED) or (BERARDINELLI adj3 LIPODYSTROPH*) or (SEIP adj3 SYNDROME) or (LIPODYSTROPH* adj3 ACROMEGALOID GIGANTISM) or (LIPOATROPH* DIABETES adj3 CONGENITAL)).mp. (344) 325     (Bisalbuminemia or (Hartnup adj3 disorder)).mp. (167) 326     Canavan Disease/ (264) 327     ((canavan adj3 (disease or syndrome)) or (aspartoacylase adj3 deficiency) or (bogaert adj3 bertrand) or (spongy degeneration and white matter and infancy) or (spongy disease adj3 central nervous system) or (spongiform adj3 leukodystrophy)).mp. (400) 328     ((MECP2 Duplication adj3 Syndrome) or (trisomy adj3 Xq28) or (Xq28 duplication adj3 syndrome)).mp. (60) 329     Methyl-CpG-Binding Protein 2/ge [Genetics] (940) 330     Cytomegalovirus Infections/cn [Congenital] (1480) 331     ((Congenital Cytomegalovirus adj3 (Infection or inclusion)) or (CMV adj3 (disease or syndrome))).mp. (3730) 332     Toxoplasmosis, Congenital/ (2530) 333     ((Congenital adj3 Toxoplasm*) or (toxoplasm* adj3 (fetal or newborn))).mp. (3029) 334     ((multiple Pterygium adj3 Syndrome) and (leathal or deadly or terminal)).mp. (1) 335     (Galactosialidosis or (Goldberg adj3 syndrome) or (Neuraminidase deficiency adj3 beta galactosidase deficiency) or (sialidosis adj3 galacto)).mp. (286) 336     Hyperglycinemia, Nonketotic/ (177) 337     ((Glycine adj3 Encephalopath*) or ((Non ketotic or nonketotic) adj3 hyperglycinemia)).mp. (427)  338     Holoprosencephaly/ (1046) 339     (Holoprosencephal* or arhinencephal*).mp. (2002) 340     ((Hyperleucine adj6 isoleucineaemia) or (Hyper Leucine adj6 isoleucine anemia)).mp. (0) 341     Striatonigral Degeneration/ (65) 342     ((Infantile adj3 Bilateral Striatal Necrosis) or (Striatonigral adj3 (Degeneration* or atroph*)) or (nigrostriatal adj3 degeneration)).mp. (1128) 343     Jacobsen Distal 11q Deletion Syndrome/ (50) 344     ((paris adj3 trousseau) or (11q23 adj3 (distal deletion or terminal deletion)) or (chromosome 11q adj3 deletion) or (jacobsen adj3 (thrombocytop?enia or syndrome))).mp. (185) 345     (((Molybdenum cofactor or Encephalopathy or Aldehyde Oxidase Combined) adj3 deficiency) or (Sulfite Oxidase adj3 Xanthine Dehydrogenase)).mp. (290) 346     Mucopolysaccharidosis VI/ (413) 347     ((Mucopolysaccharidosis adj3 (VI or type 6)) or (Mucopolysaccharidosis adj3 Aicardi) or (callosal adj3 agenesis) or (ocular adj3 abnormalit*) or (Maroteaux adj3 Lamy) or ((arylsulfatase b or arsb) adj3 deficienc*) or (dwarfism adj3 polydystrophic)).mp. (2887) 348     Mucopolysaccharidosis VII/ (251) 349     (Mucopolysaccharidosis VII or Mucopolysaccharidosis 7 or ((Beta glucuronidase or gusb) adj3 deficienc*) or (sly adj3 (disease or syndrome))).mp. (352) 350     Ornithine Carbamoyltransferase Deficiency Disease/ (844) 351     ((Ornithine Carbamoyltransferase or Ornithine Carbamoyl transferase) adj3 Deficienc*).mp. (865) 352     Lissencephaly/ (165) 353     (Pachygyria* or Lissencephal* or macrogyria* or agyria* or ((large or broad) adj3 gyri)).mp. (1615) 354     Sulfite Oxidase/df (33) 355     Sulfatidosis/ (0) 356     Sulfocysteinuria.mp. (1) 357     (Chromosome Deletion/ and Chromosomes, Human, Pair 79/) or (Chromosome Deletion/ and Chromosomes, Human, Pair 23/) or (Chromosome Deletion/ and Chromosomes, Human, Pair 24/) or (Chromosome Deletion/ and Chromosomes, Human, Pair 46/) (0) 358     (chromosome adj3 (deletion 79 or deletion 23q or deletion q24 or Deletion 46xx)).mp. (0) 359     Osteochondrodysplasias/mo (19) 360     ((Wolcott adj3 Rallison) or (Schwartz adj3 jampel) or (Myotonia adj3 chondrodystrophic) or (Stuve adj3 Wiedemann) or (osteochondrodysplasia* adj3 lethal) or Schimke immuno-osseous dysplasia or (lethal adj3 dyssegmental dysplasia) or Achondrogenesis I or Achondrogesis II or (Thanatophoric adj3 dwarfism)).mp. (547) 361     ((Pena adj3 Shokeir) or (Cerebrooculofacioskeletal adj3 syndrome) or (Arthrogryposis multiplex adj3 congenita) or COFS Syndrome).mp. (721) 362     Trisomy/ and Chromosomes, Human, Pair 10/ (183) 363     (Mosaicism adj3 Trisomy 10).mp. (9) 364     1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 58 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 78 or 80 or 81 or 82 or 83 or 84 or 85 or 86 or 87 or 88 or 90 or 92 or 93 or 94 or 95 or 96 or 97 or 98 or 99 or 100 or 101 or 102 or 103 or 104 or 105 or 106 or 107 or 108 or 109 or 110 or 111 or 112 or 113 or 114 or 115 or 116 or 117 or 118 or 119 or 120 or 121 or 122 or 123 or 124 or 125 or 126 or 127 or 128 or 129 or 130 or 131 or 132 or 133 or 134 or 135 or 136 or 137 or 138 or 139 or 140 or 141 or 142 or 143 or 144 or 145 or 146 or 147 or 148 or 149 or 150 or 151 or 152 or 153 or 154 or 155 or 156 or 157 or 158 or 159 or 160 or 161 or 162 or 163 or 164 or 165 or 166 or 167 or 168 or 169 or 170 or 171 or 173 or 174 or 175 or 176 or 177 or 178 or 179 or 180 or 181 or 182 or 183 or 184 or 185 or 187 or 188 or 190 or 191 or 192 or 193 or 194 or 195 or 196 or 197 or 198 or 199 or 200 or 201 or 202 or 203 or 204 or 205 or 206 or 207 or 208 or 209 or 210 or 211 or 212 or 213 or 214 or 215 or 216 or 217 or 218 or 219 or 220 or 221 or 222 or 223 or 224 or 225 or 227 or 229 or 230 or 231 or 232 or 233 or 234 or 235 or 236 or 237 or 238 or 239 or 240 or 241 or 242 or 243 or 244 or 245 or 246 or 247 or 248 or 249 or 250 or 251 or 252 or 253 or 254 or 256 or 258 or 259 or 260 or 261 or 262 or 263 or 264 or 265 or 266 or 267 or 268 or 269 or 270 or 271 or 272 or 273 or 274 or 275 or 276 or 277 or 278 or 279 or 280 or 282 or 283 or 284 or 285 or 286 or 287 or 288 or 289 or 290 or 292 or 293 or 294 or 295 or 296 or 297 or 298 or 299 or 300 or 301 or 302 or 303 or 304 or 305 or 306 or 307 or 308 or 309 or 310 or 311 or 312 or 313 or 314 or 315 or 316 or 317 or 318 or 319 or 321 or 323 or 324 or 325 or 326 or 327 or 328 or 329 or 330 or 331 or 332 or 333 or 334 or 335 or 336 or 337 or 338 or 339 or 340 or 341 or 342 or 343 or 344 or 345 or 346 or 347 or 348 or 349 or 350 or 351 or 352 or 353 or 354 or 355 or 356 or 357 or 358 or 359 or 360 or 361 or 362 or 363 (286895)  Symptom Management Search   365     ((practice adj3 guideline) or (health care adj3 quality) or (clinical adj3 handover) or (clinical adj3 (pathway or protocol)) or (consensus adj3 development) or (good adj3 clinical practice) or (nursing adj3 care plan) or (nursing adj3 protocol) or (refusal adj3 participate)).mp. (167722) 366     ((quality adj3 life) or (international classification adj3 functioning) or (quality adjusted adj3 life year)).mp. (236616) 367     (Management adj3 (manifestation* or comorbidity or co-morbidity)).mp. (1231) 368     Symptom Assessment/ (1307) 369     (Symptom* adj3 (assessment or evaluation or screening tool* or cluster* or control or management or intervention*)).mp. (32428) 370     Treatment Outcome/ or Treatment Failure/ (746573) 371     (treatment adj3 (outcome* or failure* or efficacy or effectiveness)).mp. (837759) 372     ((medical adj3 futility) or (outcome adj3 (management or assessment or measurement)) or (therapy adj3 outcome)).mp. (104073) 373     ((disease free adj3 (interval or period)) or (outcome adj3 assessment)).mp. (88680) 374     ((therapy adj3 failure) or (ineffective adj3 drug)).mp. (9653) 375     (clinical adj3 (effective* or efficacy or outcome*)).mp. (175344) 376     (tool* or trial* or guideline* or protocol*).mp. (2334802) 377     (Clinical rating adj3 (instrument* or tool or scale)).mp. (261) 378     Patient Acuity/ (453) 379     (patient adj3 acuit*).mp. (1489) 380     Severity of Illness Index/ (188269) 381     (illness index adj3 severit*).mp. (188317) 382     Karnofsky Performance Status/ (1959) 383     (karnofsky adj3 (index or scale or score)).mp. (2897) 384     Sickness Impact Profile/ (6447) 385     (sickness adj3 impact profile*).mp. (7163) 386     Therapeutics/ (8215) 387     (Therapeutic* or treatment* or intervention* or therapy).mp. (5585786) 388     Acoustic Stimulation/ (37593) 389     (stimulation adj3 (acoustic or auditory)).mp. (39449) 390     (((acoustic or audio) adj3 stimulus) or (sound adj3 stimulation)).mp. (1630) 391     airway management/ (1574) 392     (airway adj3 (control or management or extubation*)).mp. (8389) 393     ((breathing adj3 (control or regulation)) or (control adj3 (respiration or respiratory)) or (respiration adj3 regulation)).mp. (8556) 394     airway extubation/ or intubation, intratracheal/ (31519) 395     ((extubation* adj3 endotracheal) or (intubation adj3 (intratraceal or tracheal or endotracheal or orotracheal or trachea))).mp. (14484) 396     laryngeal masks/ (4508) 397     (laryngeal adj3 mask*).mp. (5641) 398     respiration, artificial/ (41225) 399     (artificial adj3 respiration*).mp. (41874) 400     (mechanical adj3 (ventilation* or respiration)).mp. (30508) 401     (controlled adj3 (respiration or ventilation)).mp. (3566) 402     high-frequency ventilation/ or high-frequency jet ventilation/ or liquid ventilation/ or noninvasive ventilation/ or one-lung ventilation/ (3684) 403     (ventilation* adj3 (high frequency or proportional assist or liquid or fluorocarbon or non invasive or noninvasive or one lung or one-lung or single lung)).mp. (11023) 404     interactive ventilatory support/ (127) 405     (interactive adj3 ventilatory support).mp. (128) 406     (neurally adjusted adj3 ventilatory assist).mp. (163) 407     (lung separation adj3 technique*).mp. (8) 408     positive-pressure respiration/ or continuous positive airway pressure/ or intermittent positive-pressure breathing/ (20740) 409     (positive pressure adj3 (respiration* or ventilation* or breathing)).mp. (19901) 410     (hyperbaric adj3 (respiration or ventilation)).mp. (42) 411     (end expiratory adj3 positive pressure*).mp. (27) 412     (airway pressure adj3 release ventilation).mp. (191) 413     (aprv adj3 ventilation mode).mp. (1) 414     intermittent positive-pressure ventilation/ (2108) 415     ((intermittent or inspiratory) adj3 positive pressure).mp. (3824) 416     ventilator weaning/ (3168) 417     ((ventilator or respirator) adj3 weaning).mp. (3561) 418     Tracheostomy/ (5997) 419     tracheostom*.mp. (13073) 420     Apitherapy/ (90) 421     (apitherap* or ((bee sting or bee venom or honey or propolis) adj3 therap*)).mp. (331) 422     balneology/ (5670) 423     (balneology or balneotherapy or balneo therapy or bath therapy).mp. (6027) 424     ammotherapy/ (32) 425     (((artificial or induced or treatment) adj3 hyperthermi*) or ((dry heat or fever or heat or infra red or infrared) adj3 therap*) or pyretotherapy or thermotherapy ammotherapy).mp. (19534) 426     baths/ (4847) 427     (sand bath* or sandbath* or bath).mp. (25802) 428     mud therapy/ (1311) 429     ((mud adj3 (bath* or pack* or application)) or fangotherapy or peat therapy or peloid therapy or pelotherapy).mp. (448) 430     steam bath/ (660) 431     ((bath adj3 (finnish or steam)) or sauna or sweat lodge).mp. (970) 432     Bed Rest/ (3642) 433     (bed rest* or bedrest*).mp. (6934) 434     Behavior control/ (1539) 435     (behavior?r adj3 (control or manipulation*)).mp. (0) 436     (behavior?r adj3 (control or manipulation*)).mp. (0) 437     Restraint, physical/ (10651) 438     ((physical adj3 restraint*) or (physical adj3 immobilization)).mp. (11486) 439     fecal microbiota transplantation/ (62) 440     (Fecal adj3 transplantation*).mp. (430) 441     (donor adj3 feces infusion*).mp. (2) 442     (intestinal adj3 microbiota transfer*).mp. (0) 443     Immunotherapy/ (32769) 444     (immunotherap* or (biologic* response adj3 modifier therapy) or ((immune or immunoglobulin or immunological) adj3 therapy)).mp. (80805) 445     Chronotherapy/ or Drug Chronotherapy.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (822) 446     (chronotherap* or (time dependent adj3 drug therapy)).mp. (1418) 447     Climatotherapy/ (532) 448     (((climate or climatic) adj3 therapy) or climatotherapy or thalassotherapy or climatic treatment).mp. (955) 449     Clinical Protocols/ or Antineoplastic Protocols/ or Antineoplastic Combined Chemotherapy Protocols/ (138009) 450     ((clinical or treatment or antineoplastic or cancer) adj3 protocol*).mp. (160721) 451     (((anticancer or antineoplastic) adj3 drug combinations) or ((combined antineoplastic adj3 agent*) or protocol* or regimens) or (cancer adj3 "chemotherapy protocol")).mp. (501755) 452     combined modality therapy/ (151424) 453     ((combined modality adj3 therap*) or (multimodal adj3 (treatment* or therapy)) or (multiple modality adj3 (therapy or treatment))).mp. (155297) 454     chemoradiotherapy/ or chemoradiotherapy, adjuvant/ or chemotherapy, adjuvant/ (38733) 455     (chemoradiotherap* or radiohemotherap* or chemoradiation).mp. (20364) 456     ((adjuvant adj3 (chemotherapy* or drug therapy or chemoradiotherap* or radiochemotherap* or radiotherapy*)) or (neoadjuvant adj3 chemotherapy)).mp. (67345) 457     electroacupuncture/ (2880) 458     (elctroacupuncture or electric acupunture).mp. (1) 459     photochemotherapy/ (14211) 460     (photochemotherap* or (photodynamic adj3 therap*) or (hematoporphyrin adj3 photoradiation)).mp. (19494) 461     neoadjuvant therapy/ (13369) 462     (neoadjuvant adj3 (therap* or treatment*)).mp. (17839) 463     radioimmunotherapy/ or radiotherapy, adjuvant/ (21420) 464     (radioimmunotherap* or immunoradiotherap* or (radioimmuno adj3 therapy) or (adjuvant adj3 radiotherapy)).mp. (27061) 465     complementary therapies/ (14930) 466     ((alternative adj3 (medicine or therap*)) or (complementary adj3 (medicine or therap*))).mp. (36416) 467     acupuncture therapy/ or acupuncture analgesia/ or acupuncture, ear/ or moxibustion/ (15268) 468     (acupuncture* or mox?bustion).mp. (22356) 469     auriculotherapy/ (30) 470     auriculotherap*.mp. (90) 471     diffuse noxious inhibitory control/ (13) 472     (diffuse noxious adj3 inhibitory control).mp. (105) 473     holistic health/ (7258) 474     ((holistic adj3 (health or medicine or therap*)) or (wholistic adj3 (health or medicine or therap*))).mp. (8135) 475     bioresonance therapy/ (0) 476     ((bioresonance or bio resonance or mora) adj3 therap*).mp. (29) 477     homeopathy/ (4330) 478     (hom#eopathy or homeopathia).mp. (381) 479     horticultural therapy/ (26) 480     (horticultural adj3 therap).mp. (0) 481     mesotherapy/ (51) 482     mesotherapy.mp. (191) 483     mind-body therapies/ (701) 484     (mind body adj3 (medicine or therap*)).mp. (1075) 485     aromatherapy/ (603) 486     ((aroma adj3 therap*) or aromatherap*).mp. (996) 487     ((aroma adj3 therap*) or aromatherap*).mp. (996) 488     biofeedback, psychology/ or neurofeedback/ (6943) 489     ((psychology or physiological or alpha or brainwave or elctroencephalography) adj3 biofeedback*).mp. (6558) 490     breathing exercises/ (2929) 491     (((breathing or respiratory) adj3 exercise*) or (respiratory adj3 muscle training) or ((breathing or chest physical or respiration) adj3 therapy) or chest physiotherapy).mp. (6254) 492     hypnosis/ (8494) 493     (hypnos#s* or hypnotherapy* or mesmerism).mp. (11281) 494     autogenic training/ (1024) 495     ((autogenic adj3 training) or (progressive adj3 muscle relaxation)).mp. (1535) 496     "imagery (psychotherapy)"/ (1348) 497     (imagery or (directed reverie adj3 therap*)).mp. (11123) 498     laughter therapy/ (142) 499     (laughter adj3 therapy).mp. (159) 500     meditation/ (1862) 501     meditation.mp. (3800) 502     relaxation therapy/ (5928) 503     (relaxation adj3 (technique* or therapy or training or method or technics)).mp. (8462) 504     yoga/ (1827) 505     yoga.mp. (3134) 506     musculoskeletal manipulations/ (1120) 507     ((musculoskeletal adj3 manipulation*) or ((manipulation or manipulative or manual) adj3 therap*)).mp. (5021) 508     kinesiology, applied/ (241) 509     (applied adj3 kinesiology).mp. (294) 510     manipulation, chiropractic/ or manipulation, osteopathic/ (1560) 511     (chiropractic or cheirotherapy or chiropraxi* or chirotherapy or osteopathic or osteopathy).mp. (11158) 512     therapy, soft tissue/ or acupressure/ or massage/ (5742) 513     ((soft tissue adj3 therapy) or massage or bodywork* or reflexology or rolfing or acupressure or (zone adj3 therap*)).mp. (13802) 514     naturopathy/ (903) 515     naturopath*.mp. (1263) 516     organotherapy/ (167) 517     organotherap*.mp. (202) 518     phytotherapy/ (32590) 519     (phytotherapy or ((herb or herbal) adj3 therapy)).mp. (33365) 520     reflexotherapy/ (452) 521     (reflex adj3 therapy).mp. (210) 522     sensory art therapies/ or art therapy/ (1268) 523     sensory art therapies/ or art therapy/ (1268) 524     (art adj3 (therap* or treatment)).mp. (11453) 525     color therapy/ (74) 526     (chrom#totherapy or colo#r therap*).mp. (9) 527     dance therapy/ or music therapy/ or play therapy/ (3859) 528     (((dance or music or play or sandplay) adj3 therap*) or jocotherapy).mp. (5906) 529     "continuity of patient care"/ (15790) 530     (care adj3 (continuity or continuum)).mp. (21027) 531     patient discharge/ (21738) 532     ((patient or planning* or hospital) adj3 discharge).mp. (46697) 533     patient handoff/ (482) 534     (((clinical or patient or nursing) adj3 handoff*) or ((clinical or patient or nursing) adj3 hand off*) or ((clinical or patient or nursing) adj3 handover*) or ((clinical or patient or nursing) adj3 hand over*)).mp. (925) 535     patient transfer/ (6360) 536     ((patient adj3 (transfer* or transition* or turfing* or transport or transportation)) or (care adj3 transition*)).mp. (14755) 537     transition to adult care/ (515) 538     ((transition or pe#diatric or transfer* or hand over or handoff) adj3 adult care).mp. (697) 539     transitional care/ (43) 540     (transitional adj3 care*).mp. (839) 541     Cryotherapy/ or Hypothermia, Induced/ (22312) 542     (((cold or cryogenic) adj3 therap*) or cryotherap* or ((cold or hypothermal) adj3 bath) or cryothermy or cryotreatment).mp. (8943) 543     ((induced or therapeutic) adj3 hypothermia).mp. (22010) 544     Directly Observed Therapy/ (1374) 545     (directly adj3 observed therapy).mp. (1941) 546     Drainage/ or Drainage, Postural/ or Negative-Pressure Wound Therapy/ or Paracentesis/ (40432) 547     (drainage or (vacuum assisted adj3 closure*) or (negative pressure adj3 (dressing* or therap*))).mp. (93557) 548     ((aspiration adj3 puncture) or centes#s).mp. (665) 549     Drug Therapy/ (28831) 550     ((drug adj3 (therap* or treatment)) or chemotherap* or pharmacotherap* or ((medicament or medicinal or orthomolecular or pharmaceutical or phadrarmaco or pharmacological) adj3 therapy) or ((medicament or medicinal or orthomolecular or pharmaceutical or pharmaco or pharmacological) adj3 treatment) or medication).mp. (815419) 551     Chelation Therapy/ (1239) 552     (chelation adj3 therap*).mp. (2967) 553     Chemoprevention/ or Antibiotic Prophylaxis/ (15932) 554     (chemoprevention or chemoprophylaxis or ((tuberculosis or tuberculous) adj3 chemoprophylasis) or (antibiotic adj3 (premedication* or prophylaxis))).mp. (32816) 555     Consolidation Chemotherapy/ (243) 556     (consolidation adj3 chemotherap*).mp. (1384) 557     drug administration routes/ or administration, inhalation/ (30898) 558     ((aerosol adj3 therapy) or (inhalat* adj3 (drugs or dose or administration or therapy or treatment)) or inhalational or vapo#r therapy).mp. (44654) 559     administration, intravenous/ or infusions, intravenous/ or injections, intravenous/ (130749) 560     ((intravenous adj3 (injection* or administration* of infusion* or dose or drip or therapy or medication or transfuction)) or (IV adj3 (administration or delivery or injection or therapy or infusion))).mp. (150453) 561     ((drip or intravenous or intracerebroventricular or intraventricular or spinal or subcutaneous) adj3 infusion*).mp. (79770) 562     administration, oral/ or administration, buccal/ or administration, sublingual/ or administration, topical/ or administration, cutaneous/ or administration, intravaginal/ or administration, intravesical/ or administration, mucosal/ or administration, intranasal/ or administration, rectal/ or administration, ophthalmic/ (191712) 563     ((oral or buccal or sublingual or "sub lingual" or ocular or ophthalmic or mucosal or transmucosal or bladder drug or intravesical or intra vesical or intravaginal or vaginal or intra vaginal or cutaneous or dermal or intradermal or percutaneous or transcutaneous or transdermal or skin drug or topical or topic or intranasal or nasal or anal or rectal or subcutaneous fluid) adj3 administration*).mp. (235491) 564     ((transmucosal adj3 routing*) or (mucosal adj3 (delivery or dosage or dose or injection or therapy or treatment)) or (transmucosal adj3 (delievery or dosage))).mp. (2154) 565     ((bladder or injection* or intravesical or drug) adj3 instillation*).mp. (3575) 566     (vaginal adj3 instillation*).mp. (38) 567     chemotherapy, cancer, regional perfusion/ (3381) 568     (cancer chemotherapy adj3 (regional perfusion or isolation perfusion)).mp. (10) 569     infusions, parenteral/ or infusions, intra-arterial/ or infusions, intralesional/ or infusions, intraosseous/ or infusions, intraventricular/ or infusions, spinal/ or infusions, subcutaneous/ or hypodermoclysis/ (36662) 570     ((intra abdominal or intraperitoneal or parenteral or peritoneal or intra arterial or intraarterial or regional aterial or intralesional or intra osseous or intraosseous) adj3 infusion*).mp. (38419) 571     ((subcutaneous adj3 hydration) or hypodermoclysis).mp. (201) 572     (cheek injection or (cheek adj3 drug delivery) or (buccal adj3 (dosage or dose or injection))).mp. (112) 573     ((topic adj3 (application or medication or therapy or treatment)) or topical).mp. (93946) 574     ((intravaginal adj3 (dosage or dose or drug deliver or injection or suppository or tablet or therapy or treatment)) or (vaginal adj3 (administration or dosage or dose or application or delivery or infusion or injection or suppository))).mp. (12349) 575     ((intra vesical adj3 instillation) or (intravesical adj3 (administration or application or delivery or dose or injection or instillation or medication or therapy or treatment))).mp. (4910) 576     injections/ or injections, intra-arterial/ or injections, intra-articular/ or viscosupplementation/ or injections, intralesional/ or injections, intralymphatic/ or injections, intramuscular/ or injections, intraocular/ or intravitreal injections/ or injections, intraperitoneal/ or injections, intraventricular/ or injections, spinal/ or injections, epidural/ or blood patch, epidural/ or injections, subcutaneous/ or injections, intradermal/ or injections, jet/ or biolistics/ or injection, intratympanic/ or microinjections/ (192911) 577     (injection* or injectable* or viscocupplementation* or microinjection* or epidural or biolistic*).mp. (694443) 578     (gene gun adj3 technique).mp. (13) 579     (partical mediated or ((epidermal or extradural) adj3 injection*)).mp. (179) 580     ((transtympanic adj3 administration*) or (intratypanic adj3 injection*)).mp. (39) 581     (phonophores#s or iontophores#s).mp. (8860) 582     Drug Administration Schedule/ (89362) 583     (drug schedule* adj3 administration).mp. (1) 584     Administration, Metronomic/ (166) 585     (metronomic adj3 (administration* or therap*)).mp. (316) 586     Pulse Therapy, Drug/ (1369) 587     (drug pulse adj3 therap*).mp. (3) 588     Drug Delivery System/ (42162) 589     (drug delivery adj3 system*).mp. (50445) 590     (drug adj3 targeting*).mp. (4688) 591     Delayed-Action Preparations/ (30225) 592     ((drug release or delayed action or depot or sustained release or timed release or prolonged action) adj3 preparation*).mp. (30884) 593     Drug carriers/ (28423) 594     (drug adj3 carrier*).mp. (32083) 595     Dendrimers/ (3591) 596     ((dendritic adj3 compound) or dendrimer* or dendrons or (dendritic adj3 polymer*)).mp. (6943) 597     Nanocapsules/ or Nanoconjugates/ (2704) 598     (nanocapsule or nanoconjugate).mp. (537) 599     Insulin Infusion Systems/ (4184) 600     ((artificial endocrine adj3 pancreas) or (artificial beta adj3 cell*) or (insulin infusion adj3 system*) or (programmable implantable adj3 insulin infusion)).mp. (4477) 601     Pharmaceutical Vehicles/ (4540) 602     (pharmaceutical adj3 vehicle*).mp. (4591) 603     (drug adj3 prescribing*).mp. (1776) 604     Drug substitution/ (1779) 605     ((drug adj3 (substitution* or switching*)) or ((generic or therapeutic) adj3 subsititution*)).mp. (2594) 606     "Off-label use"/ (1494) 607     ((unlabeled adj3 indication*) or (off label adj3 (prescribing* or use* or prescribing))).mp. (3883) 608     Drug therapy, Combination/ (146283) 609     ((combination adj3 (drug therapy or chemotherapy* or medication or pharmacotherapy)) or (drug adj3 (polytherap* or combinations)) or polychemotherap* or (combination drug adj3 (regimen or treatment)) or (combined drug adj3 (regimen or therapy or treatment)) or (multi drug adj3 (regimen or therapy)) or (multidrug adj3 (regimen or therapy)) or (multiple drug adj3 (regimen or therapy or treatment))).mp. (234598) 610     Antiretroviral Therapy, Highly Active/ (18158) 611     (antiretroviral therapy adj3 highly active).mp. (21863) 612     enema/ (6710) 613     (enema* or clysma or clyster or enteroclysis).mp. (12376) 614     Drug Therapy, Computer-Assisted/ (1535) 615     (computer assisted adj3 drug therap*).mp. (1540) 616     Electrochemotherapy/ (378) 617     (electrochemotherap* or (electropermeablisation adj3 therap*)).mp. (664) 618     instillation, drug/ or iontophoresis/ (8407) 619     ((instillation adj3 drug) or iontophoresis).mp. (9973) 620     phonophoresis/ (280) 621     (phonophoresis or ultrasound or ultrasonic or sonication or sonification or ultra sound or ultrashell).mp. (218760) 622     Enzyme Therapy/ or Enzyme Replacement Therapy/ (1257) 623     ((enzyme adj3 (therap* or suppletion)) or enzymotherapy).mp. (6051) 624     Fluid Therapy/ (16705) 625     ((fluid or oral rehydration) adj3 therap*).mp. (19349) 626     Hypodermoclysis/ (98) 627     ((subcutaneous adj3 (fluid administration or hydration)) or hypodermoclys#s).mp. (212) 628     Home Infusion Therapy/ (637) 629     ((home infusion or outpatient infusion) adj3 therap*).mp. (720) 630     Hormone Replacement Therapy/ (8274) 631     (hormone adj3 (replacement or substitution)).mp. (20284) 632     Estrogen Replacement Therapy/ (14316) 633     (#estrogen adj3 (replacement* or administration or substitution or therapy)).mp. (1079) 634     Induction Chemotherapy/ (1217) 635     Maintenance Chemotherapy/ (753) 636     ((induction or maintenance) adj3 chemotherap*).mp. (9564) 637     Medication Reconciliation/ (512) 638     ((medication adj3 reconciliation) or ((drug or medication) adj3 management)).mp. (7731) 639     Near Miss, Healthcare/ (9) 640     (healthcare adj3 (near miss* or close call*)).mp. (12) 641     Molecular Targeted Therapy/ (14405) 642     (target* adj3 therap*).mp. (132449) 643     Orthomolecular Therapy/ (194) 644     ((megavitamin or orthomolecular) adj3 therap*).mp. (240) 645     Photochemotherapy/ (14211) 646     (photochemotherap* or chemophototherapy or (photodynamic adj3 therap*) or (hematoporphyrin adj3 photoradiation)).mp. (19495) 647     Pleurodesis/ (1196) 648     Pleurodesis.mp. (2318) 649     Polypharmacy/ or Deprescriptions/ (2929) 650     (polypharmacy or poly pharmacy or polypragmas* or deprescribing or deprescription*).mp. (5911) 651     Premedication/ or Antibiotic Prophylaxis/ (23099) 652     (premedication* or (antibiotic adj3 (prophylaxis or prevention)) or pretreatment or (preanaesthetic adj3 (treatment or medication))).mp. (178205) 653     Sclerotherapy/ (4629) 654     (sclerotherap* or sclero#ation or sclerosing therapy).mp. (7591) 655     self administration/ (9872) 656     (self adj3 administration*).mp. (13235) 657     Self Medication/ (4217) 658     (self adj3 medication*).mp. (7461) 659     Thrombolytic Therapy/ or Hirudin Therapy/ (20684) 660     (((fibrinolytic or hirudin) adj3 therap*) or (therapeutic adj3 thrombolys#s) or (anticoagula* adj3 (therapy or treatment))).mp. (21730) 661     electric stimulation therapy/ (18018) 662     (((electric stimulation or electrostimulation) adj3 therap*) or electrotherap*).mp. (18636) 663     cardiac pacing, artificial/ (19295) 664     ((artificial cardiac or biventricular) adj3 pacing*).mp. (1460) 665     cardiac resynchronization therapy/ (2390) 666     ((cadiac adj3 resynchronic#ation*) or (biventricular adj3 pacing)).mp. (1415) 667     deep brain stimulation/ (5714) 668     (((brain adj3 stimulation*) or electrical stimulation) adj3 brain).mp. (13843) 669     electric countershock/ (13049) 670     ((cardiac adj3 electroversion*) or cardioversion* or (electric* adj3 (countershock or cadioconversion)) or (electric adj3 defibrillation)).mp. (15280) 671     pulsed radiofrequency treatment/ (170) 672     ((pulsed radio adj3 frequency treatment) or (pulsed radiofrequency adj3 treatment*)).mp. (277) 673     spinal cord stimulation/ (353) 674     (spinal adj3 stimulation).mp. (3660) 675     transcranial direct current stimulation/ (454) 676     ((transcranial direct adj3 current stimulation) or (transcranial adj3 electric stimulation)).mp. (2107) 677     transcutaneous electric nerve stimulation/ (3707) 678     ((transcutaneous electric* adj3 nerve stimulation) or (percutaneous electric* adj3 nerve stimulation) or ((analgesic cutaneous or transcutaneous or transdermal) adj3 electrostimulation) or electroanalgesia).mp. (4500) 679     vagus nerve stimulation/ (807) 680     ((vagal or vagus) adj3 nerve stimulation*).mp. (2494) 681     emergency treatment/ (9177) 682     (emergency adj3 (therap* or treatment*)).mp. (16567) 683     advanced trauma life support care/ (87) 684     (advanced trauma adj3 life support).mp. (637) 685     first aid/ (7238) 686     (first adj3 aid*).mp. (10681) 687     heimlich maneuver/ (13) 688     ((abdominal adj3 thrust*) or (Heimlich adj3 man#euver)).mp. (34) 689     resuscitation/ (23335) 690     resuscitation*.mp. (58915) 691     cardiopulmonary resuscitation/ or advanced cardiac life support/ (13277) 692     (((basic cardiac or advanced cardiac) adj3 life support) or ((cardio pulmonary or cardiopulmonary) adj3 resuscitation) or (mouth adj3 mouth resuscitation*)).mp. (18735) 693     ((cardiac or heart) adj3 massage*).mp. (3415) 694     respiration, artificial/ (41225) 695     ((artificial adj3 respiration) or (mechanical adj3 ventilation*)).mp. (59676) 696     resuscitation orders/ (3330) 697     ((resuscitation adj3 (order* or decision* or polic*)) or (do adj3 resuscitate order*) or (withholding adj3 resuscitation)).mp. (4059) 698     "transportation of patients"/ (8361) 699     (patient* adj3 (transportion* or transport or transfer)).mp. (12299) 700     Feeding Methods/ (800) 701     (feeding adj3 method*).mp. (2651) 702     Bottle Feeding/ (3422) 703     ((bottle adj3 feeding) or bottlefeeding*).mp. (4373) 704     Enteral Nutrition/ (16782) 705     ((enter* adj3 (feeding or nutrition)) or ((force or tube*) adj3 feeding) or (gastric adj3 feeding tube*) or (feeding adj3 (intestinal or intragastric))).mp. (24213) 706     Parenteral Nutrition/ or Parenteral Nutrition, Home/ or Parenteral Nutrition, Home Total/ or Parenteral Nutrition, Total/ (22059) 707     (((intravenous or parenteral) adj3 feeding*) or (parenteral adj3 nutrition)).mp. (28816) 708     (hyperalimentation adj3 (parenteral or intravenous)).mp. (866) 709     hyperthermia, induced/ (13795) 710     ((fever adj3 therap*) or (hyperthermia adj3 (induced or local or therapeutic)) or thermotherapy).mp. (19093) 711     diathermy/ (3322) 712     (diatherm* or elctrodiathermy or (high frequency adj3 (current therapy or electrotherapy or therapy))).mp. (5684) 713     short-wave therapy/ or ultrasonic therapy/ (8784) 714     ((short wave or shortwave or ultrasonic) adj3 therap*).mp. (8958) 715     ultrasound, high-intensity focused, transrectal/ (414) 716     high-intensity focused ultrasound ablation/ (885) 717     (high intensity adj3 focused ultrasound).mp. (2268) 718     Leeching/ (298) 719     (hirudotherapy or leeching or (leech adj3 therap*)).mp. (461) 720     Magnetic Field Therapy/ (779) 721     ((magnetic field or magnetic stimulation) adj3 therap*).mp. (1060) 722     Transcranial Magnetic Stimulation/ (7985) 723     (transcranial adj3 magnetic stimulation*).mp. (11803) 724     Mechanical Thrombolysis/ (407) 725     ((mechanical adj3 (clot disruption* or thrombolysis or thrombectomy or embolectomy)) or (pharmacomechanical adj3 thrombectomy)).mp. (1740) 726     nutrition therapy/ or diet therapy/ (11126) 727     (((nutrition or diet or dietary) adj3 therap*) or ((nutrition or diet or dietary) adj3 treatment)).mp. (26884) 728     caloric restriction/ or diet, diabetic/ or diet, carbohydrate-restricted/ or diet, fat-restricted/ or diet, gluten-free/ or diet, mediterranean/ or diet, paleolithic/ or diet, protein-restricted/ or diet, reducing/ or diet, sodium-restricted/ or diet, vegetarian/ or diet, macrobiotic/ or diet, vegan/ or ketogenic diet/ or nutritional support/ (41172) 729     ((caloric adj3 restriction) or (diet* adj3 (low calorie or diabetic or carbohydrate restricted or atkins or south beach or low carbohydrate or fat free or fat restricted or low fat or gluten free or Mediterranean or caveman or hunter gatherer or paleo or Paleolithic or stone age or low protein or protein free or reducing or weight loss or weight reduction or low salt or low sodium or salt free or sodium restricted or vegetarian or macrobiotic or vegan or ketogenic or supplementation))).mp. (66009) 730     ((artificial adj3 feeding) or (nutritional adj3 support)).mp. (11828) 731     orthopedic procedures/ (20226) 732     (orthopedic adj3 (procedure* or surger* or operation)).mp. (26217) 733     cementoplasty/ (68) 734     (cementoplast* or (osteoplast* adj3 percutaneous)).mp. (187) 735     vertebroplasty/ (1421) 736     vertebroplasty.mp. (2859) 737     kyphoplasty/ (496) 738     ((balloon adj3 vetebroplasty) or kyphoplasty).mp. (1369) 739     intervertebral disc chemolysis/ (459) 740     ((intervertebral adj3 dis# chemolysis) or chemonucleolys#s or discolys#s).mp. (797) 741     manipulation, orthopedic/ (3633) 742     (orthop#edic adj3 manipulation).mp. (7) 743     viscosupplementation/ (102) 744     viscocupplementation*.mp. (0) 745     Pain Management/ (23239) 746     ((pain adj3 (management* or relief)) or ((audio or sequential analgetic or surgical) adj3 analgesia) or audioanalgesia).mp. (66195) 747     patient care/ or ambulatory care/ (45981) 748     ((patient or informal or after or ambulatory or outpatient or urgent or advance) adj3 care*).mp. (267906) 749     aftercare/ (6862) 750     ((after adj3 treatment*) or aftercare or after care).mp. (317618) 751     ((clinic adj3 visit*) or (outpatient adj3 health service*)).mp. (10094) 752     peritoneal dialysis, continuous ambulatory/ (9633) 753     (continuous ambulatory adj3 peritoneal dialysis).mp. (10704) 754     "bloodless medical and surgical procedures"/ (112) 755     (((blood conservation or transfusion alternative) adj3 strateg*) or (bloodless medical adj3 (surgical procedures or surgery programs)) or ((bloodless or transfusion free) adj3 surger*)).mp. (525) 756     critical care/ (42672) 757     ((critical or intensive) adj3 care).mp. (159935) 758     intensive care, neonatal/ (4660) 759     ((neonatal or infant or newborn) adj3 intensive care).mp. (22358) 760     custodial care/ or day care, medical/ (5035) 761     ((custodial or day) adj3 care).mp. (14382) 762     (partial adj3 hospitalization).mp. (335) 763     "episode of care"/ (1563) 764     (care adj3 episode*).mp. (2966) 765     hospitalization/ (80771) 766     hospitalization*.mp. (156067) 767     "length of stay"/ (66073) 768     ((hospital adj3 stay*) or (stay* adj3 length*)).mp. (124410) 769     patient admission/ (20041) 770     ((patient or voluntary) adj3 admission).mp. (23279) 771     patient discharge/ (21738) 772     ((patient or hospital) adj3 discharge).mp. (45891) 773     patient readmission/ (10100) 774     readmission*.mp. (18514) 775     institutionalization/ or deinstitutionalization/ (8012) 776     (institutionalization or institutionalized or deinstitutionalization or deinstitutionalized).mp. (18083) 777     life support care/ (7219) 778     ((life support adj3 care) or (extraordinary adj3 treatment*) or (life adj3 prolongation)).mp. (8748) 779     advanced cardiac life support/ or advanced trauma life support care/ (870) 780     (advanced trauma adj3 life support).mp. (637) 781     long-term care/ (22903) 782     (long term adj3 care).mp. (34157) 783     night care/ (1341) 784     (night adj3 care*).mp. (1499) 785     home nursing/ (8219) 786     (home care or home nursing).mp. (50054) 787     respite care/ (922) 788     (respite adj3 care*).mp. (1315) 789     primary care nursing/ (266) 790     (primary care adj3 nursing).mp. (570) 791     palliative care/ (44133) 792     (palliative adj3 (care or surger* or therap* or treatment*)).mp. (57265) 793     "Hospice and Palliative Care Nursing"/ or Palliative Care Nursing/ (212) 794     (palliative adj3 nursing).mp. (662) 795     Palliative medicine/ or Palliative Care Medicine/ (88) 796     (palliative adj3 medicine).mp. (1594) 797     patient positioning/ (3364) 798     (patient adj3 positioning*).mp. (5809) 799     kangaroo-mother care method/ (145) 800     ((Kangaroo mother adj3 care) or (skin adj3 skin care)).mp. (6542) 801     perinatal care/ or postnatal care/ (7509) 802     (perinatal adj3 (care or medicine)).mp. (6107) 803     ((postnatal or postpartum) adj3 care).mp. (5937) 804     perioperative care/ or intraoperative care/ or perioperative nursing/ (30562) 805     ((perioperative or intraoperative or postoperative or preoperative or intraoperative) adj3 care).mp. (125003) 806     ((perianesthesia or perioperative) adj3 nursing).mp. (6644) 807     preoperative care/ or postoperative care/ (97200) 808     (postoperative adj3 (procedure* or therapy or treatment)).mp. (18963) 809     (preoperative adj3 (procedure* or therapy or treatment)).mp. (9252) 810     subacute care/ (759) 811     (("sub acute" or subacute) adj3 care*).mp. (1093) 812     Terminal Care/ (22955) 813     ((life care adj3 end*) or (terminal adj3 care)).mp. (26321) 814     hospice care/ (5074) 815     (hospice adj3 (care or program*)).mp. (7706) 816     time-to-treatment/ (1795) 817     (time adj3 (treatment* or time)).mp. (3176095) 818     transitional care/ (43) 819     (transitional adj3 care).mp. (827) 820     Euthanasia/ or Euthanasia, Active/ or Euthanasia, Active, Voluntary/ or Euthanasia, Passive/ (12848) 821     (euthanasia or mercy killing*).mp. (25217) 822     withholding treatment/ (9844) 823     ((withholding adj3 treatment) or ((cessation or withdraw*) adj3 treatment)).mp. (21925) 824     Suicide, Assisted/ (4970) 825     (assisted adj3 (death* or suicide)).mp. (5577) 826     Patient Care Bundles/ (138) 827     care bundles.mp. (287) 828     phototherapy/ (6297) 829     (phototherap* or ((light or photoradiation or ultraviolet or sunlight) adj3 therap*)).mp. (19044) 830     heliotherapy/ (443) 831     Heliotherapy.mp. (501) 832     intense pulsed light therapy/ (70) 833     (intense pulsed adj3 (therap* or treatment)).mp. (201) 834     low-level light therapy/ (3723) 835     ((low level adj3 (light therap* or laser irradiation or laser therap*)) or ((biostimuation or phototherapy) adj3 laser) or (low power adj3 (light therap* or laser irradiation or laser therap*))).mp. (4584) 836     hematoporphyrin photoradiation/ (636) 837     ((hematoporphyrin adj3 photoradiation) or photochemotherapy or chemophototherapy).mp. (15589) 838     ultraviolet therapy/ (4065) 839     ((ultraviolet adj3 therap*) or actinotherap*).mp. (4468) 840     puva therapy/ (3294) 841     ((puva adj3 (therap* or radiation)) or (psoralen ultraviolet adj3 a therapy)).mp. (3645) 842     photopheresis/ (752) 843     ((extracorporeal adj3 photochemotherap*) or photopheresis).mp. (1115) 844     physical therapy modalities/ (31080) 845     ((physical therapy adj3 (modalit* or technique*)) or neurophysiotherapy or (neurological adj3 physiotherapy)).mp. (31337) 846     animal assisted therapy/ or equine-assisted therapy/ (266) 847     (((animal or pet) adj3 assisted therap*) or (per adj3 therap*) or ((animal or pet) adj3 facilitated therap*)).mp. (2125) 848     ((equine assisted adj3 (psychotherap* or therap*)) or hippotherap* or (horseback riding adj3 therap*)).mp. (199) 849     exercise movement techniques/ (480) 850     kinesiotherapy.mp. (121) 851     qigong/ (54) 852     (Qigong or ch'I king or qi gong or chi kung or chigung).mp. (535) 853     dance therapy/ (244) 854     dance therap*.mp. (274) 855     tai ji/ (737) 856     (tai ji or tai chi or (tai adj3 ji quan) or t'ai chi or (tai chi adj3 chuan) or taijiqua).mp. (1166) 857     exercise therapy/ (29984) 858     (exercise adj3 (therap* or techniques or treatment)).mp. (35677) 859     motion therapy, continuous passive/ (596) 860     motion therap*.mp. (674) 861     muscle stretching exercises/ (1116) 862     ((stretching adj3 exercises) or ((active or ballistic or dynamic or isometric or passive or relaxed) adj3 stretching)).mp. (2291) 863     plyometric exercise/ (163) 864     ((stretch shortening adj3 (drill* or exercise*)) or plyometric*).mp. (618) 865     resistance training/ (4500) 866     ((resistance adj3 training) or ((weight lifting or weight bearing) adj3 exercise program) or (strength adj3 training)).mp. (10845) 867     hydrotherapy/ (2365) 868     (hydrotherap* or (whirlpool adj3 bath*) or (water immersion adj3 therapy)).mp. (2714) 869     therapeutic irrigation/ (15946) 870     ((therapeutic adj3 irrigation) or douching* or lavage*).mp. (64050) 871     manipulation, spinal/ (1263) 872     ((spinal or cervical or lumbar) adj3 manipulation*).mp. (2421) 873     myofunctional therapy/ (264) 874     ((myofunction adj3 therap*) or ((oral or orofacial) adj3 myotherap*)).mp. (3) 875     Placebos/ (33210) 876     (placebo* or (sham adj3 treatment)).mp. (190231) 877     Rehabilitation/ (17110) 878     (rehabilitation or habilitation).mp. (135266) 879     Activities of Daily Living/ (53891) 880     ((daily living adj3 activit*) or (chronic limitation adj3 activit*)).mp. (63638) 881     Bibliotherapy/ (365) 882     Bibliotherap*.mp. (473) 883     Correction of hearing impairment/ (1761) 884     ((audiologic adj3 (habilitation* or rehabilition*)) or (aural adj3 (habilitation* or rehabilition*)) or (hearing adj3 (habilitation* or rehabilition* or revalidation))).mp. (45) 885     Communication Methods, Total/ (276) 886     (Total adj3 communication method*).mp. (278) 887     Lipreading/ (920) 888     (lipreading or lip reading* or speechreading*).mp. (1284) 889     Sign language/ (1807) 890     sign language*.mp. (2258) 891     Manual Communication/ (513) 892     (manual adj3 communication*).mp. (593) 893     Early Ambulation/ (2314) 894     (((early or accelerated) adj3 ambulation) or (early adj3 mobilization)).mp. (5166) 895     Neurological Rehabilitation/ (19) 896     ((neurologic adj3 rehabilitation) or neurorehabilitation).mp. (1939) 897     Occupational Therapy/ (11244) 898     ((occupational adj3 therap*) or ergotherapy).mp. (16172) 899     Recreation Therapy/ (78) 900     ((recreational or recreation) adj3 therap*).mp. (435) 901     "Rehabilitation of Speech and Language Disorders"/ (0) 902     ((speech adj3 (rehabilitation or reeduction)) or (voice adj3 (reeducation or rehabilitation))).mp. (1041) 903     Language Therapy/ (1445) 904     (language adj3 (therap* or training*)).mp. (3366) 905     Speech, Alaryngeal/ (1375) 906     (alaryngeal adj3 (speech or voice)).mp. (1421) 907     Speech, Esophageal/ (622) 908     (#esophag* adj3 (speech* or voice)).mp. (860) 909     Speech, Therapy/ (5640) 910     ((speech adj3 (therap* or education or training)) or (language adj3 (learning or therapy or training)) or (logopedic adj3 (education or training)) or logotherapy or phoniatrics or phoniatry).mp. (12339) 911     Voice Training/ (1214) 912     (voice adj3 training*).mp. (1306) 913     Telereganilitation/ (0) 914     ((remote or virtual or tele) adj3 rehabilitation*).mp. (262) 915     Respiratory Therapy/ (6036) 916     ((respiratory or inhalation) adj3 therapy).mp. (21884) 917     Chest Wall Oscillation/ (237) 918     ((high frequency adj3 chest compression) or (chest wall adj3 oscillation*)).mp. (295) 919     Extracorporeal Membrane Oxygenation/ (6574) 920     ((extracorporeal or extra corporeal or extrapulmonary) adj3 oxygenation).mp. (8748) 921     Oxygen Inhalation Therapy/ (12564) 922     (oxygen adj3 (therap* or administration or insufflation or treatment)).mp. (23103) 923     Hyperbaric Oxygenation/ (10589) 924     ((hyperbaric adj3 (oxygenation* or o2 or oxygen therapy)) or ((high adj3 oxygen pressure) or tension o2 or tension oxygen)).mp. (11618) 925     Self Care/ (26463) 926     (self adj3 (care or management or treatment)).mp. (44912) 927     Blood Glucose Self-Monitoring/ (4838) 928     ((blood glucose or blood sugar) adj3 self monitoring).mp. (5568) 929     Self Administration/ (9872) 930     (self adj3 administration*).mp. (13235) 931     Self Medication/ (4217) 932     (self adj3 medication*).mp. (7461) 933     Therapies, Investigational/ (1177) 934     (((experimental or innovative or investigational) adj3 therap*) or ((experimental or innovative or investigational) adj3 treatment*)).mp. (24082) 935     "Compassionate Use Trials"/ (335) 936     (expanded access* or compassionate use* or (humanitarian adj3 device exemption*)).mp. (1632) 937     Therapy, Computer-Assisted/ or Radiotherapy Planning, Computer-Assisted/ (20604) 938     (computer assisted adj3 (protocol directed or therapy or dosimetry calculation* or radiotherapy or drug therapy)).mp. (23406) 939     Surgery, Computer-Assisted/ (11922) 940     ((computer aided or computer assisted or image guided) adj3 surger*).mp. (13086) 941     Robotic Surgical Procedures/ (1136) 942     (robotic surgical adj3 procedure*).mp. (1177) 943     Therapy with Helminths/ (50) 944     ((helminthic or helminth or worm) adj3 therap*).mp. (191) 945     or/365-944 (10516979) 946     364 and 945 (95446)   Alertness Symptom Search  947     arousal/ or attention/ or wakefulness/ (101709) 948     fatigue/ or mental fatigue/ (22958) 949     Torpor/ (63) 950     (mental adj3 fatigue*).mp. (1979) 951     (cortical adj3 vigilance).mp. (23) 952     (concentration adj3 (less or lack or reduce* or mental)).mp. (17042) 953     (alertness* or attention* or fatigue* or arousal* or wakeful* or torpor or lassitude).mp. (463225) 954     letharg*.mp. (6326) 955     fatigability.mp. (1766) 956     (awareness or consciousness or distractab* or dysthymia).mp. (140947) 957     or/946-955 (614354) 958     946 and 956 (3989)  959     limit 957 to "all child (0 to 18 years)" (1697) 960     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 961     957 and 959 (2007) 962     958 or 960 (2007)  Behaviour Symptom Search  947     Behavioral Symptoms/ (2034) 948     Psychomotor Agitation/ (4286) 949     Irritable Mood/ (1272) 950     self-injurious behavior/ or self mutilation/ (8628) 951     (behavio?r* adj3 (symptom* or disturbance* or change)).mp. (33127) 952     (psychomotor adj3 (excitement or hyperactivity)).mp. (76) 953     (body adj2 rocking).mp. (96) 954     (head adj2 banging).mp. (126) 955     agitation.mp. (14279) 956     akathisia.mp. (2489) 957     restless*.mp. (7219) 958     irritabil*.mp. (7235) 959     aggress*.mp. (168145) 960     antagonistic.mp. (24929) 961     destructive*.mp. (25892) 962     parasuicide.mp. (464) 963     (self adj3 (injur* or destructive or harm or mutilat*)).mp. (13954) 964     ((flat or negative) adj3 affect).mp. (6898) 965     or/947-964 (293813) 966     946 and 965 (2190)  967     limit 966 to "all child (0 to 18 years)" (878) 968     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 969     966 and 968 (1035) 970     967 or 969 (1035)  Bowel Incontinence Symptom Search  947     Fecal Incontinence/ (8443) 948     Feces/ (76546) 949     Defecation/ (6117) 950     Diarrhea/ (41675) 951     Gastrointestinal Motility/ (19976) 952     (defecate* or diarrh* or f#eces).mp. (112801) 953     ((symptom or function* or habit* or movement* or strain*) adj3 bowel).mp. (8874) 954     (f#ecal* adj3 (incontin* or evacuat*)).mp. (1718) 955     loose stool*.mp. (852) 956     ((intestin* or gastrointestin* or stomach) adj3 motility).mp. (23055) 957     (colon adj3 transit*).mp. (432) 958     or/947-957 (212123) 959     946 and 958 (1126)  960     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 961     959 and 960 (722) 962     limit 959 to "all child (0 to 18 years)" (652) 963     961 or 962 (722)  Breathing Difficulty Symptom Search  947     mucus/se or saliva/se (5660) 948     respiratory insufficiency/ or hypoventilation/ or hyperventilation/ (35045) 949     (hypoventilation* or hyperventilation).mp. (14497) 950     Dyspnea/ (16973) 951     Cough/ (13323) 952     cough*.mp. (47784) 953     Apnea/ (6627) 954     airway obstruction/ or nasal obstruction/ (21025) 955     ((mucus or saliv*) adj3 secretions).mp. (960) 956     ((airway adj3 obstruction*) or choking).mp. (26948) 957     dyspn#ea*.mp. (7859) 958     Apn#ea*.mp. (7006) 959     (Breath* adj3 (difficult* or abnormalit* or dysfunction*)).mp. (2228) 960     (Respirat* adj3 distress).mp. (44587) 961     ((respiratory or ventilatory) adj3 depression).mp. (5913) 962     (respiratory adj3 (failure or insufficien* or arrest)).mp. (49120) 963     (breathless* or (breath adj3 shortness*)).mp. (9321) 964     (severe adj3 paradoxical respiration).mp. (3) 965     (cardiopulmonary adj3 (arrest or insufficency)).mp. (2454) 966     (lung adj3 insufficiency).mp. (212) 967     or/947-966 (221698) 968     946 and 967 (2352)  969     limit 968 to "all child (0 to 18 years)" (1350) 970     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 971     968 and 970 (1534) 972     969 or 971 (1534)   Constipation Symptom Search  947     Constipation/ (11576) 948     Defecation/ (6117) 949     Feces/ (76546) 950     Fecal Impaction/ (962) 951     Gastrointestinal Motility/ (19976) 952     constipat*.mp. (22050) 953     ((hard or impact*) adj3 stool*).mp. (328) 954     (bowel* adj3 (symptom* or habit or evacuat* or movement* or void* or strain)).mp. (6300) 955     (f#eces adj3 (impact* or evacuate*)).mp. (13) 956     defecate*.mp. (725) 957     (intestin* adj3 (motility adj3 dysmotility)).mp. (1) 958     (gastrointestinal adj3 (motility or dysmotility)).mp. (21902) 959     (colon* adj3 (transit or inertia)).mp. (1701) 960     (bowel* adj3 (function* or habit* or symptom* or evacuat* or movement or void* or strain*)).mp. (9540) 961     (f#eces adj3 (evacuat* or impacted)).mp. (14) 962     (fecalith or dyschezia).mp. (335) 963     (abdominal adj3 disten*).mp. (5586) 964     or/947-963 (135641) 965     946 and 964 (1028)  966     limit 965 to "all child (0 to 18 years)" (732) 967     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 968     965 and 967 (800) 969     966 or 968 (800)  Feeding Difficulties Symptom Search  947     gastroesophageal reflux/ or laryngopharyngeal reflux/ (23165) 948     (feeding adj3 (difficult* or problem*)).mp. (3327) 949     Regurgitation.mp. (30040) 950     Vomiting/ (20773) 951     (vomit* or emesis).mp. (68022) 952     retch*.mp. (940) 953     Nausea/ (13833) 954     nausea.mp. (54095) 955     (feeding adj3 intolerance*).mp. (496) 956     (salivary adj3 secretion*).mp. (2622) 957     Dyspepsia/ (7862) 958     (Dyspepsia* or indigestion*).mp. (12613) 959     Deglutition Disorders/ (16424) 960     aspiration.mp. (68047) 961     ((Gastric or Gastroesophageal or gastric acid or gastro oesophageal or esophageal) adj3 reflux).mp. (29691) 962     (swallowing adj3 (difficulty or disorder* or incoordination)).mp. (2423) 963     (dysphagia or (deglutition adj2 disorder*)).mp. (28288) 964     ((oromotor or oral motor) adj3 skill*).mp. (88) 965     or/947-964 (247301) 966     946 and 965 (1983)  967     limit 966 to "all child (0 to 18 years)" (1085) 968     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 969     966 and 968 (1221) 970     967 or 969 (1221)  Sleep Symptom Search  947     Sleep Disorders/ (17223) 948     dyssomnias/ or sleep deprivation/ or sleep disorders, circadian rhythm/ or sleep disorders, intrinsic/ (9760) 949     "Sleep Initiation and Maintenance Disorders"/ (9937) 950     (sleep adj3 (disturbanc* or disorder or problem* or disturbance* or dysfunction*)).mp. (19385) 951     ((short sleeper or long sleeper or subwakefullness) adj3 syndrome*).mp. (0) 952     (neurogenic tachypneas adj3 sleep-related).mp. (0) 953     dyssomnia*.mp. (414) 954     (nocturnal adj3 "eating-drinking syndrome").mp. (4) 955     ((extrinsic or environmental or adjustment or limit-setting) adj3 sleep).mp. (344) 956     insomnia*.mp. (14655) 957     (sleep adj3 (initiation or maintenance)).mp. (10607) 958     ((lethal or severe or obstructive) adj3 sleep apn#ea).mp. (3344) 959     (sleep disordered adj3 breathing).mp. (4691) 960     or/947-959 (59359) 961     946 and 960 (704)  962     limit 961 to "all child (0 to 18 years)" (263) 963     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 964     961 and 963 (308)  Temperature Regulation Symptom Search  947     body temperature regulation/ or sweating/ or thermogenesis/ or torpor/ (28408) 948     (cold adj3 (hands or feet)).mp. (258) 949     Hypothermia/ (12765) 950     hypothermia*.mp. (39844) 951     fever/ or "fever of unknown origin"/ (37761) 952     (fever* or hyperthermia* or pyrexia*).mp. (206630) 953     (diaphoresis or sweating or perspiration).mp. (12577) 954     Shivering/ (1676) 955     shiver*.mp. (3949) 956     Primary Dysautonomias/ (185) 957     Dysautonomia*.mp. (2551) 958     (body temperature adj3 regulation*).mp. (21848) 959     (thermoregulation* or heat loss*).mp. (8002) 960     or/947-959 (279889) 961     946 and 960 (1838)  962     limit 961 to "all child (0 to 18 years)" (836) 963     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 964     961 and 963 (965) 965     962 or 964 (965)  Tone and Motor Difficulties Symptom Search  947     Muscle Spasticity/ (7830) 948     Spasm/ (6764) 949     dystonia/ or torticollis/ (8535) 950     Dystonic Disorders/ (2019) 951     Muscle Tonus/ (6457) 952     ataxia/ or cerebellar ataxia/ or gait ataxia/ (11026) 953     muscle hypertonia/ or muscle rigidity/ (2971) 954     neuromuscular manifestations/ or muscle hypotonia/ (2919) 955     Dyskinesias/ (1892) 956     hyperkinesis/ or hypokinesia/ (5051) 957     Contracture/ (7298) 958     ((tone adj3 (problem* or difficult*)) or (tone adj3 (problem* or difficult*))).mp. (101) 959     (spastic* or spasm).mp. (43371) 960     (muscle* adj3 tonus*).mp. (6739) 961     (dystonia* or toticollis).mp. (13301) 962     (ataxia* or ataxy).mp. (36497) 963     (rubral adj3 tremors).mp. (4) 964     (coordination adj3 (impairment* or lack of)).mp. (926) 965     (dyscoordination or dyssynergia).mp. (1386) 966     (muscl* adj3 (tone or hypertonicity or atonic or flaccid or poor or increase* or decrease* or spasm)).mp. (36354) 967     (((abnormal or involuntary) adj3 movement) or asterixis or dyskinesia or hemiballism* or ballismus).mp. (17182) 968     (hyperkinesi* or hypokinesia).mp. (8122) 969     (muscle* adj3 contracture*).mp. (1278) 970     (immobil* or (reduced adj3 mobilit*)).mp. (112004) 971     ((awkward or spastic) adj3 gait).mp. (362) 972     (muscular adj3 (hypotrophy or rigidity or hypertonia)).mp. (552) 973     hypotonia.mp. (7868) 974     dyskinesia.mp. (14787) 975     or/947-973 (283784) 976     946 and 975 (8395)  977     limit 976 to "all child (0 to 18 years)" (2634) 978     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616629) 979     976 and 978 (3083) 980     977 or 979 (3083)  Urinary Incontinence Symptom Search   947     Enuresis/ or Diurnal Enuresis/ or Nocturnal Enuresis/ (4496) 948     urinary incontinence/ or Urinary Incontinence, Stress/ or Urinary Incontinence, Urge/ or urinary retention/ (31813) 949     (urinary adj3 (incontinence or retention)).mp. (42020) 950     bedwetting.mp. (283) 951     enuresis.mp. (5649) 952     or/947-951 (47042) 953     946 and 952 (230)  954     limit 953 to "all child (0 to 18 years)" (93) 955     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616629) 956     953 and 955 (101) 957     954 or 956 (101)      Scoping Review of Symptoms in Children with Rare, Progressive, Life-Threatening Disorders  Colleen Pawliuk, MLIS BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada   Kim Widger, RN, PhD, CHPCN(C)  Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada   Tammie Dewan, BSc, MD, MSc Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada   Gina Brander, MLIS Saskatchewan Polytechnic, Regina, Saskatchewan, Canada  Helen Brown, MLIS University of British Columbia, Vancouver, British Columbia, Canada   Anne-Mette Hermansen, MA BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada (  Marie-Claude Grégoire, MD, MSc, FRCPC Department of Paediatrics, Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada   Rose Steele, RN, PhD 2  School of Nursing, York University, Toronto, Ontario, Canada   Harold (Hal) Siden, MD, MHSc, FRCPC Department of Pediatrics, University of British Columbia BC Children's Hospital, Vancouver, British Columbia, Canada   Corresponding Author: Harold (Hal) Siden, MD, MHSc, FRCPC Department of Pediatrics, University of British Columbia; BC Children's Hospital Research Institute, 4480 Oak Street, Room F612A Vancouver, BC V6H 3V4 Canada  Email: hsiden@bcchr.ca    This article has been accepted for publication in BMJ Supportive and Palliative Care, 2019 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/bmjspcare-2019-001943.  © the Authors   3  ABSTRACT  Background: Q3 conditions are progressive, metabolic, neurological, or chromosomal childhood conditions without a cure. Children with these conditions face an unknown lifespan as well as unstable and uncomfortable symptoms. Clinicians and other health care professionals are challenged by a lack of evidence for symptom management for these conditions. Aims: In this scoping review we systematically identified and mapped the existing literature on symptom management for children with Q3 conditions. We focussed on the most common and distressing symptoms, namely alertness, behavioral problems, bowel incontinence, breathing difficulties, constipation, feeding difficulties, sleep disturbance, temperature regulation, tone and motor problems and urinary incontinence. For children with complex health conditions, good symptom management is pertinent to ensure the highest possible quality of life.  Methods: Scoping Review. Electronic database searches in Ovid MEDLINE, Embase and CINAHL and a comprehensive grey literature search. Results: We included 292 studies in our final synthesis. The most commonly reported conditions in the studies were Rett syndrome (n=69), followed by De Lange syndrome (n=25) and tuberous sclerosis (n=16). Tone and motor problems was the most commonly investigated symptom (n=141), followed by behavioral problems (n=82) and sleep disturbance (n=71). Conclusion: The evidence for symptom management in Q3 conditions is concentrated around a few conditions and these studies may not be applicable to other conditions. The evidence is dispersed in the literature and difficult to access, which further challenges health care providers. More research needs to be done in these conditions to provide high quality evidence for the care of these children.    Running head: Scoping Review to Examine Symptoms  4  BACKGROUND Quadrant 3 (Q3) conditions are progressive, metabolic, neurological, or chromosomal childhood conditions for which there currently exists no curative treatment. They are also known as Category 3 conditions in the report by the UK-based charity, Together for Short Lives.1 Children with these conditions face an unknown lifespan and symptoms that are both unstable and uncomfortable. Although the individual diagnoses are rare, Q3 conditions are a significant cause of disability and death in childhood. These conditions are numerous and varied, however, collectively they share many features in symptoms and burden of care. Children with Q3 conditions are living longer due to medical advances, but extending the duration of life does not necessarily mean improving a child’s quality of life. Until cures are found, a clinician’s obligation is to maximize comfort and quality of life. There is a lack of research on these conditions and, particularly, their associated symptoms. Clinicians, health professionals and families caring for children with Q3 conditions are challenged by this lack of research, which limits their ability to make evidence-based care decisions. Our aim in this scoping review was to systematically identify and map the literature regarding the assessment and management of the most common symptoms in Q3 conditions. With better evidence, clinicians and families will be able to make informed decisions about care and ensure better health outcomes for children living with distressing symptoms of complex conditions.     METHODS Search Methods Our comprehensive search strategy combined 181 Q3 conditions and 10 symptoms. Q3 conditions were identified through an initial pilot literature search, our previous work in this 5  area2,3 and 2 lists of Q3 conditions written by experts in the field.4,5 When creating the search strategy for the Q3 conditions we were challenged by the lack of controlled vocabulary for many of these conditions in the databases we searched. To ensure complete retrieval of all relevant studies we included broader controlled vocabulary terms when a specific condition term was not available or had only been recently added to the database. For example, “Farber Lipogranulomatosis” was introduced as a MeSH term in 2009, so to ensure coverage to database inception we also included the broader MeSH terms “Lipidoses” and “Sphingolipidoses” that had been previously used to index this condition. See Supplementary File 1 for our full MEDLINE Search Strategy. The 10 symptoms identified in our pilot study were based on Hunt,6 Malcolm et al.7 and our Charting the Territory study.8 The investigated symptoms were alertness (fatigue, arousal, wakefulness, concentration); behavioral (agitation, irritability, aggression, self-harm, negative affect); bowel incontinence; breathing difficulties (dyspnea, cough, apnea, hypoventilation, obstruction); constipation; feeding difficulties (gastric reflux, regurgitation, emesis, retching, nausea, feeding intolerance, salivary secretions, dyspepsia, swallowing difficulty, aspiration); sleep disturbance; temperature regulation; tone and motor problems (spasticity, dystonia, ataxia); and urinary incontinence. Seizures and pain were excluded from the symptom list as seizures is a common symptom with extensive literature and pain is the subject of another scoping review by one of our investigators. “Symptom management” search terms based on the clinical experience of the investigators were added to increase the specificity of the search.  We searched MEDLINE (Ovid), Embase and CINAHL from inception until January 2018; we did not limit our search by publication date or by language. To locate grey literature sources we searched ClinicalTrials.gov, WHO International Clinical Trials Platform, Conference 6  Proceedings Citation Index- Science (Web of Science), TRIP, ProQuest Dissertations and Theses Global, OAIster and LILACS. Experts in the field were contacted through relevant listservs to locate unpublished studies. Palliative care conferences were identified and conference abstracts were hand-searched when not indexed in the electronic databases already searched. The references of all included studies were hand-searched and Web of Science was used to search the citing articles of each study. Study Inclusion Studies had to 1) include at least one of the 181 Q3 conditions, 2) report on at least one of the 10 symptoms and 3) be focused on assessment tools to evaluate symptoms or on interventions to relieve symptoms. We only included studies with pediatric populations (0-18 years) or studies with adults were there was more than one pediatric participant. We excluded non-studies (i.e. letters to the editor, commentaries) and case reports with a single participant. Languages other than English or French were excluded due to a lack of resources for translation. Study Selection All search results were imported into Endnote© and duplicates were removed. Due to the comprehensiveness of our search strategy, we returned a large number of results. To more efficiently filter these results, a single team member pre-screened by title and abstract to remove articles that did not include both a symptom and a Q3 condition. The titles and abstracts of the remaining articles were screened in more depth independently and in duplicate by team members using abstrackr.9 The resulting full-text of studies were then reviewed by team members independently and in duplicate using Rayyan.10 For articles where the 2 team members did not agree in both the screening and review phases, the team met to come to a consensus decision to 7  include or exclude. Data were extracted from the remaining full text articles using a database created in REDCap.11 We extracted data on study design, sample size, tools or scales, intervention, year of publication, journal, Q3 condition(s), symptom(s), study objective, and primary outcome(s). To summarize the charted data, we grouped the studies together by symptom and summarized the study design and study objective. We did not register the protocol for our review our scoping review. We used the PRISMA Extension for Scoping Reviews guidelines to report the methods of our scoping review.12 RESULTS Our database and grey literature search retrieved 46,644 results. We returned a high number of results due to the broadness of our search and the lack of controlled vocabulary for these conditions. Once duplicates were removed, we pre-screened 36,447 and excluded 35,294 for not including both a Q3 condition and a symptom from our list. For this phase, when there was ambiguity the team member always chose to include studies for the next phase. The resulting 1,153 titles and abstracts were then screened and 316 were excluded for lack of symptom focus, wrong study design or wrong population. The remaining 837 full-text articles were reviewed and 545 were excluded for lack of symptom focus (n=206), lack of assessment (n=73), publication type (reviews, letters, commentaries: n=68), ongoing studies without finalized data (n=57), wrong outcome (n=46), wrong population (n=39), not in English or French (n=24), wrong study design (n=14), background article (n=17), and full-text not available (n=1). This left 292 studies in our final synthesis. See Figure 1 for the PRISMA Flowchart of the study selection process.  8   Figure 1: PRISMA flow chart of study selection process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Study Characteristics One of the studies was a thesis and the other 291 studies were journal articles. The 291 studies were published in 112 different journals and 70 of these journals only had a single study to contribute to this review. See Table 1 for the 10 most common journals. There was only 1 general pediatric journal, the Journal of Pediatrics, that had 3 studies to contribute to this review. The other journals are from a wide variety of disciplines, including clinical neurology, surgery, education, rehabilitation, dermatology, genetics, otorhinolaryngology, palliative care and gastroenterology. The studies were published between 1974 and 2018, with 52% (152) published 9  in 2010 or later. Fifty-nine percent of the studies used only validated tools or scales, while 27% used non-validated tools or scales, and 14% combined both validated and non-validated tools. See Supplementary File 2 for a table of the characteristics and a full bibliography of all included studies.  Table 1: 10 most common journals  Journal Name Frequency of Articles 2017 Journal Impact Factor  Developmental Medicine & Child Neurology 20 3.289 Journal of Intellectual Disability Research 16 2.026 Journal of Child Neurology 13 1.665 American Journal of Medical Genetics Part A 12 2.264 Movement Disorders 11 8.324 Pediatric Neurology 11 2.398 Brain & Development 9 1.544 European Journal of Paediatric Neurology 9 2.362 Journal of Neurodevelopmental Disorders 8 3.500 International Journal of Pediatric Otorhinolaryngology 7 1.305  Q3 Conditions Rett syndrome was the most investigated Q3 condition (n=69) followed by De Lange syndrome (n=25), tuberous sclerosis (n=16), mucopolysaccharidosis type III (n=15), spinal muscular atrophy type 1 (n=15), Cri-du-Chat (n=14), Friedrich’s ataxia (n=13), neuronal ceroid lipofuscinosis type 3 (n=13), and Lesch-Nyhan syndrome (n=12). Only 20 conditions comprised 10  80% of the studies (Table 2). One hundred and twenty-four of the 181 Q3 conditions did not appear in a single study and the remaining 36 conditions were investigated in 5 or fewer studies. See Supplementary File 1 for a heat map of all Q3 conditions and symptoms.  Table 2: 20 most common Q3 Conditions Q3 Condition Frequency of studies  Q3 Condition Frequency of studies  Rett syndrome  69 Epidermolysis bullosa 10 De Lange syndrome  25 Infantile neuroaxonal dystrophy 10 Tuberous sclerosis  16 Mucopolysaccharidosis type I 10 Mucopolysaccharidosis type III 15 Mucopolysaccharidosis type II 10 Spinal muscular atrophy 1 15 Achondroplasia 8 Cri-du-chat 14 Ataxia telangectasia 8 Friedrich’s ataxia 13 Mucopolysaccharidosis VI 8 Neuronal ceroid lipofuscinosis 3 13 Glutaric acidemia type I 6 Lesch-Nyhan syndrome 12 Mucopolysaccharidosis type IIIA 6 Jacobsen syndrome 10 West syndrome 6  Using a classification system for these conditions,3 Neurodegenerative Diseases was the most investigated condition category (n=102), followed by Multi-Organ Congenital Abnormalities (n=97), Lysosomal Storage / Peroxisomal Diseases (n=45), Small Molecule Diseases (n=20), Neuromuscular Diseases (n=14), Other Inborn Errors of Metabolism (n=8),  Severe Neurological Impairment -Not Yet Diagnosed (n=7), Structural Central Nervous System Abnormalities (n=5), Other Conditions Not Otherwise Specified (n=4), Mitochondrial Encephalo-/Myopathies (n=2), 11  and Congenital Disorders of Glycosylation (n=1). See Figure 2 for a heat map of condition categories and symptoms.   Figure 2: Heat map of Q3 condition categories and symptoms Symptoms Alertness Fourteen studies investigated alertness in Q3 conditions: 11 cross-sectional, 1 case-control, 1 open label and 1 tool/scale development study. The single open-label study investigated a psychological intervention in Rett syndrome: structured training to increase attention and reduce help needed.13 Paulsen et al. conducted an initial validation of the PedQL Fatigue Scales in Friedrich’s ataxia.14 The remaining 12 studies provided evidence of the severity of this symptom and described its trajectory. See Figure 3 for a heat map of the study objectives and symptoms and Figure 4 for a heat map of symptoms and study designs. For children who have attentional difficulties, clinical practitioners could try structured training, as this was found to be effective in one study in Rett syndrome. Rett syndrome has a distinct clinical profile, so structured training may not be effective in other Q3 conditions. No effective interventions were found for fatigue or alertness. Future studies should focus on other Q3 conditions that may be more applicable to the 12  group as a whole. A single study suggests the PedQL Fatigue Scales may be useful to measure levels of fatigue in Friedrich’s ataxia, which may be useful in other Q3 conditions.   Figure 3: Heat map of study objectives and symptoms  Figure 4: Heat map of study designs and symptoms. Behavioral Problems The majority of the 82 studies investigating behavioral problems were cross-sectional (n=47), followed by case control (n=9), case series (n=9), tool or scale development (n=9), survey (n=9), longitudinal (n=5), open-label (n=2), retrospective chart review (n=2), N of 1 trial (n=1) and RCT (n=1). Eight studies investigated an intervention: 6 were pharmacologic and 2 were psychological. Six of the studies were in Lesch-Nyhan syndrome and investigated strategies to reduce or eliminate self-injurious behavior.15–20 Nyhan et al. tested 5-hydroxytryptophan in a case-series;15 Khasnavis et al. tested Ecopipam in a RCT;16 Anderson et al. tested L-5-hydroxytryptophan in a case-series;17 Mizuno compared L-5-Hydroxytryptophan, L-tryptophan 13  or levodopa in a case-series;18 and Visser et al. investigated levodopa and carbidopa.19 Anderson et al. also investigated if electric shock, positive reinforcement, or time-out reduced self-injury.20,21 In a case-control study Sloneem et al. investigated how environmental conditions (demand, denial, attention, no contact) affected self-injurious behavior in De Lange syndrome.22 Ucar et al. investigated risperidone in children with mucopolysaccharidosis type III in an open-label trial.23 Eight studies designed and/or aimed to validate scales or tools. Darling et al. designed and pilot tested a disease rating scale for pantothenate kinase-associated neurodegeneration that included a section on psychiatric symptoms.24 In 2 studies, de Vries et al. and Lezlezio et al. designed and pilot-validated the TAND Checklist for tuberous sclerosis, which includes questions on behavioral concerns.25,26 Mount et al. developed the Rett Syndrome Behaviour Questionnaire.27 In 3 studies, Rojahn et al. developed and validated the Behavior Problems Inventory in unspecified intellectual disabilities.28–30 Shapiro et al validated the Sanfilippo Behavior Rating Scale in mucopolysaccharidosis type III.31 The remaining 66 studies provided insight into the behavioral challenges faced by caregivers of children with Q3 conditions, identified the possible mechanisms of self-injury, or described the trajectory of this symptom.  Behavioural problems was the second most studied symptom, and most of the studies that investigated interventions focused on self-injurious behaviour. None of the pharmacologic studies showed clear and lasting effects on self-injury. Clinicians could suggest positive reinforcement and/or time-outs, as this led to reductions in self-injury in one study, while punishment led to increased self-injury. Three systematic reviews and 1 RCT were found for behavioral problems, which highlights the need for more high level studies to be conducted on 14  this challenging symptom. Some condition-specific scales have been created and/or validated for behavioral problems and may be valuable for other Q3 conditions as well.  Bowel Incontinence Five studies investigated bowel incontinence: 4 cross-sectional and 1 case-control. All the studies described incidence and/or trajectory. Bowel incontinence was the second least studied symptom. Although studies included in this review found that this is a common symptom in Q3 conditions, no studies provide evidence on which to base symptom management. Breathing Difficulties Thirty-seven studies investigated breathing difficulties: 13 cross-sectional, 7 case-series, 5 retrospective chart reviews, 4 case-controls, 4 longitudinal, 4 surveys, 2 systematic reviews, 2 RCTs and 1 tool/scale development. Seven of the studies investigated an intervention; six of these examined a combination of surgical and physical interventions. Only 1 study investigated a pharmacologic intervention: testing the efficacy of oral naltrexone in children with Leigh syndrome and other children with sleep apnea in an RCT.32 In a retrospective chart review, Tenconi et al. assessed conventional treatment options (adenotonsillectomy, continuous positive airway pressure (CPAP), losing weight) for obstructive sleep apnea (OSA) in children with achondroplasia.33 Also in achondroplasia, a case-series investigated surgery, CPAP, bilevel positive airway pressure, cervical decompression for OSA.34 In a RCT, Sudarsan et al. compared adenotonsillectomy and CPAP in children with mucopolysaccharidosis types I, II, III, VI and VII.35 Another retrospective chart review of children with mucolipidosis types II and III and mucopolysaccharidosis types I, II and III, recorded interventions used for respiratory complications, including surgery (adenotonsillectomy, tracheostomy); low flow oxygen; 15  medications (diuretics, theophylline, digoxin, beta adrenergic blockers, calcium antagonists).36 Nabatame et al. and Mellies et al. investigated the efficacy of non-invasive positive pressure ventilation for sleep disordered breathing in glycogen storage disease type II and spinal muscular atrophy type 1 respectively.37,38 Mount et al. developed the Rett Syndrome Behavior Questionnaire that includes questions on breathing problems including air swallowing, breath holding and hyperventilation.27 The remaining 29 studies described breathing difficulties in this population and provided insight into its trajectory.  Many of the studies confirm the prevalence of both sleep apnea and other breathing problems in Q3 conditions. Sleep apnea studies in achondroplasia suggest surgical intervention may be necessary, while for other Q3 conditions CPAP appears to be effective. Medications, such as naltrexone, could also be effective for sleep apnea. For other breathing problems, 1 study suggested a combination of surgical and pharmacological interventions may be effective, but a systematic review on treatments for dyspnea found the evidence to be of low quality. Our review also shows that overall there is a lack of high level evidence breathing difficulties and more research is needed. One of the studies created a Rett syndrome specific tool that includes a section on breathing problems, which may not be relevant to other Q3 conditions. Constipation Ten studies investigated constipation: 5 cross-sectional, 3 retrospective chart reviews, 2 surveys, 1 case-series and 1 open-label study. Three of the studies tested a pharmacological or dietary intervention to reduce constipation. In retrospective chart review, Mordekar et al. investigated parenteral nutrition in Rett syndrome, mucopolysaccharidosis type III and West syndrome39 and Murata et al. investigated supplementary carnitine in neuronal ceroid lipofuscinosis type 3, 16  Pelizaeus-Merzbacher disease, tuberous sclerosis and West syndrome.40 In an open-label study Haynes et al. investigated fiber-containing formula in epidermolysis bullosa.41 No studies developed or validated a tool or scale and the remaining 7 studies described the features or trajectory of this symptom.41 To help manage constipation in Q3 conditions, clinical practitioners can try parenteral nutrition, fiber-enriched formula, or supplementation with carnitine. In our Charting the Territory study we found constipation to be the fourth most commonly reported symptom by caregivers, yet only 3 studies investigate symptom management in this population.8 More studies are needed for this symptom. Feeding Difficulties Forty-five studies investigated feeding difficulties: 15 cross sectional, 12 retrospective chart reviews, 11 case series, 3 scale/tool development, 3 surveys, 2 longitudinal and 2 open-label. Thirteen studies investigated an intervention and 10 of these were surgical interventions. Seven of the surgical studies investigated balloon dilation of esophageal strictures in epidermolysis bullosa.42–48 Stehr et al. and Seguy et al. performed retrospective chart reviews of percutaneous gastrostomy placement in epidermolysis bullosa,49 spinal muscular atrophy type 1 and other congenital muscular dystrophies and congenital myopathies.50 Blommaert et al. reported a case series of bilateral submandibular gland excision and parotid duct ligation for drooling in children with MEGDEL syndrome.51 Two of the studies investigated a pharmacological intervention. Kawai et al. performed an open-label study of baclofen for emesis and gastroesophageal reflux disease in children with De Lange and West syndromes.52 Kawahara et al. reported the effects of rikkushito on gastroesophageal reflux in children with profound neurological impairment.53  17  Three studies examined physical interventions. In a longitudinal open-label study Munakata et al. investigated the effects of black pepper oil at stimulating oral feeding in Costello syndrome and lissencephaly type 1.54 Mordekar reported treating feed-induced dystonia with parenteral nutrition in Rett syndrome, mucopolysaccharidosis type III and West syndrome.39 In Rett syndrome, Morton et al. tried a variety of physical interventions to reduce air bloating and apneas at rest, including a large, flattened dummy with a hollow tube to allow the flow of air, gum shield, and palatal training devices.55 Two of the studies examined psychological interventions. Hyman et al. reported the use of positive reinforcement and guidance techniques in argininosuccinate lyase deficiency, methylmalonyl-CoA mutase deficiency, ornithine carbamoyltransferase deficiency disease and propionic acidemia.56 Piazza et al. provided training to girls with Rett syndrome in scooping food, bringing food to mouth and placing spoon in mouth by a trainer.57 Four of the studies developed or validated tools or scales. Fyfe et al. developed and validated a parent-report checklist and video-based evaluation tool for eating and drinking in Rett syndrome.58 Iturriaga el al. developed a disability scale for Niemann–Pick type C, which included scoring for feeding difficulties.59 In 2 studies, de Vries et al. and Lezlezio et al. developed and pilot-validated the TAND Checklist for tuberous sclerosis, which includes a question on feeding difficulties.25,26 The remaining 24 studies reported the trajectory, incidence and characteristics of the feeding difficulties in this population.  Several studies showed that balloon dilation can be effective for esophageal strictures in epidermolysis bullosa. Percutaneous gastrostomy placement or parenteral nutrition may also reduce feeding difficulties. For drooling, 1 study found that bilateral submandibular gland excision and/or parotid duct ligation may be helpful, but that each patient needed personalized 18  treatment for it to be effective. For gastroesophageal reflux and emesis, baclofen and rikkushito were found to reduce these symptoms. For oral feeding, black pepper oil may help stimulate appetite and positive reinforcement and training with guidance techniques may be helpful for teaching children with Q3 conditions to feed themselves. One study investigated a flattened dummy with a hollow tube to allow the flow of air, gum shield, and palatal training devices to help reduce air swallowing during feeding in Rett syndrome. None of the studies investigating feeding difficulties are RCTs or systematic reviews, highlighting that higher levels of evidence are needed for this symptom. Some condition-specific tools or scales have been developed and/or validated and may be useful to assess feeding difficulties.  Sleep Disturbance Sixty-two of the studies investigated sleep disturbance: 38 cross-sectional, 8 RCT, 6 tool/scale development, 5 case-control, 5 case series, 5 surveys, 3 open-label studies, 1 retrospective chart review and 1 systematic review. Sixteen of the studies investigated an intervention, 13 of which were pharmacologic. Twelve studies, including all 8 of the RCTs, investigated melatonin in Rett syndrome,60–63 18q deletion syndrome and mucopolysaccharidosis Type III,64 neuronal ceroid lipofuscinosis type 3,65 tuberous sclerosis66,67 and unspecified Q3 Conditions.68–72 In an open-label study, Ucar et al. investigated risperidone in mucopolysaccharidosis type III.23 The remaining 2 studies investigated psychological interventions. Piazza et al. reported a case series using a fading procedure in Rett syndrome.73 In an open-label study, Colville et al. tried a personalized sleep plan developed by a clinical psychologist for children with mucopolysaccharidosis type III.74 Seven studies developed and/or validated a tool or a scale. De Vries et al. and Lezlezio et al. designed and pilot-validated the TAND Checklist for tuberous sclerosis with a question about sleep disturbance.25,26 Two studies developed scales with 19  questions about sleep disturbance in Rett syndrome27 and Niemann–Pick type C.59 In unspecified Q3 conditions, Blankenburg et al. and Tietze et al. developed and validated and Maas et al. validated questionnaires on sleep disturbance.75–77 The remaining 44 studies described the characteristics, trajectory, mechanism and challenges of sleep disturbance.  Clinical practitioners can suggest several interventions that may be effective for sleep problems in Q3 conditions. Melatonin may slightly increase sleep duration and decrease sleep latency, but studies are mixed on its efficacy. Another study shows risperidone prescribed for behavioral problems may also increase sleep. Other non-pharmaceutical interventions, including fading procedures and personalized sleep plans, can also help to decrease sleep disturbances. Sleep problems had the highest number of RCTs of all symptoms but all of them investigated melatonin. Other high-level studies investigating other interventions are necessary. Several studies developed and validated SNAKE for diagnosing sleep disturbances in Q3 conditions, while other condition-specific tools may also be useful for measuring sleep disturbances.     Temperature Regulation Only 2 studies investigated temperature regulation. In a case-control Svedberg et al. recorded differences in hand temperatures between children with Jacobsen syndrome, spinal muscular atrophy type 1 and other central nervous system damage and healthy controls.78 In a further case-series, Svedberg et al. tested the efficacy of acupuncture in children with Smith-Lemli-Opitz syndrome and other neurological disorders.79 Temperature regulation was the least studied symptom. Clinical practitioners could suggest trying acupuncture to caregivers, as 1 study suggests it can raise skin temperature through a cumulative effect. More research is needed for this symptom.  20  Tone and Motor Problems Tone and motor problems was the most investigated symptom with 141 studies: 27 case series, 26 tool/scale development, 26 cross-sectional studies, 15 longitudinal, 11 retrospective chart reviews, 7 open-label, 5 surveys, 3 systematic reviews, 3 cohort studies, 3 N-of-1 studies and 2 RCTs. Forty-one of the 141 studies investigated an intervention, 12 of which were pharmacologic. In case-series of Lesch-Nyhan syndrome, Visser et al investigated levodopa or carbidopa19 and Mizuno et al. compared L-5-Hydroxytryptophan, L-tryptophan and levodopa. Aberg et al. compared levodopa and selegiline in neuronal ceroid lipofuscinosis types 3 and 6 in an open-label trial.80 Cak et al. investigated how tricyclic antidepressants affect cataplexy in Niemann–Pick type C.81 In x-linked adrenoleukodystrophy, Hjartarson et al. reported the use of intrathecal baclofen for spasticity and dystonia.82 Both in ataxia-telangectasia, Zannolli et al. investigated betamethasone in a RCT83and Nissenkorn et al. investigated amantadine sulfate in an longitudinal open-label study.84 In a RCT, Zweije-Horman et al. compared amantadine, fenadrine, madopar and placebo in neuronal ceroid lipofuscinosis type 3.85 In 18q Deletion syndrome, lissencephaly type 1, metachromatic leukodystrophy and neuronal ceroid lipofuscinosis type 3, Kuhlen et al. reported on the use of dronabinol for spasticity.86 Liow et al. investigated gabapentin in a cohort study in infantile neuroaxonal dystrophy and dystonia of varying aetiologies.87 Nava et al. reported the combination of both pharmacologic (botulinum toxin type A) and a physical interventions (serial casting and intensified physical therapy) for equinus deformity in mucopolysaccharidosis type II.88  Including Nava et al., 11 studies examined a physical intervention and 9 of these were in Rett syndrome. In case series of Rett syndrome for stereotypic hand movements, Bumin et al. tried hand splints or elbow restraints,89 Naganuma et al. tried thumb abduction splints,90 Sharpe et al. 21  tried elbow orthosis or thumb abduction splints,91 and Tuten et al. tried hand splints.92 Also in Rett syndrome, Stasolla et al. used assistive technologies in three studies to increase purposeful hand movements, including picture exchange communication systems compared to vocal output communication aid,93 wobble microswitch and optic sensors,94 and photocells, interface and personal computer.95 Lotan et al. investigated how a daily training treadmill program improved functional skills in Rett syndrome.96 Mordekar et al reported how switching to parenteral nutrition can improve feed-induced dystonia in Rett syndrome.39 In Friedrich’s ataxia, Ilg examined how video game-based coordinative training can improve coordination.97  Fourteen studies investigated a surgical intervention. Eleven of these studies investigated deep brain stimulation in glutaric acidemia type I,98–100 Lesch-Nyhan syndrome,98 ataxia-telangectasia,101 methylmalonyl-CoA mutase deficiency,101 nemaline myopathy,101 infantile neuroaxonal dystrophy,98,100,102–106 and other non-specified Q3 condtions.107,108 In a retrospective chart review, Buizer reported the used of selective dorsal rhizotomy in lipidoses.109 In mucolipidosis type II and mucopolysaccharidosis types I, II, III and VI, Haddad et al. investigated the effect of surgery for carpal tunnel syndrome.110 Van Heest et al. reported on the use of surgery for children with, mucopolysaccharidosis types I, III and VI and carpal tunnel syndrome and trigger digits.111 Five studies examined at psychological interventions for tone and motor problems and all were in Rett syndrome. In an open-label study, Fabio et al. investigated how selective attention training could reduce stereotypies.13 In case series, Piazza et al. examined hand function with training in scooping food, bringing food to mouth, and placing spoon in mouth by a trainer57 and Qvardfordt et al. compared hand function in guided eating to being fed.112 In case series, Lotan et al. examined daily conductive educational program113 and Wales et al. tested how different stimulation or attention conditions affected hand stereotypies.114  22  Twenty-six studies developed and/or validated a tool or scale for tone and motor problems. Nine of the studies included tools or scales for neuromuscular diseases that included spinal muscular atrophy type 1. Glanzman et al. developed and validated the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders in 2 studies.115,116 Krosschell et al. modified and validated the Hammersmith functional motor scale117 and validated the Test of Infant Motor Performance Screening Items specifically for spinal muscular atrophy type 1. Mazzone et al. compared the reliability of the Hammersmith Functional Motor Scale and the Motor Function Measure-20.118 Nelson et al. validated the Gross Motor Function Measure119 and de Lattre et al. and Vuillerot validated the Motor Function Measure.120,121 Finkel et al. tested the validity of the Test of Infant Motor Performance in children with spinal muscular atrophy type 1.122 Seven of the studies examined Rett syndrome. Downs et al. tested the use of accelerometers in 2 studies123,124 and validated the Rett Syndrome Gross Motor Scale in one study.125 Stahlhut et al. compared the modified two-minute walk test and a modified Rett syndrome specific functional mobility scale.126 Dy et al. and Fyfe et al. both developed and tested coding protocols for video-taped evaluation of hand steroteypies.58,127 Mount et al. developed the Rett Syndrome Behaviour Questionnaire that includes questions on hand behaviors.27 Four studies validated tools or scales in Friedrich’s ataxia. Cano et al. and Bürk et al. validated scales to measure the level of impairment due to ataxia128,129 and Subramony et al. developed and validated a neurologic rating scale.130 Germanotta et al. validated the use of InMotion Arm Robot to measure upper limb function.131 Nissenkorn et al. developed a clinical global impression scale for ataxia telangiectasia, which includes sections on motor function.132 For progressive myelopathy, including mucopolysaccharidosis types I and VI, Castilhos developed and validated the Severity Score System for Progressive Myelopathy.133 Darling et al. designed and pilot-tested the PKAN-23  Disease Rating Scale, which includes a motor examination protocol for infantile neuroaxonal dystrophy.24 In Niemann–Pick type C, Iturriaga developed a disability scale that includes scoring for motor disorders.59 Ruiz-Cortes validated the Motor Function Measure in unspecified hereditary neuromuscular diseases134 and van Capelle developed and validated the Quick Motor Function Test in glycogen storage disease type II.135 The remaining 48 studies described the characteristics, trajectory and challenges of tone and motor problems in this population.  As the most well studied symptom, there are several pharmacological, physical and surgical interventions for clinical practitioners to consider for the different types of tone and motor problems. Many of the studies investigated the specific stereotypic movements found in Rett syndrome. Interventions for this population include hand or finger splints or elbow restraints, assistive technologies, exercise programs, switching to parenteral nutrition to reduce dystonia and various forms of training or environmental conditions. These studies may not be relevant to other Q3 conditions, as Rett syndrome has distinct tone and motor challenges. In other conditions, several pharmacologic interventions showed some efficacy that clinical practitioners may wish to consider, including levodopa, intrathecal baclofen, tricyclic antidepressants, betamethasone, amantadine sulfate, dronabinol, gabapentin and botulinum toxin type A. Deep brain stimulation can be considered, but the results are mixed and may depend on condition and even mutation. Other surgical interventions include surgery for carpal tunnel syndrome and selective dorsal rhizotomy to reduce spasticity. Physical interventions include serial casting and intensified physical therapy for equinus deformity and video game training to improve coordination. Only 2 of the studies were RCTs and 3 were systematic reviews, showing the need for higher levels of evidence before strong recommendations for treatment can be made by clinical practitioners. Several studies developed and/or validated scales and tools for tone and 24  motor problems. Some of the tools, for example a protocol for a video-taped evaluation of hand stereotypies in Rett syndrome, may be condition-specific. However, several tools and scales may be helpful in Q3 conditions to assess and measure tone and motor difficulties. Urinary Incontinence Nine studies assessed urinary incontinence: 6 cross-sectional, 2 case-control and 1 survey. All 9 of the studies provided insight into the trajectory or characteristics of the symptom, or compared the severity or features of urinary incontinence to other populations. No evidence on interventions or tools to assess urinary incontinence were found for Q3 conditions. More research is needed for this symptom. DISCUSSION This scoping review identified tools to best assess and interventions to best manage troubling symptoms for children living with Q3 conditions. While many of the tools and scales found in this review are condition specific and may not be useful in other Q3 conditions, we did locate some that are either intended for the larger category of Q3 conditions or may be valid in other populations. More research should be done to design tools for symptoms without any current tools and to validate existing tools in Q3 conditions as a whole. Tone and motor problems was the most investigated symptom. Many of the studies investigated the specific stereotypic movements found in Rett syndrome and these studies may not be relevant to other Q3 conditions. Studies showed some efficacy for a variety of pharmacological interventions, other surgical and physical interventions and mixed results for deep brain stimulation We can only guess as to why tone and motor problems, and specifically the ones associated with Rett syndrome, have been more thoroughly investigated that other symptoms. 25  One suggestion is that as an outwardly evident symptom, in a clearly diagnosed condition, it is seemingly easier for researchers to investigate. Behavioural problems were the second most studied symptom, and most of the studies that investigated interventions focused on self-injurious behaviour, particularly in Lesch-Nyhan syndrome. Again, we can only guess as to why self-injury is so well-studied in comparison to other symptoms, but it may be due to the disturbing nature of the symptom for caregivers and the ease at which an investigator can measure changes. No pharmacologic studies showed clear and lasting effects on self-injury, but some behavioral studies provided effective strategies.  Sleep difficulties was the third most studied symptom. Melatonin was overwhelmingly the most studied intervention, but studies were mixed on the efficacy of melatonin in Q3 conditions. Other interventions studies included risperidone prescribed for behavioral problems, fading procedures and personalized sleep plans. Sleep problems had the highest number of RCTs of all symptoms, all of which investigated melatonin.  As the fourth most studied symptom, studies about feeding difficulties investigated a variety of interventions, but several of the studies may only be relevant in epidermolysis bullosa and Rett syndrome. Studies that may be more generalizable to Q3 conditions include, percutaneous gastrostomy placement, parenteral nutrition, bilateral submandibular gland excision and/or parotid duct ligation, baclofen, rikkushito, black pepper oil and behavioral strategies.  Breathing problems were the fifth mostly commonly investigated symptom. Sleep apnea studies in achondroplasia suggest surgical intervention may be necessary, while for other Q3 conditions CPAP or medications, such as naltrexone, appear to be effective. The evidence for other breathing difficulties is mixed and of low quality. 26  Alertness, constipation, urinary and bowel incontinence and were the fifth, fourth, third and second least studied symptom respectively. For alertness, structured training to increase attention in Rett syndrome was the only intervention studied. For constipation some studies suggest parenteral nutrition, fiber-enriched formula, or supplementation with carnitine. For urinary and bowel incontinence no interventions were studied. The least studied symptom was temperature regulation. Only acupuncture was studied which may increase skin temperature over time.  Overall this scoping review found that very little evidence exists for symptom management in Q3 Conditions. Given the absence of cures for these conditions, the clinical focus should be on symptom management and its contribution to quality of life. We found that most of the studies are concentrated on a handful of diseases, particularly Rett syndrome. Rett syndrome has a distinct clinical profile and interventions used for this condition may not be generalizable to other conditions. Additionally, no condition has a consistent evidence base for all 10 symptoms, and most have only limited evidence for a single symptom. Furthermore, some symptoms, such as temperature regulation problems that have been identified as important to parents, have received little attention in the published clinical research. With the exception of melatonin for sleeping difficulties, there is also a lack of high-level evidence for all symptoms. In conclusion, there is an urgent need for higher levels of evidence for reliable assessment tools and effective interventions for managing prevalent symptoms in Q3 conditions. Implications for Practice The studies found in this scoping review are dispersed across multiple disciplines and major general pediatric journals are not represented, except for the Journal of Pediatrics. As a result, general pediatricians or even specialists are unlikely to see most of the articles that would 27  provide valuable evidence to ensure optimal symptom management in this population. Retrieval of this evidence is further complicated by the lack of an accepted and widely used term for this group of progressive, life-threatening conditions. “Q3” is a term used amongst clinicians working with this specific population, but not a term that is reflected in scientific literature and thus a disconnect happens when care providers are looking for evidence of best practices. It is unlikely that a clinician would find these studies through a quick online search. This situation ultimately leaves clinicians with little to no evidence of effective symptoms management for their patients and a distressing inability to improve health outcomes informed by research rather than anecdotal evidence or individual experience.  Limitations and Future Directions This scoping review is limited by our last search date of January 2018, as more recent studies may have been published within the past year. Additionally, we were not able to translate studies that were not in English or French due to a lack of resources and we were not able to locate the full-text of some studies. This may introduce bias into our results as some studies were excluded before our team had the opportunity to review the full-text. Despite these limitations, it is clear that there needs to be more research done on these symptoms to have a strong evidence base on which to base treatment. For clinical practitioners who must manage the symptoms of child with a Q3 condition with little or no evidence, studies from other conditions may provide the only guidance available for measurement tools and interventions. This scoping review highlights gaps in our knowledge regarding the management of common symptoms in children with neurological, genetic, or chromosome-based conditions that impair quality of life.  Researchers and clinicians can use this information to develop broader programs of research to develop 28  assessment tools and then test interventions that will have a meaningful impact on these children and their families.  Abbreviations CPAP – Continuous positive airway pressure  OSA – Obstructive sleep apnea  RCT – Randomized controlled trial Q3 – Quadrant 3   Authorship:  C. Pawliuk developed and implemented the search strategy, reviewed abstracts, titles and full articles, and contributed to the writing of the manuscript and revised it for important intellectual content. K. Widger participated in planning the study, reviewed abstracts, titles and full articles, and revised the manuscript for important intellectual content. T. Dewan participated in planning the study, reviewed abstracts, titles and full articles, and revised the manuscript for important intellectual content. G. Brander implemented the search strategy and revised the manuscript for important intellectual content. H. Brown provided methodological guidance and revised the manuscript for important intellectual content. A.-M. Hermansen reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. M.-C. Grégoire participated in planning the study, reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. R. Steele participated in planning the study, reviewed abstracts, titles and full articles and revised the manuscript for important intellectual content. H. Siden conceptualized the study, participated in planning the study, reviewed abstracts, titles and full articles, contributed to the writing and revised it for important intellectual content.  29  Funding: This work was supported by the Canadian Institutes of Health Research (CIHR) Knowledge Synthesis Grant #328968.  Declaration of conflicts of interest: None declared.  Acknowledgements: The authors would like to thank Charlotte Beck for her methodological guidance in the early stage of the review   Data management and sharing: All available data has been included in this publication and supplementary materials.  Licence for Publication: The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ Supportive and Palliative Care and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructions-for-authors/licence-forms).  30  REFERENCES 1.  Association for Children’s Palliative Care. A Guide to the Development of Children’s Palliative Care Services. 3rd ed. Report, Bristol, UK. 2009. 2.  Siden H, Steele R, Brant R, et al. 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Res Autism Spectr Disord 2014;8:1269–1278. 94.  Stasolla F and Caffò AO. Promoting adaptive behaviors by two girls with Rett syndrome through a microswitch-based program. Res Autism Spectr Disord 2013;7:1265–1272. 95.  Stasolla F, Perilli V, Di Leone A, et al. Technological aids to support choice strategies by three girls with Rett syndrome. Res Dev Disabil 2015;36:36–44. 96.  Lotan M, Isakov E and Merrick J. Improving functional skills and physical fitness in children with Rett syndrome. J Intellect Disabil Res 2004;48:730–5. 97.  Ilg W, Schatton C, Schicks J, et al. Video game-based coordinative training improves ataxia in children with degenerative ataxia. Neurology 2012;79:2056–2060. 98.  Air EL, Ostrem JL, Sanger TD, et al. Deep brain stimulation in children: experience and technical pearls. J Neurosurg Pediatr 2011;8:566–74. 37  99.  Gimeno H, Tustin K, Selway R, et al. Beyond the Burke-Fahn-Marsden Dystonia Rating Scale: deep brain stimulation in childhood secondary dystonia. Eur J Paediatr Neurol 2012;16:501–508. 100.  Tsering D, Tochen L, Lavenstein B, et al. Considerations in deep brain stimulation (DBS) for pediatric secondary dystonia. Childs Nerv Syst 2017;33:631–637. 101.  Beaulieu-Boire I, Aquino CC, Fasano A, et al. Deep brain stimulation in rare inherited dystonias. Brain Stimul 2016;9:905–910. 102.  Castelnau P, Cif L, Valente EM, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol 2005;57:738–41. 103.  Holloway KL, Baron MS, Brown R, et al. Deep brain stimulation for dystonia: a meta-analysis. Neuromodulation 2006;9:253–261. 104.  Lim BC, Ki CS, Cho A, et al. Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation. Eur J Neurol 2012;19:556–61. 105.  Timmermann L, Pauls KA, Wieland K, et al. Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation. Brain 2010;133:701–12. 106.  Liu Z, Liu Y, Yang Y, et al. Subthalamic Nuclei Stimulation in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN). Neuromodulation 2017;20:484–491. 107.  Park HR, Lee JM, Ehm G, et al. Long-term clinical outcome of internal globus pallidus deep brain stimulation for dystonia. PLoS ONE 2016;11:e0146644 108.  Susatia F, Malaty IA, Foote KD, et al. An evaluation of rating scales utilized for deep brain stimulation for dystonia. J Neurol 2010;257:44–58. 109.  Buizer AI, van Schie PEM, Bolster EAM, et al. Effect of selective dorsal rhizotomy on daily care and comfort in non-walking children and adolescents with severe spasticity. Eur J Paediatr Neurol 2017;21:350–357. 110.  Haddad FS, Jones DH, Vellodi A, et al. Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses. J Bone Joint Surg Br 1997;79:576–582. 111.  Van Heest AE, House J, Krivit W, et al. Surgical treatment of carpal tunnel syndrome and trigger digits in children with mucopolysaccharide storage disorders. J Hand Surg Am 1998;23A:236–243. 112.  Qvarfordt I, Engerstrom IW and Eliasson AC. Guided eating or feeding: three girls with Rett syndrome. Scand J Occup Ther 2009;16:33–39. 113.  Lotan M, Schenker R, Wine J, et al. The conductive environment enhances gross motor function of girls with Rett syndrome. A pilot study. Dev Neurorehabil 2012;15:19–25. 38  114.  Wales L, Charman T and Mount RH. An analogue assessment of repetitive hand behaviours in girls and young women with Rett syndrome. J Intellect Disabil Res 2004;48:672–8. 115.  Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): Test development and reliability. Neuromuscul Disord 2010;20:155–161. 116.  Glanzman AM, McDermott MP, Montes J, et al. Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther 2011;23:322–326. 117.  Krosschell KJ, Maczulski JA, Crawford TO, et al. A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy. Neuromuscul Disord 2006;16:417–26. 118.  Mazzone E, De Sanctis R, Fanelli L, et al. Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients. Neuromusc Disord 2014;24:347–352. 119.  Nelson L, Owens H, Hynan LS, et al. The gross motor function measure is a valid and sensitive outcome measure for spinal muscular atrophy. Neuromusc Disord 2006;16:374–80. 120.  de Lattre C, Payan C, Vuillerot C, et al. Motor Function Measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil 2013;94:2218–2226. 121.  Vuillerot C, Payan C, Girardot F, et al. 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Castilhos RM, Blank D, Netto CBO, et al. Severity score system for progressive myelopathy: development and validation of a new clinical scale. Braz J Med Biol Res 2012;45:565–572. 134.  Ruiz-Cortes X, Ortiz-Corredor F and Mendoza-Pulido C. Reliability of home-based, motor function measure in hereditary neuromuscular diseases. J Int Med Res 2017;45:261–271. 135.  van Capelle CI, van der Beek N, de Vries JM, et al. The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients. J Inherit Metab Dis 2012;35:317–323.             Supplementary File 1: MEDLINE Search Strategy  1     Achondroplasia/ or Thanatophoric Dysplasia/ [Bone Diseases, Developmental] (2080) 2     (saddan dysplasia* or Achondroplasia* or achondroplasy or achondrosis).mp. (2247) 3     Acrocallosal Syndrome/ (77) 4     Acrocallosal.mp. (152) 5     Aicardi Syndrome/ (56) 6     (Aicardi or (callosal adj3 agenesis) or (ocular adj3 abnormalit*)).mp. (2860) 7     (((3-Methylcrotonyl-CoA Carboxylase or 3MCC or BMCC) adj3 Deficiency) or 3-Methylcrotonylglycinuria).mp. (93) 8     Encephalomyelitis, Acute Disseminated/ (1708) 9     (((post or acute) adj3 vaccina* encephalitis*) or ((post or acute) adj3 infection* encephalitis*)).mp. (72) 10     "Agenesis of Corpus Callosum"/ (1967) 11     ((Agenesis adj2 Corpus Callosum) or ((hypogenes* or dysgenes* or absence*) adj2 corpus Callosum)).mp. (2300) 12     Aicardi Goutieres.mp. (289) 13     Alagille Syndrome/ (525) 14     (watson miller or alagille* or cadiovertebral or hepatofacioneurocardiovertebral or arteriohepatic displasia or (hepatic ductular adj2 hypoplasia)).mp. (835) 15     Holoprosencephaly/ (1046) 16     (Holoprosencephal* or arhinencephal*).mp. (2002) 17     Aspartylglucosaminuria/ (111) 18     ((Aspartylglucosaminuria* or glycoasparaginase* or aspartylglucosamidase) adj3 deficienc*).mp. (4) 19     ((Asphyxiating Thoracic adj3 dystroph*) or (short rib thoratic adj1 dysplasia*) or (jeune adj3 syndrome)).mp. (235) 20     Ataxia Telangiectasia/ (3029) 21     ((Ataxia adj3 Telangiectasia) or (Louis adj2 Bar)).mp. (8344) 22     Rett Syndrome/ (2049) 23     ((Rett adj3 (Syndrome or morbus)) or (cerebroatrophic adj3 hyperammonemia*)).mp. (2858) 24     Bartter Syndrome/ (1300) 25     Bartter.mp.  (1626) 26     ((Bowen adj3 Conradi) or (Bowen adj3 Hutterite)).mp. (26) 27     Carbamoyl-Phosphate Synthase I Deficiency Disease/ (100) 28     ("Carbamoyl-Phosphate Synthase I Deficiency Disease" or "Carbamoyl Phosphate Synthase I Deficiency Disease").mp. (100) 29     Carbohydrate-Deficient Glycoprotein Syndrome/ (498) 30     ("Carbohydrate-Deficient Glycoprotein Syndrome" or "Carbohydrate Deficient Glycoprotein Syndrome" or (congenital adj3 glycosylation) or (congenital adj3 dyserythropoietic anemia) or (fukuyama congenital adj3 dystrophy) or (hereditary multiple adj3 exostosis) or (walker adj3 Warburg)).mp. (1821) 31     Carnitine O-Palmitoyltransferase/df (397) 32     (Carnitine O-Palmitoyltransferase adj3 deficienc*).mp. (0) 33     myopathies, structural, congenital/ or myopathies, nemaline/ or myopathy, central core/  (987) 34     ((Centronuclear or myotubular) adj3 myopath*).mp. (581) 35     ((autosomal recessive or Charlevoix Saguenay) adj2 Spastic Ataxia).mp. (130) 36     Cholesterol Ester Storage Disease/ (111) 37     ("Cholester#l Ester Storage Disease" or "Cholester#lester Storage Disease").mp. (207) 38     Wolf-Hirschhorn Syndrome/ (103) 39     ((Wolf adj3 Hirschhorn) or (Pitt Rogers adj3 Danks) or (Chromosome 4p adj2 (Deletion or syndrome* or monosomy))).mp. (436) 40     Cri-du-Chat Syndrome/ (623) 41     Crying Cat Syndrome/ (623) 42     limit 41 to yr="1964 - 1976" (298) 43     ((Chromosome 5p adj3 Deletion) or Cri-du-Chat or (Crying adj3 Cat) or (cat adj3 cry)).mp. (706) 44     Chromosomes, Human, Pair 5/ and (Tetrasomy/ or Mosaicism/) (37) 45     (Tetrasomy 5p adj3 Mosaicism).mp. (4) 46     Chromosomes, Human, Pair 9/ and (Trisomy/ or Mosaicism/) (405) 47     (Mosaic adj3 Trisomy 9).mp. (48) 48     (Chromosomes, Human, Pair 18/ and Trisomy/) or (Chromosomes, Human, Pair 11/ and Trisomy/) (1659) 49     (Trisomy 11 or Trisomy 18).mp. (2224) 50     Chromosomes, Human, Pair 12/ and (Tetrasomy/ or Mosaicism/) (141) 51     ((Pallister adj3 Killian) or (isochromosome adj2 12p) or (Chromosome 12p adj2 (Mosaicism or Tetrasomy))).mp. (279) 52     Chromosomes, Human, Pair 13/ and Trisomy/ (928) 53     (Patau or Trisomy 13 or Trisomy d).mp. (1447) 54     Chromosomes, Human, Pair 18/ and Trisomy/ (1400) 55     ((Edward* adj3 Syndrome) or trisomy 18 or trisomy e).mp. (2249) 56     Down Syndrome/ (21870) 57     Down's Syndrome/ (21870) 58     limit 57 to yr="1975 - 1992" (5759) 59     Mongolism/ (21870) 60     limit 59 to yr="1966 - 1974" (2473) 61     (Trisomy 21 or (Down* adj2 Syndrome) or mongolism or mongoloid*).mp. (28715) 62     Chromosomes, Human, Pair 22/ and (Trisomy/ or Mosaic/) (265) 63     ((Whole chromosome adj3 trisomy) or (Meiotic adj3 Nondisjuntion) or Trisomy 22).mp. (274) 64     DiGeorge Syndrome/ (1677) 65     (DiGeorge or "Chromosome 22q11.2 Deletion").mp. (2345) 66     Common Variable Immunodeficiency/ (1718) 67     ("Common Variable Immunodeficiency" or (hypogammaglobulin?emia* adj3 (acquired or common variable)) or (agammaglobulin?emia* adj3 (acquired or common variable))).mp. (2753) 68     "Congenital Disorders of Glycosylation"/ (498) 69     ((Congenital Disorder* adj3 Glycosylation) or (carbohydrate deficient adj2 glycoprotein)).mp. (953) 70     Hydrocephalus/cn (215) 71     (Congenital adj3 Hydrocephal*).mp. (962) 72     (Congenital Myopathies and fib?r* type disproportion).mp. (51) 73     ((Congenital or Fetal) adj3 Varicella).mp. (235) 74     Costello Syndrome/ (89) 75     (Costello or faciocutaneoskeletal).mp. (472) 76     Creutzfeldt-Jakob Syndrome/ (5925) 77     Jakob-Creutzfeldt Syndrome/ (5925) 78     limit 77 to yr="1981 - 1990" (686) 79     Creutzfeldt-Jakob Disease/ (5925) 80     limit 79 to yr="1969 - 1980" (467) 81     ((Creutzfeldt adj3 Jakob) or (spongiform encephalopathy adj3 subacute) or (corticostriatospinal adj3 degeneration) or (spastic adj3 pseudosclerosis)).mp. (7453) 82     De Lange Syndrome/ (680) 83     (De Lange* or "Bushy Syndrome" or "Amsterdam dwarfism").mp. (1290) 84     "Diffuse Cerebral Sclerosis of Schilder"/ (2317) 85     (Alper#s or (myelinoclastic adj3 diffuse sclerosis) or (diffuse cerebral adj3 sclerosis) or (balo* adj3 concentric sclerosis) or (progressive adj3 sclerosing poliodystroph*) or schilder*).mp. (2479) 86     Epidermolysis Bullosa, Junctional/ or Epidermolysis Bullosa/ (2829) 87     ((Epidermolysis adj3 Bullosa) or Herlitzs).mp. (5195) 88     Farber Lipogranulomatosis/ (25) 89     Lipidoses/ (3927) 90     limit 89 to yr="1976 - 2008" (974) 91     Sphingolipidoses/ (343) 92     limit 91 to yr="1992 - 2008" (108) 93     (Farber* or ((ceramidase or n-laurylsphingosine deacylase) adj3 deficienc*)).mp. (942) 94     Friedreich Ataxia/ (2270) 95     ((Friedreich* adj3 (Ataxia or disease or syndrome)) or (hereditary adj3 (spinal scleroses or spinal staxia)) or (spinal adj3 heredoataxia)).mp. (3007) 96     Fucosidosis/ (138 97     (Fucosidosis or (alpha fucosidase adj3 deficienc*)).mp. (309) 98     Gangliosidoses/ [Lysosomal Storage Diseases, Nervous System] (567) 99     (Gangliosidos* or (ganglioside adj3 (storage or lipidosis))).mp (1761) 100     alpha-N-Acetylgalactosaminidase/df [Deficiency] (5) 101     (((alpha-N-Acetylgalactosaminidase or alpha-NAGA) adj3 Deficienc*) or Schindler or Kanzaki).mp. (171) 102     Argininosuccinic Aciduria/  (139) 103     ((Argininosuccinic adj3 Aciduria*) or ((Argininosuccinate Lyase or argininosuccinase or ALS) adj3 deficienc*) or (arginino adj3 succinic) or mckusick 20790 or argininosuccinicaciduria).mp. (311) 104     Chromosomes, Human, Pair 1/ and monosomy/ (103) 105     (Chromosome 1p36 adj3 (Monosomy or deletion)).mp. (49) 106     Chromosomes, Human, Pair 3/ and Chromosome Inversion/  (111) 107     (Chromosome 3 adj3 Inversion).mp.   (42) 108     Chromosomes, Human, Pair 3/ and Monosomy/ and (Chromosomes, Human, Pair 5/ and Trisomy/)  (2) 109     (Chromosome adj3 (3p25 Partial Monosomy or 5p15* Trisomy)).mp. (0) 110     Chromosomes, Human, Pair 5/ and Trisomy/ (206) 111     (Chromosome 5 adj3 Trisomy).mp.   (42) 112     Chromosomes, Human, Pair 5/ and Chromosome Deletion/ (861) 113     (Chromosome 5q14* adj5 Deletion).mp. (0) 114     (Chromosomes, Human, Pair 6/ and Translocation, Genetic/) or (Chromosomes, Human, Pair 4/ and Translocation, Genetic/)  (1445) 115     ((Chromosome 6 or Chromosome 4) and Unbalanced Translocation).mp.   (32) 116     (Chromosomes, Human, Pair 7/ and Trisomy/) or (Chromosomes, Human, Pair 6/ and Monosomy/)   (426) 117     ((Chromosome adj3 Unbalanced Rearrangement) or Partial Trisomy 7 or Monosomy 6).mp.   (46) 118     Chromosomes, Human, Pair 14/ and Chromosome Deletion/   (303) 119     (Chromosome 14 adj3 Deletion).mp.   (42) 120     Chromosomes, Human, Pair 18/ and Chromosome Deletion/   (447) 121     (Chromosome 18q adj3 Deletion).mp.   (38) 122     Chromosomes, Human, Pair 18/ and Chromosomes, Human, Pair 5/ and Chromosome Deletion/   (35) 123     (Chromosome 18 and Chromosome 5 and Deletion).mp.   (14) 124     Triploidy/   (226) 125     (Chromosome 69 adj3 Triploidy).mp. (0) 126     (Desminopath* or (Myopath* adj3 Myofibrillar) or (Desmin adj3 Related)).mp.   (441) 127     ((Dilated Cardiomyopathy adj3 Ataxia) or (3 Methylglutaconic adj3 Aciduria)).mp.   (159) 128     Epilepsies, Myoclonic/ [Epilepsy] (2619) 129     ((Infantile Myoclonic adj3 Epilepsy) or Dravet*).mp. (544) 130     (Early adj3 Myoclonic Encephalopathy).mp. (77) 131     Gangliosidoses, GM2/ or Tay-Sachs Disease/ or Tay-Sachs Disease, AB Variant/ (1303) 132     ((GM2 adj3 Gangliosidos*) or (Tay adj2 Sach*) or (hexosaminidase adj3 deficiency)).mp. (2215) 133     (Gangliosidos* adj4 GM3).mp. (5) 134     Glucosephosphate Dehydrogenase Deficiency/ (4294) 135     ((Glucosephosphate Dehydrogenase or g6pd or Glucose-6-Phosphate Dehydrogenase) adj3 Deficiency).mp. (5089) 136     Glutaryl-CoA Dehydrogenase/df [Deficiency] (120) 137     ((Glutaric adj3 Acidemia Type I) or (Glutaric adj3 Aciduria 1) or (Glutaryl-CoA dehydrogenase adj3 deficienc*)).mp.   (210) 138     Multiple Acyl Coenzyme A Dehydrogenase Deficiency/  (90) 139     ((Glutaric Aciduria adj3 (Type 2 or Type II)) or ((Multiple Acyl Coenzyme A Dehydrogenase or Electron transfer flavoprotein or oxidoreductase) adj3 deficienc*)).mp (340) 140     Glycogen Storage Disease Type II/ [Lysosomal Storage Diseases, Nervous System] (1323) 141     ((Glycogen Storage Disease adj3 Type II) or Pompe* or ((acid maltase or alpha-glucosidase) adj3 deficienc*)).mp. [Lysosomal Storage Diseases, Nervous System] (2342) 142     Glycogen Storage Disease Type IIb/ (98) 143     (Danon or antopol or (glycogen storage adj3 cardiomyopath*) or pseudoglycogenosis 2 or ((LAMP-2 or LAMP2 or lysosome associated membrane protein 2) adj3 deficenc*)).mp. (190) 144     Glycogen Storage Disease Type IV/ (176) 145     ((Glycogen Storage adj3 (Type IV or type 4)) or brancher or (andersen* adj3 disease) or glycogenos*).mp. (1783) 146     Hereditary Central Nervous System Demyelinating Diseases/ (282) 147     (Hereditary Central Nervous System adj3 Demyelinat*).mp. (282) 148     Histiocytosis, Langerhans-Cell/ (5024) 149     (((Histiocytos* or granulomatos*) adj3 Langerhans Cell) or (hand schu#ller adj3 Christian) or (aleukemic adj3 reticuloendotheliosis) or (histiocytos* adj3 x)).mp. (7973) 150     Hyperargininemia/ (166) 151     (Hyperargininemia* or (arginase adj3 deficienc*) or argininemia*).mp. (272) 152     Incontinentia Pigmenti/ (628) 153     (Incontinentia Pigmenti or (bloc* adj3 sulzberger) or (hypomelanosis adj3 ito) or (neonatal pigment adj3 incontinence)).mp. (1272) 154     Pantothenate Kinase-Associated Neurodegeneration/ (430) 155     ((Infantile Neuroaxonal adj3 Dystrophy) or (Pantothenate Kinase-Associated adj3 Neurodegeneration) or (Pigmentary Pallidal adj3 Degeneration) or hallervorden spatz).mp. (787) 156     Refsum Disease, Infantile/ (8) 157     ((Infantile adj3 Refsum) or (infantile adj3 phytanic acid storage disease)).mp. (135) 158     ((Joubert or Boltshauser) adj3 syndrome).mp.   (557) 159     Huntington Disease/ (10175) 160     (huntington* adj5 juvenile).mp. (126) 161     Kearns-Sayre Syndrome/ (606) 162     ((Kearns adj3 Sayre) or (cpeo adj3 myopathy) or oculocraniosomatic or ophthalmoplegia).mp. (10663) 163     Klippel-Trenaunay-Weber Syndrome/ (1083) 164     (Klippel Trenaunay or angioosteohypertrophy or angio osteohypertrophy or (dysplastic adj3 angiopathy congenital) or congenital angiodysplasisa or (osteohypertrophic varicose adj3 naevus) or (parkes adj3 weber)).mp. (1525) 165     Leukodystrophy, Globoid Cell/ (860) 166     (Krabbe or (Leukodystrophy adj3 Globoid Cell) or (galactosylceramide beta galactosidase adj3 deficienc*)).mp. (1191) 167     Lafora Disease/ (222) 168     (Lafora or (progressive myoclonic epilepsy adj3 (type 2 or type II))).mp. (525) 169     Leigh Disease/ (864) 170     ((Leigh adj3 (syndrome or disease)) or (necrotizing encephalomyelopath* adj3 subacute)).mp. (1237) 171     Lennox Gastaut Syndrome/ (192) 172     Spasms, Infantile/ (3025) 173     limit 172 to yr="1988 - 2014" (2109) 174     ((Lennox adj4 Gastaut) or (childhood epileptic adj3 encephalopathy)).mp. (1139) 175     Lesch-Nyhan Syndrome/ (1160) 176     (Lesch Nyhan or (juvenile adj3 hyperuricemia) or (guanine phosphoribosyltransferase adj3 deficienc*) or (hypoxanthine phosphoribosyltransferase adj3 deficienc*) or (choreoathetosis adj3 self mutilation)).mp. (1485) 177     Alexander Disease/ or Leukodystrophy, Metachromatic/ or Adrenoleukodystrophy/ or Pelizaeus-Merzbacher Disease/ or Hereditary Central Nervous System Demyelinating Diseases/ (3349) 178     ((Alexander adj3 Disease) or Leukodystrophy or Adrenoleukodystrophy or (Pelizaeus adj3 Merzbacher)).mp. (5722) 179     Lipidoses/ or Cholesterol Ester Storage Disease/ or Sjogren-Larsson Syndrome/ or Gaucher Disease/ (8094) 180     (Lipidos* or (lipid storage adj3 disorder*) or (cerebroside adj3 lipidosis) or Sphingolipidoses or (glucocerebrosidase adj3 deficienc*) or (Sjogren adj3 Larsson) or Gaucher or Ichthyosis).mp. (14996) 181     "Classical Lissencephalies and Subcortical Band Heterotopias"/ (107) 182     (Lissencephal* or (Miller adj3 Dieker) or (agyria pachygyria adj3 band spectrum)).mp. (1397) 183     Infant/ and Osteopetrosis/ (443) 184     (Malignant Infantile adj3 Osteopetrosis).mp. (58) 185     alpha-Mannosidosis/ (236) 186     Mannosidosis/ (5) 187     limit 186 to yr="1985 - 2003" (1) 188     beta-Mannosidosis/ (9) 189     Mannosidase Deficiency Diseases/ (5) 190     limit 189 to yr="1984 - 2003" (1) 191     ((alpha or beta) adj3 Mannosidos*).mp. (361) 192     ((Marshall adj3 Smith) or (Greig* adj3 syndrome) or (Polysyndactyly adj3 cephalopolysyndactyly)).mp. (194) 193     (Meckel or Gruver or (Dysencephalia adj3 Splanchnocystica)).mp. (4100) 194     (Menkes or (copper transport adj3 disease) or ((steely or kinky) adj3 hair) or (dystrophy adj3 trichopolio) or trichopoliodystrophy).mp. (1425) 195     MERRF Syndrome/ (321) 196     (MERRF or ((myoclon* adj3 epilepsy) and ragged red fibers) or fukuhara).mp. (629) 197     Leukodystrophy, Metachromatic/ (1139) 198     ((Metachromic Leukodystroph* adj3 Juvenile) or ((arylsulfatase or sulfatid*) adj3 deficienc*) or (sulfatid* adj3 lipidosis)).mp. (235) 199     ((Methylcrotonyl-CoA Carboxylase adj3 Deficienc*) or 3 Methylcrotonygycinuria or (Methylcrotonygycinuria adj3 type 1)).mp. (87) 200     Methylmalonyl-CoA Mutase/df [Deficiency] (105) 201     ((Methylmalonyl CoA Mutase adj3 deficienc*) or (methylmalonic adj3 acidemia)).mp. (565) 202     Mevalonate Kinase Deficiency/ (135) 203     ((Mevalonate Kinase adj3 Deficienc*) or mevalonicacidurias or (hyper igd adj3 syndrome*) or hyperimmunoglobulinemia d).mp. (366) 204     Mitochondrial Diseases/ (3856) 205     (((Mitochondrial adj3 (Disorder* or Disease*)) or (phosphorylation oxidative mitochondrial or electron transport chain or mitochondrial respiratory chain)) adj3 deficienc*).mp. (232) 206     MELAS Syndrome/ (1079) 207     ((MELAS adj3 Syndrome*) or ((mitochondrial myopathy adj3 encephalopathy) and lactic acidosis)).mp. (1377) 208     mitochondrial encephalomyopathies/ (939) 209     (Mitochondria* adj3 Encephalomyopath*).mp. (1683) 210     Mitochondrial Myopathies/ (1499) 211     ((Mitochondrial adj3 Myopath*) or (luft* adj3 disease*) or (megaconial adj3 myopath*)).mp. (2907) 212     ((Mowat adj3 Wilson) or (microcephaly adj3 mental) or (hirschsprung adj3 disease)).mp. (4771) 213     Mucolipidoses/ (925) 214     ((Mucolipidos* adj3 Type III) or (Pseudo Hurler adj3 Polydystrophy)).mp. (82) 215     (Mucolipidos* adj3 Type IV).mp. (140) 216     ((Mucolipidos* adj3 Type II) or (i cell adj3 Disease) or sialolipidos* or mucolipidos* or (myoclonus adj3 cherry red spot) or (glycoprotein neuraminidase adj3 deficienc*) or (inclusion cell adj3 disease)).mp. (1330) 217     Mucopolysaccharidosis I/ (1578) 218     (Mucopolysaccharidosis I or Hurler or Scheie or (alpha l iduronidase adj3 deficienc*) or gargoylism or lipochondrodystroph*).mp. (2034) 219     Mucopolysaccharidosis II/ (820) 220     ((Mucopolysaccharidosis adj3 (II or type 2)) or (Hunter adj3 syndrome) or (iduronate sulfatase adj3 deficienc*)).mp. (1004) 221     Mucopolysaccharidosis III/ (572) 222     ((Mucopolysaccharidosis adj3 (III or type 2)) or Sanfilippo* or San filippo* or ((n-acetylglucosamine-6-sulfatase or acetyl-coa:alpha-glucosaminide n-acetyltransferase or sulfamidase) adj3 deficienc*) or oligophrenia polydystrophic).mp. (781) 223     (((Mucopolysaccharidosis adj3 (IIIa or type 3a)) or (Heperan sulfate or sulfamidase)) adj3 deficienc*).mp. (23) 224     (((Mucopolysaccharidosis adj3 (IIIb or type 3b)) or (n acetyl alpha d glucosaminidase or naglu)) adj3 deficienc*).mp. (11) 225     Multiple Sulfatase Deficiency Disease/ (24) 226     SPHINGOLIPIDOSES/ (343) 227     limit 226 to yr="2000 - 2006" (63) 228     Sulfatases/ (3289) 229     limit 228 to yr="1973 - 2006" (2109) 230     ((Multiple Sulfatase adj3 Deficienc*) or (Austin adj3 Disease) or mucosulfatidosis or (juvenile adj3 sulfatidos*)).mp. (124) 231     Myoclonic Epilepsies, Progressive/ (298) 232     ((Myoclon* Epileps* adj3 Progressive) or (haw adj3 river) or encephalopathyadj3 biotin-responsive or (naito adj2 oyanagi) or (dentatorubral-pallidoluysian adj3 atrophy) or (myoclonus adj3 nephropathy) or (atypical adj3 inclusion-body) or (may adj2 white) or (dentatorubral pallidoluysian adj3 atrophy)).mp. (1755) 233     ((myotubular or x-linked centronuclear) adj3 myopath*).mp. (348) 234     Myopathies, Nemaline/ (408) 235     ((Rod adj3 Myopath*) or (nemaline adj3 myopath*)).mp. (749) 236     Neuroaxonal Dystrophies/cn [Congenital] (1) 237     (Seitelberger*adj3 Disease or (Neuroaxonal Dystroph* adj3 Congenital) or (congenital adj3 neuroaxonal dystrophy)).mp. (1) 238     Neuronal Ceroid-Lipofuscinoses/ (1741) 239     ((Neuronal Ceroid Lipofuscinosis adj3 (Type 3 or juvenile)) or cerebroretinaladj3 degeneration* or (batten adj3 disease) or (vogt adj3 spielmeyer) or (spielmeyer adj3 sjogren) or (Janksy adj3 Bielschowsky) or (Kuf* adj3 Disease) or (Spielmeyer Vogt adj3 Sjogren Batten) or (amaurotic adj3 idocy)).mp. (852) 240     (Neuronal Ceroid Lipofuscinosis adj3 (Type 6 or late infantile)).mp. (255) 241     Niemann-Pick Disease, Type A/ (38) 242     ((Niemann Pick adj3 (Type A or classical)) or (neuronal cholesterol adj3 lipidos*) or (sphingomyelinas* adj3 deficienc*) or (sphingomyelin adj3 (lipidos* or storage disease))).mp. (319) 243     Niemann-Pick Disease, Type C/ (430) 244     (Niemann-Pick Disease adj3 (Type C or nova scotia*)).mp. (786) 245     Hyperglycinemia, Nonketotic/ (177) 246     ((Hyperglycin?emia* adj3 (Nonketotic or non ketotic)) or (glycine adj3 encephalopath*)).mp. (496) 247     Oculocerebrorenal Syndrome/ (359) 248     Olivopontocerebellar Atrophies/ (633) 249     ((Olivopontocerebellar adj3 (Atroph* or degeneration*)) or (olivo ponto cerebellar adj3 (Atroph* or degeneration*)) or (pontoolivocerebellar adj3 (Atroph* or degeneration*)) or (dejerine adj3 thomas) or (presenile adj3 ataxias) or (Lowe* adj3 syndrome)).mp. (3366) 250     Sleep Apnea, Central/ (1015) 251     ((Ondine* adj3 curse) or (congenital adj3 central hypoventilation) or (primary alveolar adj3 hypoventilation) or (central sleep breathings adj3 disorder*)).mp. (629) 252     Ophthalmoplegia, Chronic Progressive External/ (488) 253     ((Ophthalmoplegia Chronic adj3 Progressive) or (ocular myopathy adj3 von graefe fuchs) or (dystrophy ocular adj3 muscular) or (ocular myopathy adj3 mitochondrial) or (graefe* adj3 disease)).mp. (505) 254     Pelizaeus-Merzbacher Disease/ (269) 255     "Diffuse Cerebral Sclerosis of Schilder"/ (2317) 256     limit 255 to yr="1966 - 1999" (1716) 257     Multiple Sclerosis/ (43327) 258     limit 257 to yr="1966 - 1999" (17568) 259     ((Pelizaeus adj3 Merzbacher) or (leukodystrophy adj3 hypomyelinating 1) or (balo adj3 disease) or ((brain or cerebral) adj3 sclerosis) or (concentric adj3 periaxial encephalitis)).mp. (3896) 260     Peroxisomal Disorders/ (507) 261     ((Peroxisomal adj3 (Disorder* or disease)) or disfunction* or (adrenoleukodystrophy autosomal adj3 neonatal) or hyperpipecolatemia* or (acidemia* adj3 hyperpipecolic) or (neonatal adj3 adrenoleukodystroph*)).mp. (2589) 262     ((Pontocerebellar Hypoplasia adj3 (Type II or type 2)) or (volendam adj3 neurodegenerative)).mp. (21) 263     (3 Hydroxyisobutyric adj3 Aciduria).mp. (15) 264     Progeria/ (1274) 265     ((Hutchinson adj3 Gilford) or Gilford or progeria or premature senility).mp. (1739) 266     Propionic Acidemia/ (109) 267     ((Propionic* adj3 Acidemia*) or (propionyl coa carboxylase adj3 deficienc*) or (hyperglycinemia ketoacidosis adj3 leukopenia) or propionicaciduria* or (glycin?emia* adj3 ketotic)).mp. (492) 268     Pyruvate Carboxylase Deficiency Disease/ (139) 269     ((Pyruvate Carboxylase adj3 Deficienc*) or (ataxia adj3 lactic acidosis)).mp. (186) 270     Pyruvate Dehydrogenase Complex Deficiency Disease/ (366) 271     (Pyruvate Dehydrogenase Complex adj3 Deficienc*).mp. (404) 272     Pyruvate Metabolism, Inborn Errors/ (54) 273     (Pyruvate Metabolism adj3 Inborn Errors).mp. (55) 274     Refsum Disease/ (625) 275     ((Refsum adj2 (Disease or syndrome)) or ((hereditary motor adj3 sensory neuropathy) and (type iv or type 4)) or (polyneuritiformis hemeralopia adj3 heredoataxia) or (phytanic acid oxidase adj3 (deficienc* or storage disease)) or (heredopathia adj3 (atactica polyneuritiformis or atacticapolyneuritiformis))).mp. (785) 276     Rubinstein-Taybi Syndrome/ (433) 277     ((Rubinstein adj3 Taybi) or (broad thumb adj3 hallux) or (rubinstein adj3 syndrome)).mp. (640) 278     Sandhoff Disease/ (395) 279     ((Sandhoff adj3 Disease) or ((total hexosaminidase or beta hexosaminidase beta subunit) adj3 deficienc*) or ((hexosaminidases adj5 deficiency) and (a and b))).mp. (512) 280     "Malformations of Cortical Development"/ (947) 281     Cerebral Cortex/ab [Abnormalities] (1727) 282     limit 281 to yr="1995 - 2007" (1073) 283     ((Schizencephaly adj2 (Type 2 or type II)) or (cerebral cortical adj3 dysplasia*) or (cortical development adj3 malformation*) or (schizocephal* adj3 (Type 2 or type II))).mp. (1514) 284     Short Rib-Polydactyly Syndrome/ (126) 285     ((Short Rib adj3 Polydactyly) or (polydactyly adj3 neonatal chondrodystrophy) or (saldino adj3 noonan) or (majewski adj3 syndrome)).mp. (234) 286     Sialic Acid Storage Disease/ (64) 287     ((Sialic Acid adj3 Storage Disease) or (sialuria* adj3 (finnish type or french type))).mp. (121) 288     "Spinal Muscular Atrophies of Childhood"/ (1031) 289     ((Spinal Muscular Atrophy adj3 (Type 1 or type i)) or (Infantile adj3 (spinal Muscular Atrophy or muscular atrophy)) or (Werdnig adj3 Hoffmann) or (hereditary progressive spinal adj3 muscular atrophy)).mp. (585) 290     Smith-Lemli-Opitz Syndrome/ (519) 291     Abnormalities, Multiple/ (38849) 292     limit 291 to yr="1967 - 1995" (19000) 293     (((Smith Lemli Opitz or reductase deficiency 7-dehydrocholesterol or rutledge friedman harrod or lethal acrodysgenital or rutledge lethal multiple congenital anomaly) adj2 Syndrome) or (hyperotosis corticalis adj3 generalisata familiaris)).mp. (785) 294     "NAV1.1 Voltage-Gated Sodium Channel"/ (597) 295     ((Voltage-Gated Sodium Channel adj3 "NAV1.1") or (Sodium channel voltage-gated adj3 (alpha subunit and type 1))).mp. (602) 296     Sphingolipidoses/ (343) 297     (Sphingolipidoses or (sphingolipid storage adj3 diseases)).mp. (458) 298     Subacute Sclerosing Panencephalitis/ (2223) 299     ((Subacute Sclerosing adj3 Panencephalitis) or ((Dawson or Bogaert*) adj3 Disease) or (sclerosing leukoencephalitid* adj3 subacute) or (inclusion body encephalitis adj3 measles)).mp. (2649) 300     ((Systemic adj3 Juvenile Xanthogranulomato*) or JXK).mp. (4) 301     Tuberous Sclerosis/ (5188) 302     ((Tuberous adj3 Sclerosis) or (bourneville adj3 pringle*) or (bourneville adj3 (syndrome or phacomatosis or adenoma sebace*))).mp. (7889) 303     Unverricht-Lundborg Syndrome/ (118) 304     ((Unverricht adj3 Lundborg) or (mediterranean adj3 myoclonic epileps*) or (unverricht adj3 disease*) or (myoclon* adj3 baltic) or (epilepsy progressive adj3 myoclonic 1a)).mp. (297) 305     von Hippel-Lindau Disease/ (2293) 306     ((von Hippel adj3 Lindau) or (lindau adj3 disease*) or (retina* adj5 angiomatos*) or (cerebelloretinal adj3 hemangioblastomatosis)).mp. (5235)  307     Spasms, Infantile/ (3025) 308     ((West adj3 Syndrome) or ((juvenile or infantile) adj3 spasm*)).mp. (4116) 309     Wolman Disease/ (166) 310     ((Wolman* adj3 (Disease or xanthomatos*)) or (familial adj3 xanthomatos*) or (acid lipase adj3 deficienc*)).mp. (413) 311     Adrenoleukodystrophy/ (1546) 312     ((X linked adj3 Adrenoleukodystroph*) or (Addison adj3 Schilder) or (Addison adj3 disease)).mp. (5274) 313     Xeroderma Pigmentosum/ (3302) 314     (((Xeroderma or atrophoderma) adj3 Pigmentos*) or (kaposi* adj3 disease) or (melanosis lenticularis adj3 progressiva)).mp. (6076) 315     Zellweger Syndrome/ (531) 316     (((Zellweger adj3 (Syndrome or disease)) or (cerebro hepato renal or cerebrohepatorenal)) adj3 syndrome*).mp. (942) 317     Anencephaly/ (2970) 318     (Anencephal* or (congenital absence adj3 brain)).mp. (4021) 319     Lipodystrophy, Congenital Generalized/ (126) 320     DIABETES MELLITUS, LIPOATROPHIC/ (194) 321     limit 320 to yr="2005 - 2006" (30) 322     Lipodystrophy/ (3042) 323     limit 322 to yr="1968 - 2006" (1880) 324     ((LIPODYSTROPH* adj3 CONGENITAL GENERALIZED) or (BERARDINELLI adj3 LIPODYSTROPH*) or (SEIP adj3 SYNDROME) or (LIPODYSTROPH* adj3 ACROMEGALOID GIGANTISM) or (LIPOATROPH* DIABETES adj3 CONGENITAL)).mp. (344) 325     (Bisalbuminemia or (Hartnup adj3 disorder)).mp. (167) 326     Canavan Disease/ (264) 327     ((canavan adj3 (disease or syndrome)) or (aspartoacylase adj3 deficiency) or (bogaert adj3 bertrand) or (spongy degeneration and white matter and infancy) or (spongy disease adj3 central nervous system) or (spongiform adj3 leukodystrophy)).mp. (400) 328     ((MECP2 Duplication adj3 Syndrome) or (trisomy adj3 Xq28) or (Xq28 duplication adj3 syndrome)).mp. (60) 329     Methyl-CpG-Binding Protein 2/ge [Genetics] (940) 330     Cytomegalovirus Infections/cn [Congenital] (1480) 331     ((Congenital Cytomegalovirus adj3 (Infection or inclusion)) or (CMV adj3 (disease or syndrome))).mp. (3730) 332     Toxoplasmosis, Congenital/ (2530) 333     ((Congenital adj3 Toxoplasm*) or (toxoplasm* adj3 (fetal or newborn))).mp. (3029) 334     ((multiple Pterygium adj3 Syndrome) and (leathal or deadly or terminal)).mp. (1) 335     (Galactosialidosis or (Goldberg adj3 syndrome) or (Neuraminidase deficiency adj3 beta galactosidase deficiency) or (sialidosis adj3 galacto)).mp. (286) 336     Hyperglycinemia, Nonketotic/ (177) 337     ((Glycine adj3 Encephalopath*) or ((Non ketotic or nonketotic) adj3 hyperglycinemia)).mp. (427)  338     Holoprosencephaly/ (1046) 339     (Holoprosencephal* or arhinencephal*).mp. (2002) 340     ((Hyperleucine adj6 isoleucineaemia) or (Hyper Leucine adj6 isoleucine anemia)).mp. (0) 341     Striatonigral Degeneration/ (65) 342     ((Infantile adj3 Bilateral Striatal Necrosis) or (Striatonigral adj3 (Degeneration* or atroph*)) or (nigrostriatal adj3 degeneration)).mp. (1128) 343     Jacobsen Distal 11q Deletion Syndrome/ (50) 344     ((paris adj3 trousseau) or (11q23 adj3 (distal deletion or terminal deletion)) or (chromosome 11q adj3 deletion) or (jacobsen adj3 (thrombocytop?enia or syndrome))).mp. (185) 345     (((Molybdenum cofactor or Encephalopathy or Aldehyde Oxidase Combined) adj3 deficiency) or (Sulfite Oxidase adj3 Xanthine Dehydrogenase)).mp. (290) 346     Mucopolysaccharidosis VI/ (413) 347     ((Mucopolysaccharidosis adj3 (VI or type 6)) or (Mucopolysaccharidosis adj3 Aicardi) or (callosal adj3 agenesis) or (ocular adj3 abnormalit*) or (Maroteaux adj3 Lamy) or ((arylsulfatase b or arsb) adj3 deficienc*) or (dwarfism adj3 polydystrophic)).mp. (2887) 348     Mucopolysaccharidosis VII/ (251) 349     (Mucopolysaccharidosis VII or Mucopolysaccharidosis 7 or ((Beta glucuronidase or gusb) adj3 deficienc*) or (sly adj3 (disease or syndrome))).mp. (352) 350     Ornithine Carbamoyltransferase Deficiency Disease/ (844) 351     ((Ornithine Carbamoyltransferase or Ornithine Carbamoyl transferase) adj3 Deficienc*).mp. (865) 352     Lissencephaly/ (165) 353     (Pachygyria* or Lissencephal* or macrogyria* or agyria* or ((large or broad) adj3 gyri)).mp. (1615) 354     Sulfite Oxidase/df (33) 355     Sulfatidosis/ (0) 356     Sulfocysteinuria.mp. (1) 357     (Chromosome Deletion/ and Chromosomes, Human, Pair 79/) or (Chromosome Deletion/ and Chromosomes, Human, Pair 23/) or (Chromosome Deletion/ and Chromosomes, Human, Pair 24/) or (Chromosome Deletion/ and Chromosomes, Human, Pair 46/) (0) 358     (chromosome adj3 (deletion 79 or deletion 23q or deletion q24 or Deletion 46xx)).mp. (0) 359     Osteochondrodysplasias/mo (19) 360     ((Wolcott adj3 Rallison) or (Schwartz adj3 jampel) or (Myotonia adj3 chondrodystrophic) or (Stuve adj3 Wiedemann) or (osteochondrodysplasia* adj3 lethal) or Schimke immuno-osseous dysplasia or (lethal adj3 dyssegmental dysplasia) or Achondrogenesis I or Achondrogesis II or (Thanatophoric adj3 dwarfism)).mp. (547) 361     ((Pena adj3 Shokeir) or (Cerebrooculofacioskeletal adj3 syndrome) or (Arthrogryposis multiplex adj3 congenita) or COFS Syndrome).mp. (721) 362     Trisomy/ and Chromosomes, Human, Pair 10/ (183) 363     (Mosaicism adj3 Trisomy 10).mp. (9) 364     1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 58 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 78 or 80 or 81 or 82 or 83 or 84 or 85 or 86 or 87 or 88 or 90 or 92 or 93 or 94 or 95 or 96 or 97 or 98 or 99 or 100 or 101 or 102 or 103 or 104 or 105 or 106 or 107 or 108 or 109 or 110 or 111 or 112 or 113 or 114 or 115 or 116 or 117 or 118 or 119 or 120 or 121 or 122 or 123 or 124 or 125 or 126 or 127 or 128 or 129 or 130 or 131 or 132 or 133 or 134 or 135 or 136 or 137 or 138 or 139 or 140 or 141 or 142 or 143 or 144 or 145 or 146 or 147 or 148 or 149 or 150 or 151 or 152 or 153 or 154 or 155 or 156 or 157 or 158 or 159 or 160 or 161 or 162 or 163 or 164 or 165 or 166 or 167 or 168 or 169 or 170 or 171 or 173 or 174 or 175 or 176 or 177 or 178 or 179 or 180 or 181 or 182 or 183 or 184 or 185 or 187 or 188 or 190 or 191 or 192 or 193 or 194 or 195 or 196 or 197 or 198 or 199 or 200 or 201 or 202 or 203 or 204 or 205 or 206 or 207 or 208 or 209 or 210 or 211 or 212 or 213 or 214 or 215 or 216 or 217 or 218 or 219 or 220 or 221 or 222 or 223 or 224 or 225 or 227 or 229 or 230 or 231 or 232 or 233 or 234 or 235 or 236 or 237 or 238 or 239 or 240 or 241 or 242 or 243 or 244 or 245 or 246 or 247 or 248 or 249 or 250 or 251 or 252 or 253 or 254 or 256 or 258 or 259 or 260 or 261 or 262 or 263 or 264 or 265 or 266 or 267 or 268 or 269 or 270 or 271 or 272 or 273 or 274 or 275 or 276 or 277 or 278 or 279 or 280 or 282 or 283 or 284 or 285 or 286 or 287 or 288 or 289 or 290 or 292 or 293 or 294 or 295 or 296 or 297 or 298 or 299 or 300 or 301 or 302 or 303 or 304 or 305 or 306 or 307 or 308 or 309 or 310 or 311 or 312 or 313 or 314 or 315 or 316 or 317 or 318 or 319 or 321 or 323 or 324 or 325 or 326 or 327 or 328 or 329 or 330 or 331 or 332 or 333 or 334 or 335 or 336 or 337 or 338 or 339 or 340 or 341 or 342 or 343 or 344 or 345 or 346 or 347 or 348 or 349 or 350 or 351 or 352 or 353 or 354 or 355 or 356 or 357 or 358 or 359 or 360 or 361 or 362 or 363 (286895)  Symptom Management Search   365     ((practice adj3 guideline) or (health care adj3 quality) or (clinical adj3 handover) or (clinical adj3 (pathway or protocol)) or (consensus adj3 development) or (good adj3 clinical practice) or (nursing adj3 care plan) or (nursing adj3 protocol) or (refusal adj3 participate)).mp. (167722) 366     ((quality adj3 life) or (international classification adj3 functioning) or (quality adjusted adj3 life year)).mp. (236616) 367     (Management adj3 (manifestation* or comorbidity or co-morbidity)).mp. (1231) 368     Symptom Assessment/ (1307) 369     (Symptom* adj3 (assessment or evaluation or screening tool* or cluster* or control or management or intervention*)).mp. (32428) 370     Treatment Outcome/ or Treatment Failure/ (746573) 371     (treatment adj3 (outcome* or failure* or efficacy or effectiveness)).mp. (837759) 372     ((medical adj3 futility) or (outcome adj3 (management or assessment or measurement)) or (therapy adj3 outcome)).mp. (104073) 373     ((disease free adj3 (interval or period)) or (outcome adj3 assessment)).mp. (88680) 374     ((therapy adj3 failure) or (ineffective adj3 drug)).mp. (9653) 375     (clinical adj3 (effective* or efficacy or outcome*)).mp. (175344) 376     (tool* or trial* or guideline* or protocol*).mp. (2334802) 377     (Clinical rating adj3 (instrument* or tool or scale)).mp. (261) 378     Patient Acuity/ (453) 379     (patient adj3 acuit*).mp. (1489) 380     Severity of Illness Index/ (188269) 381     (illness index adj3 severit*).mp. (188317) 382     Karnofsky Performance Status/ (1959) 383     (karnofsky adj3 (index or scale or score)).mp. (2897) 384     Sickness Impact Profile/ (6447) 385     (sickness adj3 impact profile*).mp. (7163) 386     Therapeutics/ (8215) 387     (Therapeutic* or treatment* or intervention* or therapy).mp. (5585786) 388     Acoustic Stimulation/ (37593) 389     (stimulation adj3 (acoustic or auditory)).mp. (39449) 390     (((acoustic or audio) adj3 stimulus) or (sound adj3 stimulation)).mp. (1630) 391     airway management/ (1574) 392     (airway adj3 (control or management or extubation*)).mp. (8389) 393     ((breathing adj3 (control or regulation)) or (control adj3 (respiration or respiratory)) or (respiration adj3 regulation)).mp. (8556) 394     airway extubation/ or intubation, intratracheal/ (31519) 395     ((extubation* adj3 endotracheal) or (intubation adj3 (intratraceal or tracheal or endotracheal or orotracheal or trachea))).mp. (14484) 396     laryngeal masks/ (4508) 397     (laryngeal adj3 mask*).mp. (5641) 398     respiration, artificial/ (41225) 399     (artificial adj3 respiration*).mp. (41874) 400     (mechanical adj3 (ventilation* or respiration)).mp. (30508) 401     (controlled adj3 (respiration or ventilation)).mp. (3566) 402     high-frequency ventilation/ or high-frequency jet ventilation/ or liquid ventilation/ or noninvasive ventilation/ or one-lung ventilation/ (3684) 403     (ventilation* adj3 (high frequency or proportional assist or liquid or fluorocarbon or non invasive or noninvasive or one lung or one-lung or single lung)).mp. (11023) 404     interactive ventilatory support/ (127) 405     (interactive adj3 ventilatory support).mp. (128) 406     (neurally adjusted adj3 ventilatory assist).mp. (163) 407     (lung separation adj3 technique*).mp. (8) 408     positive-pressure respiration/ or continuous positive airway pressure/ or intermittent positive-pressure breathing/ (20740) 409     (positive pressure adj3 (respiration* or ventilation* or breathing)).mp. (19901) 410     (hyperbaric adj3 (respiration or ventilation)).mp. (42) 411     (end expiratory adj3 positive pressure*).mp. (27) 412     (airway pressure adj3 release ventilation).mp. (191) 413     (aprv adj3 ventilation mode).mp. (1) 414     intermittent positive-pressure ventilation/ (2108) 415     ((intermittent or inspiratory) adj3 positive pressure).mp. (3824) 416     ventilator weaning/ (3168) 417     ((ventilator or respirator) adj3 weaning).mp. (3561) 418     Tracheostomy/ (5997) 419     tracheostom*.mp. (13073) 420     Apitherapy/ (90) 421     (apitherap* or ((bee sting or bee venom or honey or propolis) adj3 therap*)).mp. (331) 422     balneology/ (5670) 423     (balneology or balneotherapy or balneo therapy or bath therapy).mp. (6027) 424     ammotherapy/ (32) 425     (((artificial or induced or treatment) adj3 hyperthermi*) or ((dry heat or fever or heat or infra red or infrared) adj3 therap*) or pyretotherapy or thermotherapy ammotherapy).mp. (19534) 426     baths/ (4847) 427     (sand bath* or sandbath* or bath).mp. (25802) 428     mud therapy/ (1311) 429     ((mud adj3 (bath* or pack* or application)) or fangotherapy or peat therapy or peloid therapy or pelotherapy).mp. (448) 430     steam bath/ (660) 431     ((bath adj3 (finnish or steam)) or sauna or sweat lodge).mp. (970) 432     Bed Rest/ (3642) 433     (bed rest* or bedrest*).mp. (6934) 434     Behavior control/ (1539) 435     (behavior?r adj3 (control or manipulation*)).mp. (0) 436     (behavior?r adj3 (control or manipulation*)).mp. (0) 437     Restraint, physical/ (10651) 438     ((physical adj3 restraint*) or (physical adj3 immobilization)).mp. (11486) 439     fecal microbiota transplantation/ (62) 440     (Fecal adj3 transplantation*).mp. (430) 441     (donor adj3 feces infusion*).mp. (2) 442     (intestinal adj3 microbiota transfer*).mp. (0) 443     Immunotherapy/ (32769) 444     (immunotherap* or (biologic* response adj3 modifier therapy) or ((immune or immunoglobulin or immunological) adj3 therapy)).mp. (80805) 445     Chronotherapy/ or Drug Chronotherapy.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (822) 446     (chronotherap* or (time dependent adj3 drug therapy)).mp. (1418) 447     Climatotherapy/ (532) 448     (((climate or climatic) adj3 therapy) or climatotherapy or thalassotherapy or climatic treatment).mp. (955) 449     Clinical Protocols/ or Antineoplastic Protocols/ or Antineoplastic Combined Chemotherapy Protocols/ (138009) 450     ((clinical or treatment or antineoplastic or cancer) adj3 protocol*).mp. (160721) 451     (((anticancer or antineoplastic) adj3 drug combinations) or ((combined antineoplastic adj3 agent*) or protocol* or regimens) or (cancer adj3 "chemotherapy protocol")).mp. (501755) 452     combined modality therapy/ (151424) 453     ((combined modality adj3 therap*) or (multimodal adj3 (treatment* or therapy)) or (multiple modality adj3 (therapy or treatment))).mp. (155297) 454     chemoradiotherapy/ or chemoradiotherapy, adjuvant/ or chemotherapy, adjuvant/ (38733) 455     (chemoradiotherap* or radiohemotherap* or chemoradiation).mp. (20364) 456     ((adjuvant adj3 (chemotherapy* or drug therapy or chemoradiotherap* or radiochemotherap* or radiotherapy*)) or (neoadjuvant adj3 chemotherapy)).mp. (67345) 457     electroacupuncture/ (2880) 458     (elctroacupuncture or electric acupunture).mp. (1) 459     photochemotherapy/ (14211) 460     (photochemotherap* or (photodynamic adj3 therap*) or (hematoporphyrin adj3 photoradiation)).mp. (19494) 461     neoadjuvant therapy/ (13369) 462     (neoadjuvant adj3 (therap* or treatment*)).mp. (17839) 463     radioimmunotherapy/ or radiotherapy, adjuvant/ (21420) 464     (radioimmunotherap* or immunoradiotherap* or (radioimmuno adj3 therapy) or (adjuvant adj3 radiotherapy)).mp. (27061) 465     complementary therapies/ (14930) 466     ((alternative adj3 (medicine or therap*)) or (complementary adj3 (medicine or therap*))).mp. (36416) 467     acupuncture therapy/ or acupuncture analgesia/ or acupuncture, ear/ or moxibustion/ (15268) 468     (acupuncture* or mox?bustion).mp. (22356) 469     auriculotherapy/ (30) 470     auriculotherap*.mp. (90) 471     diffuse noxious inhibitory control/ (13) 472     (diffuse noxious adj3 inhibitory control).mp. (105) 473     holistic health/ (7258) 474     ((holistic adj3 (health or medicine or therap*)) or (wholistic adj3 (health or medicine or therap*))).mp. (8135) 475     bioresonance therapy/ (0) 476     ((bioresonance or bio resonance or mora) adj3 therap*).mp. (29) 477     homeopathy/ (4330) 478     (hom#eopathy or homeopathia).mp. (381) 479     horticultural therapy/ (26) 480     (horticultural adj3 therap).mp. (0) 481     mesotherapy/ (51) 482     mesotherapy.mp. (191) 483     mind-body therapies/ (701) 484     (mind body adj3 (medicine or therap*)).mp. (1075) 485     aromatherapy/ (603) 486     ((aroma adj3 therap*) or aromatherap*).mp. (996) 487     ((aroma adj3 therap*) or aromatherap*).mp. (996) 488     biofeedback, psychology/ or neurofeedback/ (6943) 489     ((psychology or physiological or alpha or brainwave or elctroencephalography) adj3 biofeedback*).mp. (6558) 490     breathing exercises/ (2929) 491     (((breathing or respiratory) adj3 exercise*) or (respiratory adj3 muscle training) or ((breathing or chest physical or respiration) adj3 therapy) or chest physiotherapy).mp. (6254) 492     hypnosis/ (8494) 493     (hypnos#s* or hypnotherapy* or mesmerism).mp. (11281) 494     autogenic training/ (1024) 495     ((autogenic adj3 training) or (progressive adj3 muscle relaxation)).mp. (1535) 496     "imagery (psychotherapy)"/ (1348) 497     (imagery or (directed reverie adj3 therap*)).mp. (11123) 498     laughter therapy/ (142) 499     (laughter adj3 therapy).mp. (159) 500     meditation/ (1862) 501     meditation.mp. (3800) 502     relaxation therapy/ (5928) 503     (relaxation adj3 (technique* or therapy or training or method or technics)).mp. (8462) 504     yoga/ (1827) 505     yoga.mp. (3134) 506     musculoskeletal manipulations/ (1120) 507     ((musculoskeletal adj3 manipulation*) or ((manipulation or manipulative or manual) adj3 therap*)).mp. (5021) 508     kinesiology, applied/ (241) 509     (applied adj3 kinesiology).mp. (294) 510     manipulation, chiropractic/ or manipulation, osteopathic/ (1560) 511     (chiropractic or cheirotherapy or chiropraxi* or chirotherapy or osteopathic or osteopathy).mp. (11158) 512     therapy, soft tissue/ or acupressure/ or massage/ (5742) 513     ((soft tissue adj3 therapy) or massage or bodywork* or reflexology or rolfing or acupressure or (zone adj3 therap*)).mp. (13802) 514     naturopathy/ (903) 515     naturopath*.mp. (1263) 516     organotherapy/ (167) 517     organotherap*.mp. (202) 518     phytotherapy/ (32590) 519     (phytotherapy or ((herb or herbal) adj3 therapy)).mp. (33365) 520     reflexotherapy/ (452) 521     (reflex adj3 therapy).mp. (210) 522     sensory art therapies/ or art therapy/ (1268) 523     sensory art therapies/ or art therapy/ (1268) 524     (art adj3 (therap* or treatment)).mp. (11453) 525     color therapy/ (74) 526     (chrom#totherapy or colo#r therap*).mp. (9) 527     dance therapy/ or music therapy/ or play therapy/ (3859) 528     (((dance or music or play or sandplay) adj3 therap*) or jocotherapy).mp. (5906) 529     "continuity of patient care"/ (15790) 530     (care adj3 (continuity or continuum)).mp. (21027) 531     patient discharge/ (21738) 532     ((patient or planning* or hospital) adj3 discharge).mp. (46697) 533     patient handoff/ (482) 534     (((clinical or patient or nursing) adj3 handoff*) or ((clinical or patient or nursing) adj3 hand off*) or ((clinical or patient or nursing) adj3 handover*) or ((clinical or patient or nursing) adj3 hand over*)).mp. (925) 535     patient transfer/ (6360) 536     ((patient adj3 (transfer* or transition* or turfing* or transport or transportation)) or (care adj3 transition*)).mp. (14755) 537     transition to adult care/ (515) 538     ((transition or pe#diatric or transfer* or hand over or handoff) adj3 adult care).mp. (697) 539     transitional care/ (43) 540     (transitional adj3 care*).mp. (839) 541     Cryotherapy/ or Hypothermia, Induced/ (22312) 542     (((cold or cryogenic) adj3 therap*) or cryotherap* or ((cold or hypothermal) adj3 bath) or cryothermy or cryotreatment).mp. (8943) 543     ((induced or therapeutic) adj3 hypothermia).mp. (22010) 544     Directly Observed Therapy/ (1374) 545     (directly adj3 observed therapy).mp. (1941) 546     Drainage/ or Drainage, Postural/ or Negative-Pressure Wound Therapy/ or Paracentesis/ (40432) 547     (drainage or (vacuum assisted adj3 closure*) or (negative pressure adj3 (dressing* or therap*))).mp. (93557) 548     ((aspiration adj3 puncture) or centes#s).mp. (665) 549     Drug Therapy/ (28831) 550     ((drug adj3 (therap* or treatment)) or chemotherap* or pharmacotherap* or ((medicament or medicinal or orthomolecular or pharmaceutical or phadrarmaco or pharmacological) adj3 therapy) or ((medicament or medicinal or orthomolecular or pharmaceutical or pharmaco or pharmacological) adj3 treatment) or medication).mp. (815419) 551     Chelation Therapy/ (1239) 552     (chelation adj3 therap*).mp. (2967) 553     Chemoprevention/ or Antibiotic Prophylaxis/ (15932) 554     (chemoprevention or chemoprophylaxis or ((tuberculosis or tuberculous) adj3 chemoprophylasis) or (antibiotic adj3 (premedication* or prophylaxis))).mp. (32816) 555     Consolidation Chemotherapy/ (243) 556     (consolidation adj3 chemotherap*).mp. (1384) 557     drug administration routes/ or administration, inhalation/ (30898) 558     ((aerosol adj3 therapy) or (inhalat* adj3 (drugs or dose or administration or therapy or treatment)) or inhalational or vapo#r therapy).mp. (44654) 559     administration, intravenous/ or infusions, intravenous/ or injections, intravenous/ (130749) 560     ((intravenous adj3 (injection* or administration* of infusion* or dose or drip or therapy or medication or transfuction)) or (IV adj3 (administration or delivery or injection or therapy or infusion))).mp. (150453) 561     ((drip or intravenous or intracerebroventricular or intraventricular or spinal or subcutaneous) adj3 infusion*).mp. (79770) 562     administration, oral/ or administration, buccal/ or administration, sublingual/ or administration, topical/ or administration, cutaneous/ or administration, intravaginal/ or administration, intravesical/ or administration, mucosal/ or administration, intranasal/ or administration, rectal/ or administration, ophthalmic/ (191712) 563     ((oral or buccal or sublingual or "sub lingual" or ocular or ophthalmic or mucosal or transmucosal or bladder drug or intravesical or intra vesical or intravaginal or vaginal or intra vaginal or cutaneous or dermal or intradermal or percutaneous or transcutaneous or transdermal or skin drug or topical or topic or intranasal or nasal or anal or rectal or subcutaneous fluid) adj3 administration*).mp. (235491) 564     ((transmucosal adj3 routing*) or (mucosal adj3 (delivery or dosage or dose or injection or therapy or treatment)) or (transmucosal adj3 (delievery or dosage))).mp. (2154) 565     ((bladder or injection* or intravesical or drug) adj3 instillation*).mp. (3575) 566     (vaginal adj3 instillation*).mp. (38) 567     chemotherapy, cancer, regional perfusion/ (3381) 568     (cancer chemotherapy adj3 (regional perfusion or isolation perfusion)).mp. (10) 569     infusions, parenteral/ or infusions, intra-arterial/ or infusions, intralesional/ or infusions, intraosseous/ or infusions, intraventricular/ or infusions, spinal/ or infusions, subcutaneous/ or hypodermoclysis/ (36662) 570     ((intra abdominal or intraperitoneal or parenteral or peritoneal or intra arterial or intraarterial or regional aterial or intralesional or intra osseous or intraosseous) adj3 infusion*).mp. (38419) 571     ((subcutaneous adj3 hydration) or hypodermoclysis).mp. (201) 572     (cheek injection or (cheek adj3 drug delivery) or (buccal adj3 (dosage or dose or injection))).mp. (112) 573     ((topic adj3 (application or medication or therapy or treatment)) or topical).mp. (93946) 574     ((intravaginal adj3 (dosage or dose or drug deliver or injection or suppository or tablet or therapy or treatment)) or (vaginal adj3 (administration or dosage or dose or application or delivery or infusion or injection or suppository))).mp. (12349) 575     ((intra vesical adj3 instillation) or (intravesical adj3 (administration or application or delivery or dose or injection or instillation or medication or therapy or treatment))).mp. (4910) 576     injections/ or injections, intra-arterial/ or injections, intra-articular/ or viscosupplementation/ or injections, intralesional/ or injections, intralymphatic/ or injections, intramuscular/ or injections, intraocular/ or intravitreal injections/ or injections, intraperitoneal/ or injections, intraventricular/ or injections, spinal/ or injections, epidural/ or blood patch, epidural/ or injections, subcutaneous/ or injections, intradermal/ or injections, jet/ or biolistics/ or injection, intratympanic/ or microinjections/ (192911) 577     (injection* or injectable* or viscocupplementation* or microinjection* or epidural or biolistic*).mp. (694443) 578     (gene gun adj3 technique).mp. (13) 579     (partical mediated or ((epidermal or extradural) adj3 injection*)).mp. (179) 580     ((transtympanic adj3 administration*) or (intratypanic adj3 injection*)).mp. (39) 581     (phonophores#s or iontophores#s).mp. (8860) 582     Drug Administration Schedule/ (89362) 583     (drug schedule* adj3 administration).mp. (1) 584     Administration, Metronomic/ (166) 585     (metronomic adj3 (administration* or therap*)).mp. (316) 586     Pulse Therapy, Drug/ (1369) 587     (drug pulse adj3 therap*).mp. (3) 588     Drug Delivery System/ (42162) 589     (drug delivery adj3 system*).mp. (50445) 590     (drug adj3 targeting*).mp. (4688) 591     Delayed-Action Preparations/ (30225) 592     ((drug release or delayed action or depot or sustained release or timed release or prolonged action) adj3 preparation*).mp. (30884) 593     Drug carriers/ (28423) 594     (drug adj3 carrier*).mp. (32083) 595     Dendrimers/ (3591) 596     ((dendritic adj3 compound) or dendrimer* or dendrons or (dendritic adj3 polymer*)).mp. (6943) 597     Nanocapsules/ or Nanoconjugates/ (2704) 598     (nanocapsule or nanoconjugate).mp. (537) 599     Insulin Infusion Systems/ (4184) 600     ((artificial endocrine adj3 pancreas) or (artificial beta adj3 cell*) or (insulin infusion adj3 system*) or (programmable implantable adj3 insulin infusion)).mp. (4477) 601     Pharmaceutical Vehicles/ (4540) 602     (pharmaceutical adj3 vehicle*).mp. (4591) 603     (drug adj3 prescribing*).mp. (1776) 604     Drug substitution/ (1779) 605     ((drug adj3 (substitution* or switching*)) or ((generic or therapeutic) adj3 subsititution*)).mp. (2594) 606     "Off-label use"/ (1494) 607     ((unlabeled adj3 indication*) or (off label adj3 (prescribing* or use* or prescribing))).mp. (3883) 608     Drug therapy, Combination/ (146283) 609     ((combination adj3 (drug therapy or chemotherapy* or medication or pharmacotherapy)) or (drug adj3 (polytherap* or combinations)) or polychemotherap* or (combination drug adj3 (regimen or treatment)) or (combined drug adj3 (regimen or therapy or treatment)) or (multi drug adj3 (regimen or therapy)) or (multidrug adj3 (regimen or therapy)) or (multiple drug adj3 (regimen or therapy or treatment))).mp. (234598) 610     Antiretroviral Therapy, Highly Active/ (18158) 611     (antiretroviral therapy adj3 highly active).mp. (21863) 612     enema/ (6710) 613     (enema* or clysma or clyster or enteroclysis).mp. (12376) 614     Drug Therapy, Computer-Assisted/ (1535) 615     (computer assisted adj3 drug therap*).mp. (1540) 616     Electrochemotherapy/ (378) 617     (electrochemotherap* or (electropermeablisation adj3 therap*)).mp. (664) 618     instillation, drug/ or iontophoresis/ (8407) 619     ((instillation adj3 drug) or iontophoresis).mp. (9973) 620     phonophoresis/ (280) 621     (phonophoresis or ultrasound or ultrasonic or sonication or sonification or ultra sound or ultrashell).mp. (218760) 622     Enzyme Therapy/ or Enzyme Replacement Therapy/ (1257) 623     ((enzyme adj3 (therap* or suppletion)) or enzymotherapy).mp. (6051) 624     Fluid Therapy/ (16705) 625     ((fluid or oral rehydration) adj3 therap*).mp. (19349) 626     Hypodermoclysis/ (98) 627     ((subcutaneous adj3 (fluid administration or hydration)) or hypodermoclys#s).mp. (212) 628     Home Infusion Therapy/ (637) 629     ((home infusion or outpatient infusion) adj3 therap*).mp. (720) 630     Hormone Replacement Therapy/ (8274) 631     (hormone adj3 (replacement or substitution)).mp. (20284) 632     Estrogen Replacement Therapy/ (14316) 633     (#estrogen adj3 (replacement* or administration or substitution or therapy)).mp. (1079) 634     Induction Chemotherapy/ (1217) 635     Maintenance Chemotherapy/ (753) 636     ((induction or maintenance) adj3 chemotherap*).mp. (9564) 637     Medication Reconciliation/ (512) 638     ((medication adj3 reconciliation) or ((drug or medication) adj3 management)).mp. (7731) 639     Near Miss, Healthcare/ (9) 640     (healthcare adj3 (near miss* or close call*)).mp. (12) 641     Molecular Targeted Therapy/ (14405) 642     (target* adj3 therap*).mp. (132449) 643     Orthomolecular Therapy/ (194) 644     ((megavitamin or orthomolecular) adj3 therap*).mp. (240) 645     Photochemotherapy/ (14211) 646     (photochemotherap* or chemophototherapy or (photodynamic adj3 therap*) or (hematoporphyrin adj3 photoradiation)).mp. (19495) 647     Pleurodesis/ (1196) 648     Pleurodesis.mp. (2318) 649     Polypharmacy/ or Deprescriptions/ (2929) 650     (polypharmacy or poly pharmacy or polypragmas* or deprescribing or deprescription*).mp. (5911) 651     Premedication/ or Antibiotic Prophylaxis/ (23099) 652     (premedication* or (antibiotic adj3 (prophylaxis or prevention)) or pretreatment or (preanaesthetic adj3 (treatment or medication))).mp. (178205) 653     Sclerotherapy/ (4629) 654     (sclerotherap* or sclero#ation or sclerosing therapy).mp. (7591) 655     self administration/ (9872) 656     (self adj3 administration*).mp. (13235) 657     Self Medication/ (4217) 658     (self adj3 medication*).mp. (7461) 659     Thrombolytic Therapy/ or Hirudin Therapy/ (20684) 660     (((fibrinolytic or hirudin) adj3 therap*) or (therapeutic adj3 thrombolys#s) or (anticoagula* adj3 (therapy or treatment))).mp. (21730) 661     electric stimulation therapy/ (18018) 662     (((electric stimulation or electrostimulation) adj3 therap*) or electrotherap*).mp. (18636) 663     cardiac pacing, artificial/ (19295) 664     ((artificial cardiac or biventricular) adj3 pacing*).mp. (1460) 665     cardiac resynchronization therapy/ (2390) 666     ((cadiac adj3 resynchronic#ation*) or (biventricular adj3 pacing)).mp. (1415) 667     deep brain stimulation/ (5714) 668     (((brain adj3 stimulation*) or electrical stimulation) adj3 brain).mp. (13843) 669     electric countershock/ (13049) 670     ((cardiac adj3 electroversion*) or cardioversion* or (electric* adj3 (countershock or cadioconversion)) or (electric adj3 defibrillation)).mp. (15280) 671     pulsed radiofrequency treatment/ (170) 672     ((pulsed radio adj3 frequency treatment) or (pulsed radiofrequency adj3 treatment*)).mp. (277) 673     spinal cord stimulation/ (353) 674     (spinal adj3 stimulation).mp. (3660) 675     transcranial direct current stimulation/ (454) 676     ((transcranial direct adj3 current stimulation) or (transcranial adj3 electric stimulation)).mp. (2107) 677     transcutaneous electric nerve stimulation/ (3707) 678     ((transcutaneous electric* adj3 nerve stimulation) or (percutaneous electric* adj3 nerve stimulation) or ((analgesic cutaneous or transcutaneous or transdermal) adj3 electrostimulation) or electroanalgesia).mp. (4500) 679     vagus nerve stimulation/ (807) 680     ((vagal or vagus) adj3 nerve stimulation*).mp. (2494) 681     emergency treatment/ (9177) 682     (emergency adj3 (therap* or treatment*)).mp. (16567) 683     advanced trauma life support care/ (87) 684     (advanced trauma adj3 life support).mp. (637) 685     first aid/ (7238) 686     (first adj3 aid*).mp. (10681) 687     heimlich maneuver/ (13) 688     ((abdominal adj3 thrust*) or (Heimlich adj3 man#euver)).mp. (34) 689     resuscitation/ (23335) 690     resuscitation*.mp. (58915) 691     cardiopulmonary resuscitation/ or advanced cardiac life support/ (13277) 692     (((basic cardiac or advanced cardiac) adj3 life support) or ((cardio pulmonary or cardiopulmonary) adj3 resuscitation) or (mouth adj3 mouth resuscitation*)).mp. (18735) 693     ((cardiac or heart) adj3 massage*).mp. (3415) 694     respiration, artificial/ (41225) 695     ((artificial adj3 respiration) or (mechanical adj3 ventilation*)).mp. (59676) 696     resuscitation orders/ (3330) 697     ((resuscitation adj3 (order* or decision* or polic*)) or (do adj3 resuscitate order*) or (withholding adj3 resuscitation)).mp. (4059) 698     "transportation of patients"/ (8361) 699     (patient* adj3 (transportion* or transport or transfer)).mp. (12299) 700     Feeding Methods/ (800) 701     (feeding adj3 method*).mp. (2651) 702     Bottle Feeding/ (3422) 703     ((bottle adj3 feeding) or bottlefeeding*).mp. (4373) 704     Enteral Nutrition/ (16782) 705     ((enter* adj3 (feeding or nutrition)) or ((force or tube*) adj3 feeding) or (gastric adj3 feeding tube*) or (feeding adj3 (intestinal or intragastric))).mp. (24213) 706     Parenteral Nutrition/ or Parenteral Nutrition, Home/ or Parenteral Nutrition, Home Total/ or Parenteral Nutrition, Total/ (22059) 707     (((intravenous or parenteral) adj3 feeding*) or (parenteral adj3 nutrition)).mp. (28816) 708     (hyperalimentation adj3 (parenteral or intravenous)).mp. (866) 709     hyperthermia, induced/ (13795) 710     ((fever adj3 therap*) or (hyperthermia adj3 (induced or local or therapeutic)) or thermotherapy).mp. (19093) 711     diathermy/ (3322) 712     (diatherm* or elctrodiathermy or (high frequency adj3 (current therapy or electrotherapy or therapy))).mp. (5684) 713     short-wave therapy/ or ultrasonic therapy/ (8784) 714     ((short wave or shortwave or ultrasonic) adj3 therap*).mp. (8958) 715     ultrasound, high-intensity focused, transrectal/ (414) 716     high-intensity focused ultrasound ablation/ (885) 717     (high intensity adj3 focused ultrasound).mp. (2268) 718     Leeching/ (298) 719     (hirudotherapy or leeching or (leech adj3 therap*)).mp. (461) 720     Magnetic Field Therapy/ (779) 721     ((magnetic field or magnetic stimulation) adj3 therap*).mp. (1060) 722     Transcranial Magnetic Stimulation/ (7985) 723     (transcranial adj3 magnetic stimulation*).mp. (11803) 724     Mechanical Thrombolysis/ (407) 725     ((mechanical adj3 (clot disruption* or thrombolysis or thrombectomy or embolectomy)) or (pharmacomechanical adj3 thrombectomy)).mp. (1740) 726     nutrition therapy/ or diet therapy/ (11126) 727     (((nutrition or diet or dietary) adj3 therap*) or ((nutrition or diet or dietary) adj3 treatment)).mp. (26884) 728     caloric restriction/ or diet, diabetic/ or diet, carbohydrate-restricted/ or diet, fat-restricted/ or diet, gluten-free/ or diet, mediterranean/ or diet, paleolithic/ or diet, protein-restricted/ or diet, reducing/ or diet, sodium-restricted/ or diet, vegetarian/ or diet, macrobiotic/ or diet, vegan/ or ketogenic diet/ or nutritional support/ (41172) 729     ((caloric adj3 restriction) or (diet* adj3 (low calorie or diabetic or carbohydrate restricted or atkins or south beach or low carbohydrate or fat free or fat restricted or low fat or gluten free or Mediterranean or caveman or hunter gatherer or paleo or Paleolithic or stone age or low protein or protein free or reducing or weight loss or weight reduction or low salt or low sodium or salt free or sodium restricted or vegetarian or macrobiotic or vegan or ketogenic or supplementation))).mp. (66009) 730     ((artificial adj3 feeding) or (nutritional adj3 support)).mp. (11828) 731     orthopedic procedures/ (20226) 732     (orthopedic adj3 (procedure* or surger* or operation)).mp. (26217) 733     cementoplasty/ (68) 734     (cementoplast* or (osteoplast* adj3 percutaneous)).mp. (187) 735     vertebroplasty/ (1421) 736     vertebroplasty.mp. (2859) 737     kyphoplasty/ (496) 738     ((balloon adj3 vetebroplasty) or kyphoplasty).mp. (1369) 739     intervertebral disc chemolysis/ (459) 740     ((intervertebral adj3 dis# chemolysis) or chemonucleolys#s or discolys#s).mp. (797) 741     manipulation, orthopedic/ (3633) 742     (orthop#edic adj3 manipulation).mp. (7) 743     viscosupplementation/ (102) 744     viscocupplementation*.mp. (0) 745     Pain Management/ (23239) 746     ((pain adj3 (management* or relief)) or ((audio or sequential analgetic or surgical) adj3 analgesia) or audioanalgesia).mp. (66195) 747     patient care/ or ambulatory care/ (45981) 748     ((patient or informal or after or ambulatory or outpatient or urgent or advance) adj3 care*).mp. (267906) 749     aftercare/ (6862) 750     ((after adj3 treatment*) or aftercare or after care).mp. (317618) 751     ((clinic adj3 visit*) or (outpatient adj3 health service*)).mp. (10094) 752     peritoneal dialysis, continuous ambulatory/ (9633) 753     (continuous ambulatory adj3 peritoneal dialysis).mp. (10704) 754     "bloodless medical and surgical procedures"/ (112) 755     (((blood conservation or transfusion alternative) adj3 strateg*) or (bloodless medical adj3 (surgical procedures or surgery programs)) or ((bloodless or transfusion free) adj3 surger*)).mp. (525) 756     critical care/ (42672) 757     ((critical or intensive) adj3 care).mp. (159935) 758     intensive care, neonatal/ (4660) 759     ((neonatal or infant or newborn) adj3 intensive care).mp. (22358) 760     custodial care/ or day care, medical/ (5035) 761     ((custodial or day) adj3 care).mp. (14382) 762     (partial adj3 hospitalization).mp. (335) 763     "episode of care"/ (1563) 764     (care adj3 episode*).mp. (2966) 765     hospitalization/ (80771) 766     hospitalization*.mp. (156067) 767     "length of stay"/ (66073) 768     ((hospital adj3 stay*) or (stay* adj3 length*)).mp. (124410) 769     patient admission/ (20041) 770     ((patient or voluntary) adj3 admission).mp. (23279) 771     patient discharge/ (21738) 772     ((patient or hospital) adj3 discharge).mp. (45891) 773     patient readmission/ (10100) 774     readmission*.mp. (18514) 775     institutionalization/ or deinstitutionalization/ (8012) 776     (institutionalization or institutionalized or deinstitutionalization or deinstitutionalized).mp. (18083) 777     life support care/ (7219) 778     ((life support adj3 care) or (extraordinary adj3 treatment*) or (life adj3 prolongation)).mp. (8748) 779     advanced cardiac life support/ or advanced trauma life support care/ (870) 780     (advanced trauma adj3 life support).mp. (637) 781     long-term care/ (22903) 782     (long term adj3 care).mp. (34157) 783     night care/ (1341) 784     (night adj3 care*).mp. (1499) 785     home nursing/ (8219) 786     (home care or home nursing).mp. (50054) 787     respite care/ (922) 788     (respite adj3 care*).mp. (1315) 789     primary care nursing/ (266) 790     (primary care adj3 nursing).mp. (570) 791     palliative care/ (44133) 792     (palliative adj3 (care or surger* or therap* or treatment*)).mp. (57265) 793     "Hospice and Palliative Care Nursing"/ or Palliative Care Nursing/ (212) 794     (palliative adj3 nursing).mp. (662) 795     Palliative medicine/ or Palliative Care Medicine/ (88) 796     (palliative adj3 medicine).mp. (1594) 797     patient positioning/ (3364) 798     (patient adj3 positioning*).mp. (5809) 799     kangaroo-mother care method/ (145) 800     ((Kangaroo mother adj3 care) or (skin adj3 skin care)).mp. (6542) 801     perinatal care/ or postnatal care/ (7509) 802     (perinatal adj3 (care or medicine)).mp. (6107) 803     ((postnatal or postpartum) adj3 care).mp. (5937) 804     perioperative care/ or intraoperative care/ or perioperative nursing/ (30562) 805     ((perioperative or intraoperative or postoperative or preoperative or intraoperative) adj3 care).mp. (125003) 806     ((perianesthesia or perioperative) adj3 nursing).mp. (6644) 807     preoperative care/ or postoperative care/ (97200) 808     (postoperative adj3 (procedure* or therapy or treatment)).mp. (18963) 809     (preoperative adj3 (procedure* or therapy or treatment)).mp. (9252) 810     subacute care/ (759) 811     (("sub acute" or subacute) adj3 care*).mp. (1093) 812     Terminal Care/ (22955) 813     ((life care adj3 end*) or (terminal adj3 care)).mp. (26321) 814     hospice care/ (5074) 815     (hospice adj3 (care or program*)).mp. (7706) 816     time-to-treatment/ (1795) 817     (time adj3 (treatment* or time)).mp. (3176095) 818     transitional care/ (43) 819     (transitional adj3 care).mp. (827) 820     Euthanasia/ or Euthanasia, Active/ or Euthanasia, Active, Voluntary/ or Euthanasia, Passive/ (12848) 821     (euthanasia or mercy killing*).mp. (25217) 822     withholding treatment/ (9844) 823     ((withholding adj3 treatment) or ((cessation or withdraw*) adj3 treatment)).mp. (21925) 824     Suicide, Assisted/ (4970) 825     (assisted adj3 (death* or suicide)).mp. (5577) 826     Patient Care Bundles/ (138) 827     care bundles.mp. (287) 828     phototherapy/ (6297) 829     (phototherap* or ((light or photoradiation or ultraviolet or sunlight) adj3 therap*)).mp. (19044) 830     heliotherapy/ (443) 831     Heliotherapy.mp. (501) 832     intense pulsed light therapy/ (70) 833     (intense pulsed adj3 (therap* or treatment)).mp. (201) 834     low-level light therapy/ (3723) 835     ((low level adj3 (light therap* or laser irradiation or laser therap*)) or ((biostimuation or phototherapy) adj3 laser) or (low power adj3 (light therap* or laser irradiation or laser therap*))).mp. (4584) 836     hematoporphyrin photoradiation/ (636) 837     ((hematoporphyrin adj3 photoradiation) or photochemotherapy or chemophototherapy).mp. (15589) 838     ultraviolet therapy/ (4065) 839     ((ultraviolet adj3 therap*) or actinotherap*).mp. (4468) 840     puva therapy/ (3294) 841     ((puva adj3 (therap* or radiation)) or (psoralen ultraviolet adj3 a therapy)).mp. (3645) 842     photopheresis/ (752) 843     ((extracorporeal adj3 photochemotherap*) or photopheresis).mp. (1115) 844     physical therapy modalities/ (31080) 845     ((physical therapy adj3 (modalit* or technique*)) or neurophysiotherapy or (neurological adj3 physiotherapy)).mp. (31337) 846     animal assisted therapy/ or equine-assisted therapy/ (266) 847     (((animal or pet) adj3 assisted therap*) or (per adj3 therap*) or ((animal or pet) adj3 facilitated therap*)).mp. (2125) 848     ((equine assisted adj3 (psychotherap* or therap*)) or hippotherap* or (horseback riding adj3 therap*)).mp. (199) 849     exercise movement techniques/ (480) 850     kinesiotherapy.mp. (121) 851     qigong/ (54) 852     (Qigong or ch'I king or qi gong or chi kung or chigung).mp. (535) 853     dance therapy/ (244) 854     dance therap*.mp. (274) 855     tai ji/ (737) 856     (tai ji or tai chi or (tai adj3 ji quan) or t'ai chi or (tai chi adj3 chuan) or taijiqua).mp. (1166) 857     exercise therapy/ (29984) 858     (exercise adj3 (therap* or techniques or treatment)).mp. (35677) 859     motion therapy, continuous passive/ (596) 860     motion therap*.mp. (674) 861     muscle stretching exercises/ (1116) 862     ((stretching adj3 exercises) or ((active or ballistic or dynamic or isometric or passive or relaxed) adj3 stretching)).mp. (2291) 863     plyometric exercise/ (163) 864     ((stretch shortening adj3 (drill* or exercise*)) or plyometric*).mp. (618) 865     resistance training/ (4500) 866     ((resistance adj3 training) or ((weight lifting or weight bearing) adj3 exercise program) or (strength adj3 training)).mp. (10845) 867     hydrotherapy/ (2365) 868     (hydrotherap* or (whirlpool adj3 bath*) or (water immersion adj3 therapy)).mp. (2714) 869     therapeutic irrigation/ (15946) 870     ((therapeutic adj3 irrigation) or douching* or lavage*).mp. (64050) 871     manipulation, spinal/ (1263) 872     ((spinal or cervical or lumbar) adj3 manipulation*).mp. (2421) 873     myofunctional therapy/ (264) 874     ((myofunction adj3 therap*) or ((oral or orofacial) adj3 myotherap*)).mp. (3) 875     Placebos/ (33210) 876     (placebo* or (sham adj3 treatment)).mp. (190231) 877     Rehabilitation/ (17110) 878     (rehabilitation or habilitation).mp. (135266) 879     Activities of Daily Living/ (53891) 880     ((daily living adj3 activit*) or (chronic limitation adj3 activit*)).mp. (63638) 881     Bibliotherapy/ (365) 882     Bibliotherap*.mp. (473) 883     Correction of hearing impairment/ (1761) 884     ((audiologic adj3 (habilitation* or rehabilition*)) or (aural adj3 (habilitation* or rehabilition*)) or (hearing adj3 (habilitation* or rehabilition* or revalidation))).mp. (45) 885     Communication Methods, Total/ (276) 886     (Total adj3 communication method*).mp. (278) 887     Lipreading/ (920) 888     (lipreading or lip reading* or speechreading*).mp. (1284) 889     Sign language/ (1807) 890     sign language*.mp. (2258) 891     Manual Communication/ (513) 892     (manual adj3 communication*).mp. (593) 893     Early Ambulation/ (2314) 894     (((early or accelerated) adj3 ambulation) or (early adj3 mobilization)).mp. (5166) 895     Neurological Rehabilitation/ (19) 896     ((neurologic adj3 rehabilitation) or neurorehabilitation).mp. (1939) 897     Occupational Therapy/ (11244) 898     ((occupational adj3 therap*) or ergotherapy).mp. (16172) 899     Recreation Therapy/ (78) 900     ((recreational or recreation) adj3 therap*).mp. (435) 901     "Rehabilitation of Speech and Language Disorders"/ (0) 902     ((speech adj3 (rehabilitation or reeduction)) or (voice adj3 (reeducation or rehabilitation))).mp. (1041) 903     Language Therapy/ (1445) 904     (language adj3 (therap* or training*)).mp. (3366) 905     Speech, Alaryngeal/ (1375) 906     (alaryngeal adj3 (speech or voice)).mp. (1421) 907     Speech, Esophageal/ (622) 908     (#esophag* adj3 (speech* or voice)).mp. (860) 909     Speech, Therapy/ (5640) 910     ((speech adj3 (therap* or education or training)) or (language adj3 (learning or therapy or training)) or (logopedic adj3 (education or training)) or logotherapy or phoniatrics or phoniatry).mp. (12339) 911     Voice Training/ (1214) 912     (voice adj3 training*).mp. (1306) 913     Telereganilitation/ (0) 914     ((remote or virtual or tele) adj3 rehabilitation*).mp. (262) 915     Respiratory Therapy/ (6036) 916     ((respiratory or inhalation) adj3 therapy).mp. (21884) 917     Chest Wall Oscillation/ (237) 918     ((high frequency adj3 chest compression) or (chest wall adj3 oscillation*)).mp. (295) 919     Extracorporeal Membrane Oxygenation/ (6574) 920     ((extracorporeal or extra corporeal or extrapulmonary) adj3 oxygenation).mp. (8748) 921     Oxygen Inhalation Therapy/ (12564) 922     (oxygen adj3 (therap* or administration or insufflation or treatment)).mp. (23103) 923     Hyperbaric Oxygenation/ (10589) 924     ((hyperbaric adj3 (oxygenation* or o2 or oxygen therapy)) or ((high adj3 oxygen pressure) or tension o2 or tension oxygen)).mp. (11618) 925     Self Care/ (26463) 926     (self adj3 (care or management or treatment)).mp. (44912) 927     Blood Glucose Self-Monitoring/ (4838) 928     ((blood glucose or blood sugar) adj3 self monitoring).mp. (5568) 929     Self Administration/ (9872) 930     (self adj3 administration*).mp. (13235) 931     Self Medication/ (4217) 932     (self adj3 medication*).mp. (7461) 933     Therapies, Investigational/ (1177) 934     (((experimental or innovative or investigational) adj3 therap*) or ((experimental or innovative or investigational) adj3 treatment*)).mp. (24082) 935     "Compassionate Use Trials"/ (335) 936     (expanded access* or compassionate use* or (humanitarian adj3 device exemption*)).mp. (1632) 937     Therapy, Computer-Assisted/ or Radiotherapy Planning, Computer-Assisted/ (20604) 938     (computer assisted adj3 (protocol directed or therapy or dosimetry calculation* or radiotherapy or drug therapy)).mp. (23406) 939     Surgery, Computer-Assisted/ (11922) 940     ((computer aided or computer assisted or image guided) adj3 surger*).mp. (13086) 941     Robotic Surgical Procedures/ (1136) 942     (robotic surgical adj3 procedure*).mp. (1177) 943     Therapy with Helminths/ (50) 944     ((helminthic or helminth or worm) adj3 therap*).mp. (191) 945     or/365-944 (10516979) 946     364 and 945 (95446)   Alertness Symptom Search  947     arousal/ or attention/ or wakefulness/ (101709) 948     fatigue/ or mental fatigue/ (22958) 949     Torpor/ (63) 950     (mental adj3 fatigue*).mp. (1979) 951     (cortical adj3 vigilance).mp. (23) 952     (concentration adj3 (less or lack or reduce* or mental)).mp. (17042) 953     (alertness* or attention* or fatigue* or arousal* or wakeful* or torpor or lassitude).mp. (463225) 954     letharg*.mp. (6326) 955     fatigability.mp. (1766) 956     (awareness or consciousness or distractab* or dysthymia).mp. (140947) 957     or/946-955 (614354) 958     946 and 956 (3989)  959     limit 957 to "all child (0 to 18 years)" (1697) 960     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 961     957 and 959 (2007) 962     958 or 960 (2007)  Behaviour Symptom Search  947     Behavioral Symptoms/ (2034) 948     Psychomotor Agitation/ (4286) 949     Irritable Mood/ (1272) 950     self-injurious behavior/ or self mutilation/ (8628) 951     (behavio?r* adj3 (symptom* or disturbance* or change)).mp. (33127) 952     (psychomotor adj3 (excitement or hyperactivity)).mp. (76) 953     (body adj2 rocking).mp. (96) 954     (head adj2 banging).mp. (126) 955     agitation.mp. (14279) 956     akathisia.mp. (2489) 957     restless*.mp. (7219) 958     irritabil*.mp. (7235) 959     aggress*.mp. (168145) 960     antagonistic.mp. (24929) 961     destructive*.mp. (25892) 962     parasuicide.mp. (464) 963     (self adj3 (injur* or destructive or harm or mutilat*)).mp. (13954) 964     ((flat or negative) adj3 affect).mp. (6898) 965     or/947-964 (293813) 966     946 and 965 (2190)  967     limit 966 to "all child (0 to 18 years)" (878) 968     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 969     966 and 968 (1035) 970     967 or 969 (1035)  Bowel Incontinence Symptom Search  947     Fecal Incontinence/ (8443) 948     Feces/ (76546) 949     Defecation/ (6117) 950     Diarrhea/ (41675) 951     Gastrointestinal Motility/ (19976) 952     (defecate* or diarrh* or f#eces).mp. (112801) 953     ((symptom or function* or habit* or movement* or strain*) adj3 bowel).mp. (8874) 954     (f#ecal* adj3 (incontin* or evacuat*)).mp. (1718) 955     loose stool*.mp. (852) 956     ((intestin* or gastrointestin* or stomach) adj3 motility).mp. (23055) 957     (colon adj3 transit*).mp. (432) 958     or/947-957 (212123) 959     946 and 958 (1126)  960     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 961     959 and 960 (722) 962     limit 959 to "all child (0 to 18 years)" (652) 963     961 or 962 (722)  Breathing Difficulty Symptom Search  947     mucus/se or saliva/se (5660) 948     respiratory insufficiency/ or hypoventilation/ or hyperventilation/ (35045) 949     (hypoventilation* or hyperventilation).mp. (14497) 950     Dyspnea/ (16973) 951     Cough/ (13323) 952     cough*.mp. (47784) 953     Apnea/ (6627) 954     airway obstruction/ or nasal obstruction/ (21025) 955     ((mucus or saliv*) adj3 secretions).mp. (960) 956     ((airway adj3 obstruction*) or choking).mp. (26948) 957     dyspn#ea*.mp. (7859) 958     Apn#ea*.mp. (7006) 959     (Breath* adj3 (difficult* or abnormalit* or dysfunction*)).mp. (2228) 960     (Respirat* adj3 distress).mp. (44587) 961     ((respiratory or ventilatory) adj3 depression).mp. (5913) 962     (respiratory adj3 (failure or insufficien* or arrest)).mp. (49120) 963     (breathless* or (breath adj3 shortness*)).mp. (9321) 964     (severe adj3 paradoxical respiration).mp. (3) 965     (cardiopulmonary adj3 (arrest or insufficency)).mp. (2454) 966     (lung adj3 insufficiency).mp. (212) 967     or/947-966 (221698) 968     946 and 967 (2352)  969     limit 968 to "all child (0 to 18 years)" (1350) 970     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 971     968 and 970 (1534) 972     969 or 971 (1534)   Constipation Symptom Search  947     Constipation/ (11576) 948     Defecation/ (6117) 949     Feces/ (76546) 950     Fecal Impaction/ (962) 951     Gastrointestinal Motility/ (19976) 952     constipat*.mp. (22050) 953     ((hard or impact*) adj3 stool*).mp. (328) 954     (bowel* adj3 (symptom* or habit or evacuat* or movement* or void* or strain)).mp. (6300) 955     (f#eces adj3 (impact* or evacuate*)).mp. (13) 956     defecate*.mp. (725) 957     (intestin* adj3 (motility adj3 dysmotility)).mp. (1) 958     (gastrointestinal adj3 (motility or dysmotility)).mp. (21902) 959     (colon* adj3 (transit or inertia)).mp. (1701) 960     (bowel* adj3 (function* or habit* or symptom* or evacuat* or movement or void* or strain*)).mp. (9540) 961     (f#eces adj3 (evacuat* or impacted)).mp. (14) 962     (fecalith or dyschezia).mp. (335) 963     (abdominal adj3 disten*).mp. (5586) 964     or/947-963 (135641) 965     946 and 964 (1028)  966     limit 965 to "all child (0 to 18 years)" (732) 967     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 968     965 and 967 (800) 969     966 or 968 (800)  Feeding Difficulties Symptom Search  947     gastroesophageal reflux/ or laryngopharyngeal reflux/ (23165) 948     (feeding adj3 (difficult* or problem*)).mp. (3327) 949     Regurgitation.mp. (30040) 950     Vomiting/ (20773) 951     (vomit* or emesis).mp. (68022) 952     retch*.mp. (940) 953     Nausea/ (13833) 954     nausea.mp. (54095) 955     (feeding adj3 intolerance*).mp. (496) 956     (salivary adj3 secretion*).mp. (2622) 957     Dyspepsia/ (7862) 958     (Dyspepsia* or indigestion*).mp. (12613) 959     Deglutition Disorders/ (16424) 960     aspiration.mp. (68047) 961     ((Gastric or Gastroesophageal or gastric acid or gastro oesophageal or esophageal) adj3 reflux).mp. (29691) 962     (swallowing adj3 (difficulty or disorder* or incoordination)).mp. (2423) 963     (dysphagia or (deglutition adj2 disorder*)).mp. (28288) 964     ((oromotor or oral motor) adj3 skill*).mp. (88) 965     or/947-964 (247301) 966     946 and 965 (1983)  967     limit 966 to "all child (0 to 18 years)" (1085) 968     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 969     966 and 968 (1221) 970     967 or 969 (1221)  Sleep Symptom Search  947     Sleep Disorders/ (17223) 948     dyssomnias/ or sleep deprivation/ or sleep disorders, circadian rhythm/ or sleep disorders, intrinsic/ (9760) 949     "Sleep Initiation and Maintenance Disorders"/ (9937) 950     (sleep adj3 (disturbanc* or disorder or problem* or disturbance* or dysfunction*)).mp. (19385) 951     ((short sleeper or long sleeper or subwakefullness) adj3 syndrome*).mp. (0) 952     (neurogenic tachypneas adj3 sleep-related).mp. (0) 953     dyssomnia*.mp. (414) 954     (nocturnal adj3 "eating-drinking syndrome").mp. (4) 955     ((extrinsic or environmental or adjustment or limit-setting) adj3 sleep).mp. (344) 956     insomnia*.mp. (14655) 957     (sleep adj3 (initiation or maintenance)).mp. (10607) 958     ((lethal or severe or obstructive) adj3 sleep apn#ea).mp. (3344) 959     (sleep disordered adj3 breathing).mp. (4691) 960     or/947-959 (59359) 961     946 and 960 (704)  962     limit 961 to "all child (0 to 18 years)" (263) 963     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 964     961 and 963 (308)  Temperature Regulation Symptom Search  947     body temperature regulation/ or sweating/ or thermogenesis/ or torpor/ (28408) 948     (cold adj3 (hands or feet)).mp. (258) 949     Hypothermia/ (12765) 950     hypothermia*.mp. (39844) 951     fever/ or "fever of unknown origin"/ (37761) 952     (fever* or hyperthermia* or pyrexia*).mp. (206630) 953     (diaphoresis or sweating or perspiration).mp. (12577) 954     Shivering/ (1676) 955     shiver*.mp. (3949) 956     Primary Dysautonomias/ (185) 957     Dysautonomia*.mp. (2551) 958     (body temperature adj3 regulation*).mp. (21848) 959     (thermoregulation* or heat loss*).mp. (8002) 960     or/947-959 (279889) 961     946 and 960 (1838)  962     limit 961 to "all child (0 to 18 years)" (836) 963     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616267) 964     961 and 963 (965) 965     962 or 964 (965)  Tone and Motor Difficulties Symptom Search  947     Muscle Spasticity/ (7830) 948     Spasm/ (6764) 949     dystonia/ or torticollis/ (8535) 950     Dystonic Disorders/ (2019) 951     Muscle Tonus/ (6457) 952     ataxia/ or cerebellar ataxia/ or gait ataxia/ (11026) 953     muscle hypertonia/ or muscle rigidity/ (2971) 954     neuromuscular manifestations/ or muscle hypotonia/ (2919) 955     Dyskinesias/ (1892) 956     hyperkinesis/ or hypokinesia/ (5051) 957     Contracture/ (7298) 958     ((tone adj3 (problem* or difficult*)) or (tone adj3 (problem* or difficult*))).mp. (101) 959     (spastic* or spasm).mp. (43371) 960     (muscle* adj3 tonus*).mp. (6739) 961     (dystonia* or toticollis).mp. (13301) 962     (ataxia* or ataxy).mp. (36497) 963     (rubral adj3 tremors).mp. (4) 964     (coordination adj3 (impairment* or lack of)).mp. (926) 965     (dyscoordination or dyssynergia).mp. (1386) 966     (muscl* adj3 (tone or hypertonicity or atonic or flaccid or poor or increase* or decrease* or spasm)).mp. (36354) 967     (((abnormal or involuntary) adj3 movement) or asterixis or dyskinesia or hemiballism* or ballismus).mp. (17182) 968     (hyperkinesi* or hypokinesia).mp. (8122) 969     (muscle* adj3 contracture*).mp. (1278) 970     (immobil* or (reduced adj3 mobilit*)).mp. (112004) 971     ((awkward or spastic) adj3 gait).mp. (362) 972     (muscular adj3 (hypotrophy or rigidity or hypertonia)).mp. (552) 973     hypotonia.mp. (7868) 974     dyskinesia.mp. (14787) 975     or/947-973 (283784) 976     946 and 975 (8395)  977     limit 976 to "all child (0 to 18 years)" (2634) 978     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616629) 979     976 and 978 (3083) 980     977 or 979 (3083)  Urinary Incontinence Symptom Search   947     Enuresis/ or Diurnal Enuresis/ or Nocturnal Enuresis/ (4496) 948     urinary incontinence/ or Urinary Incontinence, Stress/ or Urinary Incontinence, Urge/ or urinary retention/ (31813) 949     (urinary adj3 (incontinence or retention)).mp. (42020) 950     bedwetting.mp. (283) 951     enuresis.mp. (5649) 952     or/947-951 (47042) 953     946 and 952 (230)  954     limit 953 to "all child (0 to 18 years)" (93) 955     (infan* or neonat* or newborn* or baby or babies or toddler* or p?ediatric* or child* or teen* or adoles* or youth*).mp. (3616629) 956     953 and 955 (101) 957     954 or 956 (101)      Supplementary File 2 Figure 1: Heat map of Q3 conditions and symptoms  Table 1: Characteristics of included studies with a single symptom First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Alertness       Bossie 20171 Cross-sectional Friedrich’s ataxia 16 + 10 controls (3 children) TEF Describes trajectory or characteristics  No difference between FA and controls in mitochondrial capacity, but HA has lower muscle endurance and lower feelings of physical energy. de Vries 20092 Cross-sectional Tuberous sclerosis  37 + 37 sibling controls CPRS, TEA-CH Describes trajectory or characteristics TSC group had significantly more neuropsychological attention deficits Fabio 20093 Case Control Rett syndrome 10 + 10 controls VABS Describes trajectory or characteristics Children with Rett have deficits in ability to pay attention to selective sources of information. Looman 20104 Cross-sectional 22q11.2 deletion syndrome 45 + 10,343 healthy controls and 683 with chronic conidtions PedsQL Multidimensional Fatigue Scale, 22qFamily Matters Survey Describes trajectory or characteristics Children with 22q11.2 deletion have significantly more fatigue than controls. Parrish 20125 Cross-sectional Acquired demyelinating syndromes 49 + 92 healthy controls PedsQL Multidimensional Fatigue Scale Describes trajectory or characteristics Parent and self-report showed elevated fatigue symptoms in comparison to controls. Paulsen 20106 Tool / Scale Development Friedrich’s ataxia 43 + 43 healthy controls PedsQL Generic Core and Multidimensional Fatigue Scale Tool or scale development Children with FA had higher fatigue scores than controls. More studies are needed to validate the PedQL Fatigue Scales in this population.  Quintero7 2014 Cross-sectional 22q11.2 deletion syndrome 32 with VCFS + 55 with other conditions + 42 healthy controls Attention Network Test, Flanker Test Describes trajectory or characteristics The control but not the implementation of attention is selectively impaired in girls with 22q11.2 deletion and but all attentional efficiency improves with age. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Behavioral Problems     Adams 20068 Cross-sectional NCL3, NCL6 26 CBCL, SIB-R, Y-BOCS Describes trajectory or characteristics Participants showed a broad range of behavioral and psychiatric problems that can be used as a quantitative baseline to measure further decline. Anderson 19769 Case Series Lesch-Nyhan syndrome 4 Number of biting attempts, Behavior assessed on scale of 1-5 Pharmacologic intervention; L-5- hydroxyl-tryptophan No change in self-mutilation seen Anderson 1977,10 197811 Case Series Lesch-Nyhan syndrome 5 Finger to mouth contacts per minute Psychological intervention; Aversive stimulation (electric shock) / Positive reinforcement and / or time-out Positive reinforcement and/or time-out led to reductions in self-injury, punishment encouraged self-injury Anderson 199412 Cross-sectional Lesch-Nyhan syndrome 40 - Describes trajectory or characteristics Severity of self-injury does not change over time and earlier the age of onset of self-injury the worse it became. Arron 201113 Cross-sectional Cri-du-Chat, De Lange syndrome 741 (58 with CdC, 101 with DL) RBQ Describes trajectory or characteristics  High prevalence of self-injury in this population; self-injury associated with repetitive and impulsive behavior. Aneja 200714 Case control 22q11.2 deletion syndrome 86 + 36 controls with ADHD CBCL Describes trajectory or characteristics Participants with 22q11.2 deletion had elevated scores on the CBCL  Basile 200715 Cross-sectional De Lange syndrome  56 DBC-P Describes trajectory or characteristics Participants showed variable behavioral characteristics consistent with CdLS, including hyperactivity, attention disorder, anxiety, compulsive disorders, self-injurious behavior and autistic-like features. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Clarke 199816 Cross-sectional, Survey Cri-du-chat  38 CdC + 75 other conditions  ABC Describes trajectory or characteristics CdC associated with greater ratings of problems behaviors on at least one ABC subscale than comparison groups with intellectual disability. Cornish 199817 Cross-sectional Cri-du-chat 20 VABS Describes trajectory or characteristics 50% of participants had externalizing behaviors, including poor concentration, hyperactivity and impulsiveness. Cross 201418 Cross-sectional MPS III 20 + 25 with Intellectual Disability VABS, ABC, EDBI, SBRS Describes trajectory or characteristics Middle phase (2-9 years) of MPS III associated with greater frequency of challenging behaviors than late phase (10-15 years) Duijff 201319 Longitudinal Study 22q11.2 deletion syndrome 53 CNCL Describes trajectory or characteristics As children with 22q11.2 deletion get older internalizing behaviors increase while externalizing behaviors decrease.  Dykens 199720 Cross-sectional Cri-du-chat  146 ABC Describes trajectory or characteristics Children with CdC show hyperactivity, aggression, tantrums and self-injurious behavior.  Eden 201421 Cross-sectional De Lange syndrome, tuberous sclerosis  37 with TS + control of 404, 61 with CdLS CBQ, Wessex Behaviour Schedule, RBQ,  Describes trajectory or characteristics Rates of self-injury and aggression were high, but not significantly higher than children in the control groups; both self-injury and aggression were associated with stereotyped and pain behaviors, low mood, hyperactivity, impulsivity and repetitive language use. Eom 201722 Cross-sectional Leigh syndrome, mitochondrial disorders, MELAS syndrome 16 with LS, 3 with MELAS, 51 non-specific MD CBCL Describes trajectory or characteristics Mean score of total behavioral problem was close to clinical cutoff score and 43% were within in clinical range. Fabbro 201223 Cross-sectional 22q11.2 deletion syndrome 74 VABS Describes trajectory or characteristics Lower adaptive behavior scores were strongly associated with high depression or anxiety scores, lower IQ and higher age. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Feinstein 200224 Case control 22q11.2 deletion syndrome 28 + 29 cognitively matched controls CBCL Describes trajectory or characteristics CBCL score were elevated in comparison to general population, but not significantly higher than matched controls. Freeman 201325 Cross-sectional Smith-Lemli-Opitz syndrome 13 Behavior Problem Questionnaire  Describes trajectory or characteristics Greater severity of cholesterol synthesis defect correlated with severity of challenging behaviors. Galera 200626 Cross-sectional Costello syndrome  11 + 33 controls CBCL Describes trajectory or characteristics CS had significantly higher Internalizing Problems, but not Externalizing Problems than controls. Hall 200127 Longitudinal Lesch-Nyhan syndrome 3 - Describes trajectory or characteristics Parents reported that self-injury began suddenly and violently; self-injury may occur more frequently when child is left alone. Hyman 200228 Cross-sectional De Lange syndrome  88 Wessex Scale, The Self-Restraint Checklist, Compulsive Behavior Checklist Describes trajectory or characteristics Found a significant association between self-injurious behavior and self-restraint, with those displaying both having significantly more compulsive behavior.  Jansen 200729 Case control 22q11.2 deletion syndrome 69 with VCFS + 69 controls CBCL Describes trajectory or characteristics Children with 22q11.2 deletion showed more behavioral problems than control. Khasnavis 201630 RCT Lesch-Nyhan syndrome 8 + 1 adult BPI Pharmacologic intervention; Ecopipam Appears to reduce self-injury, but study terminated early due to side effects. Klaassen 201331 Case control 22q11.2 deletion syndrome 90 + 33 control CBCL Describes trajectory or characteristics About 30% of children with 22q11.2 deletion are above the 97th percentile for at least one behavior subscale on the CBCL. Kopp 200832 Cross-sectional Tuberous sclerosis  87 BSI-2 Describes trajectory or characteristics 40% showed of children with TS clinically significant behavioral problems and 50% of their parents reported significant parenting stress. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Lal 201633 Cross-sectional De Lange syndrome  15 ABC Describes trajectory or characteristics 14 of the 15 children had abnormal scores in more than one behavioral area and these behavioral problems can exist in children with normal brain structure. Leclezio 201534 Tool / Scale Development Tuberous sclerosis  62 caregivers of children with TS TAND Checklist Tool or scale development Pilot validation suggests that the TAND Checklist is a useful tool for behavioral problems in TS.  Moss 200535 Cross-sectional De Lange syndrome  8 CBI Describes trajectory or characteristics 7 of the 8 participants showed self-injurious behavior that was associated with a particular setting events. Mulder 201736 Systematic Review De Lange syndrome  - - Describes trajectory or characteristics There is a lack of uniform and validated assessment tools used in studies of this population.  Nelson 201437 Longitudinal, Survey  Cri-du-chat, De Lange syndrome  42 with CdC, 67 with DLS, 142 controls with other conditions RBQ, MIPQ Describes trajectory or characteristics DLS showed significantly lower levels of mood, interest and pleasure than CDC and control group. Nyhan 198038 Case Series Lesch-Nyhan syndrome 9 - Pharmacologic intervention; 5-hydroxy-tryptophan Immediate reduction in self-injurious behavior, but after 1-3 months this reduction disappeared. Oliver 200639 N of 1 Trials De Lange syndrome  16 CBI, Coding system for videotaped behaviors Describes trajectory or characteristics For 9 of the participants self-injury was related to levels of adult attention, showing SIB can be affected by environmental factors. Oliver 200840 Case control De Lange syndrome  54 with DLS + 46 matched controls CBI, ISQ, ABC, CBC, Frequency of behavior Describes trajectory or characteristics No difference between groups in global behavior disorder. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Oliver 200941 Case control De Lange syndrome  54 with CdLS + 46 matched controls CBI, ISQ, ABC, CBC, Frequency of behavior Describes trajectory or characteristics Self-injurious behavior was not more prevalent in DLS then the controls, but was predicted by hyperactivity, stereotyped and compulsive behaviors. Oliver 201242 Cross-sectional Children with severe intellectual disability 943 WBS Describes trajectory or characteristics High frequency repetitive or ritualistic behavior associated with great risk of self-injury and showing two or more sever challenging behaviors.  Robey 200343 Cross-sectional Lesch-Nyhan syndrome 64 Questionnaire designed for study Describes trajectory or characteristics Most common forms of self-injury was biting of lip and/or fingers. Rojahn 200144 Tool / Scale Development Unspecified ID 1122 BPI, ABC, NCBRF, DASH-II Tool or scale development BPI is a valid tool; 43% of participants showed self-injury, 54% showed stereotyped behavior, 38% showed aggressive behavior. Rojahn 201245 Tool / Scale Development Unspecified ID 1122 BPI, BFI-S Tool or scale development BPI Short Form is equally sensitive compared to original BPI.  Rojahn 201346 Cross-sectional, Tool / Scale Development De Lange syndrome  180 BPI, BFI-S Describes trajectory or characteristics BPI and BPI-S are both valid tools for behavioral problems in intellectual disabilities.  Shapiro 201547 Longitudinal, Tool / Scale Development MPSIII 25 SBRS Describes trajectory or characteristics The SBRS is a valid scale in MPSIII Sloneem 200948 Case Control De Lange syndrome  47 + 17 matched controls CBI, Operational definitions of self-injury Psychological intervention; Environmental conditions: demand, denial, attention, no contact The association between environment and self-injury in DLS did not differ from the controls. Srivastava 201449 Cross-sectional De Lange syndrome  41 CARS, ABC, VABS Describes trajectory or characteristics The highest ABC subscales in children with DLS were Hyperactivity and Irritability.  First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Staley 200850 Retrospective Chart Review Tuberous sclerosis  257 - Describes trajectory or characteristics 10% of children with TS showed SIB. Teixeira 201151 Cross-sectional Cri-du-chat  10 The Psychoeducational Profile - Revised  Describes trajectory or characteristics The number of maladaptive behaviors was difference between the participants. Uesugi 201052 Cross-sectional Mowat-Wilson syndrome, Pena Shokeir syndrome, tuberous sclerosis , West syndrome 6 with Q3 conditions, 20 with other conditions  ABC Describes trajectory or characteristics Most common behavioral problem subscales were Irritability and Lethargy, both of which were higher than in controls Uesugi 201353 Cross-sectional Mowat-Wilson syndrome, Pena Shokeir syndrome, tuberous sclerosis , West syndrome 86 ABC Describes trajectory or characteristics No significant differences between levels of intellectual disability and behavioral subscales, expect for stereotypy and lethargy Yagihashi 201254 Cross-sectional Rubinstein-Taybi syndrome 63 CBCL Describes trajectory or characteristics Older group shoed higher scores in Anxious/Depression and Aggressive Behavior. Breathing Difficulties      Afsharpaiman 201155 Retrospective Chart Review Achondroplasia 46 - Describes trajectory or characteristics 25 of the 46 participants had obstructive sleep apnea. Corben 201356 Longitudinal  Friedrich’s ataxia 82 ESS Describes trajectory or characteristics 21% of the participants were diagnosed with obstructive sleep apnea, showing the importance of regular screenings in this population. Finkel 201457 Longitudinal SMA1 7 - Describes trajectory or characteristics Respiratory muscle strength a deteriorating trend over time. Hagebeuk 201258 Cross-sectional Rett syndrome 12 SDSC Describes trajectory or characteristics In 8 children central apneas present during the day often with obstructive apneas at night; polysomnography is recommended. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) John 201159 Cross-sectional MPSVI 28 - Describes trajectory or characteristics Snoring, witnessed apnea and macroglossia common findings in this population. Julu 200160 Case Control Rett syndrome 4 - Describes trajectory or characteristics Respiratory rhythm was normal during sleep and abnormal when awake. Mackay 201761 Cross-sectional Rett syndrome 413 Questionnaire designed for study Describes trajectory or characteristics Breath-holding reported in 69% of RS participants, hyperventilation in 46% and abdominal bloating in 42%.  Mellies 200462 Case Series, Longitudinal SMA1 6 with SMA1 + 1 with SMA2  Questionnaire designed for study Physical intervention; Non-invasive (positive pressure) ventilation Non-invasive ventilation during sleep completely eliminated disordered breathing. Mogayzel 199863 Retrospective chart review Achondroplasia 88 - Describes trajectory or characteristics The majority of patients did not have OSA or central apnea, but a substantial minority are severely affected.  Myer 199064 RCT Leigh syndrome 3 with LS + 11 with other diagnoses - Pharmacologic intervention; Oral naltrexone No apneic events occurred during naltrexone therapy, but reoccurred when treatment was discontinued. Nabatame 200965 Retrospective Chart Review Glycogen storage disease type II 4 - Physical intervention; Non-invasive (positive pressure) ventilation Sleep-related symptoms resolved, but no improvement in respiratory function over 2 year follow-up period. Pieper 201866 Systematic Review Complex chronic conditions - - Pharmacological and physical interventions; various Evidence for effectiveness of treatment approaches for dyspnea is low. Rohdin 200767 Case Series Rett syndrome 12 - Describes trajectory or characteristics All subjects showed apnea, shallow breathing or hypoventilation when awake and asleep. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Kasapkara 201468 Cross-sectional MPS I, MPS II, MPS VI 19 - Describes trajectory or characteristics Study showed severe OSA in 11 participants and moderate in 2; home sleep studies are quick and accessible screening methods. Schulter 199569 Case-series Rett syndrome 2 - Describes trajectory or characteristics Study showed primary hyperventilation that lead to hypocapnia and apnea. In younger patient this occurred only during awake state, but in older patient this occurred when awake and asleep.  Semenza 198870 Retrospective Chart Review MLII, MLIII, MPSI, MPSII, MPSVI 21 - Surgical and pharmacologic interventions; Tonsillectomy, adenoidectomy, tracheostomy, diuretics, theophylline, digoxin, beta adrenergic blockers, calcium antagonists Respiratory problems in ML and MPS are complex and multifactorial.  Sudarsan 201471 RCT MPSI, MPSII, MPSIII, MPSIIIA, MPSIIIB,   MPSVI, MPSVII 32 with MPS + 48 ESS-C  Surgical and physical interventions; Adenotonsillectomy vs. CPAP Both groups showed significant improvement, with CPCP showing immediate improvement.   Tenconi 201772 Retrospective Chart Review Achondroplasia 43 - Surgical and physical interventions; ENT surgery, CPAP, BiPAP, cervical decompression OSA is common in children with Achondroplasia. Vilozni 201073 Longitudinal Ataxia telangectasia 28 - Describes trajectory or characteristics Rapid lung function deterioration occurs with respiratory infection. Waters 199374 Cross-sectional Achondroplasia 20 (15 children) - Describes trajectory or characteristics All participants had upper airways obstruction.  First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Waters 199575 Case Series Achondroplasia 21 - Surgical and physical interventions; Adenotonsillectomy, losing weight, CPAP Sleep studies after interventions show reduction in respiratory disturbance index. Weese-Mayer 200676 Case Control Rett syndrome 47 + 47 matched controls LifeShirt Describes trajectory or characteristics Breathing was more irregular, with increased breathing frequency, mean airflow and hear rate in RS than in the controls. Weese-Mayer 200877 Case-control Rett syndrome 47 + 47 controls LifeShirt Describes trajectory or characteristics Breathing was more irregular with increased breathing frequency in daytime compared to nighttime. Constipation     Haynes 199778 Open-label Epidermolysis bullosa 20 Questionnaire developed for study Pharmacologic intervention; Fiber-containing liquid formula (Enrich) All participants showed substantial improvement in constipation. Murata 201779 Retrospective Chart Review NCL3, Pelizaeus-Merzbacher bisease, tuberous sclerosis, West syndrome 59 Constipation severity measure on numeric scale, Bristol Stool Scale Pharmacologic intervention; Carnitine Constipation improved after supplementation with carnitine. Feeding Difficulties     Alshammari 201180 Retrospective Chart Review Epidermolysis bullosa 49 (7 with EB) Success judged as taking food by mouth, no dysphagia, no vomiting, good weight gain and not residual stricture Surgical intervention; Endoscopic balloon dilatation Treatment successful in 86% of patients First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Anderson 200481 Cross-sectional Epidermolysis bullosa 53 Dysphagia score (0-4) Surgical intervention; Endoscopic balloon dilatation 50 of 53 had improvement in dysphagia score. Azizkhan 200682 Retrospective Chart Review Epidermolysis bullosa 25 - Surgical intervention; Fluoroscopically guided balloon dilatation Most patients had immediate relief of symptoms, rapid recovery and able to take food within 1 day Blommaert 201683 Case Series MEGDEL syndrome 4 DSFS Surgical and pharmacologic intervention; Bilateral submandibular gland excision and parotid duct ligation, advice to interrupt tongue protrusion, adenotonsillectomy,  feeding advice, antireflux medication Each patient needs stepwise, personalized treatment  Bruns 201384 Longitudinal Chromosome 18 trisomy 10 Tracking Rare Incidence Syndromes Feeding Protocol Describes trajectory or characteristics Description of primary feeding methods and identification and treatment of gastroesophageal reflux. Fortunato 200885 Case Series Rett syndrome 32 - Describes trajectory or characteristics Participants with GERD or dysphagia had more swallows followed by abnormal esophageal peristalsis compared to those without symptoms. Gollu 201786 Retrospective Chart Review Epidermolysis bullosa 9 (7 children) Dysphagia score (0-4) Surgical intervention; Endoscopic balloon dilatation 7 participants can easily swallow solid food, but 2 have some difficulties in swallowing between dilatations. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Hyman 198787 Case Series Argininosuccinate kyase deficiency, MCM deficiency, ornithine carbamoyltransferase deficiency disease, propionic acidemia 6 Percent of offered bites, number of inappropriate behaviors Psychological intervention; Positive reinforcement and guidance techniques 5 children responded to treatment and for them food acceptance increased.  Isaacs 200388 Retrospective Chart Review Rett syndrome 22 + 22 matched controls Nutrition assessment Describes trajectory or characteristics Significant difference in feeding skills and irregular breathing patterns that may interfere with eating reported significantly more in RS than control group. Kawahara 200789 Case Series Profound neurological impairment 8 (6 children) 24 hour esophageal pH study Pharmacologic; rikkunshito Rikkunshito reduced the frequency of emesis in 3 patients and mean percentage time of esophageal and mean duration of reflux decreased significantly.  Kawai 200490 Open Label De Lange syndrome, West syndrome  4 + 4 with Cerebral Palsy Frequency of emesis (score 1 to 5) Pharmacologic intervention; Baclofen Frequency of emesis significantly decreased with baclofen treatment. Keage 201791 Cross-sectional Friedrich’s ataxia 60 Swal-QOL, FARS Describes trajectory or characteristics 98% of participants reported dysphagia; no reliable predictors of penetration or aspiration were identified. Lefton-Greif 200092 Cross-sectional Ataxia telangectasia 70 (unclear how many chidren - Describes trajectory or characteristics 27% of participants with dysphagia demonstrated aspiration; those who aspirated had significantly lower weight.  Lefton-Greif 201693 Cross-sectional Ataxia telangectasia 20 + 82 matched controls - Describes trajectory or characteristics Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in AT than in controls.  Luzzani 200394 Case Series De Lange syndrome 43 - Describes trajectory or characteristics Confirms the high incidence of GER in DLS regardless of clinical phenotype. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Markos 201695 Case Series Epidermolysis bullosa 6 (2 children) Mean dysphagia free interval Surgical intervention; Esophageal stricture dilatation Dysphagia free interval for 2 children participants was 4 and 9 months. Mezzedimi 201796 Cross-sectional Rett syndrome 61 Dysphagia severity (scale 0-3) Describes trajectory or characteristics Progressive feeding deterioration reported by caregivers.  Morgan 200897 Cross-sectional Rett syndrome 9 + 9 matched controls CAPND, DOSS,  pulse oximetry Describes trajectory or characteristics Pulse oximetry may be useful for dysphagia screening. Morton 199798 Cross-sectional Rett syndrome 20 (18 children) Videofluoroscopy abnormalities (scale 0-3), Chewing score (scale 0-3), Carer’s feeding score (scale 0-3) Describes trajectory or characteristics All participants had reduced tongue movements with premature spillover into the pharynx and delayed pharyngeal swallow. Morton 200099 Cross-sectional Rett syndrome 33 (21 children) - Physical intervention; Large, flattened dummy with a hollow tube running through, gum shield and palatal training devices 20 participants had air bloat, 17 of these 20 swallowed air during breath-holding and 3 gulped air during hyperventilation.  Munakata 2008100 Longitudinal, Open Label Costello syndrome; lissencephaly type 1 8 - Physical intervention; Black Pepper Oil Five of 8 participants showed increases in amount of oral intake, but need for enteral nutrition was not completely eliminated.   First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Seguy 2002101 Retrospective Chart Review SMA type I 3 with SMA;  - Surgical intervention; Percutaneous endoscopic gastrostomy  Height and weight for age improved, but complication in children who had preexisting gastroesophageal reflux. Sommer 1993102 Case Series, Retrospective Chart Review De Lange syndrome 17 (16 children) - Describes trajectory or characteristics 13 participants had gastroesophageal reflux and also signs of the Sandifer complex.  Spiliopoulos 2012103 Retrospective Chart Review Epidermolysis bullosa 19 (at least 5 children) Simplified 0-4 dysphagia score Surgical intervention; Fluoroscopically Guided Dilation of Esophageal Strictures The mean dysphasia score improved significantly compared to baseline, but 5 pediatric patients suffered from nutritional failure and required gastronomy tube placement.  Stehr 2008104 Retrospective Chart Review Epidermolysis bullosa 5 - Surgical intervention; Non-endoscopic percutaneous gastrostomy All patients tolerated gastronomy tube placement, with no perioperative complications. Vowinkel 2014105 Case-series Epidermolysis bullosa 12 - Surgical intervention; Orthograde balloon dilation followed by retrograde dilation via the established gastrostomy 11 of the children showed improvement in growth and nutrition after a 24 month follow-up.   Zaffanello 2017106 Case-series Achondroplasia 9 Sleep control test questionnaire Describes trajectory or characteristics 78% had respiratory sleep disorder, but it was generally mild. Sleep Disturbance / Disorders      First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Appleton 2012107 RCT Undefined neuro-developmental disorders 146 Sleep diary, SCHQ, CSI, ESS, ABC Pharmacologic intervention; Melatonin Mean amount of sleep difference between placebo and melatonin was 22.43 minutes Blankenburg 2003108 Tool / Scale Development Specific Q3 conditions not reported 224 SNAKE, SDSC Tool or scale development SNAKE is a valid tool for diagnosing sleep disturbance in this population. Boban 2015,109 2016110 Cross-sectional Rett syndrome 364 SDSC, CSHQ Describes trajectory or characteristics Waking at night the most prevalent sleep problem in all children, affecting over 80%; while initiating and maintain sleep was most prevalent in younger children. Braam 2008111 RCT Chromosome 18q deletion, MPS III 51 Sleep diary Pharmacologic intervention; Melatonin Compared with placebo mean sleep onset time increased by 34 minutes, sleep latency decreased by 29 minutes, and total sleep time increased by 48 minutes Bruni 1995112 Case control, Longitudinal Tuberous sclerosis  10 + 10 healthy controls Sleep diary Describes trajectory or characteristics Children with TS had shorter total sleep time, reduced sleep efficiency and more awakenings compared to controls. Camfield 1996113 Case series Undefined neuro-developmental disorders 6 Parent report of when child awake or asleep Pharmacologic intervention; Melatonin No notable difference in sleep pattern reported Colville 1996114 Cross-sectional, Survey, Case series MPSIII 80  (5 for intervention) Questionnaire developed for study Psychological intervention; Treatment goals set by a child psychologist, including set bedtime, if child awakes at night put back to bed firmly, set time allowed out of bed  Most treatment goals achieved in study period First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) de Leersnyder 2011115 Open-label Rett syndrome 88 Questionnaire developed for study Pharmacologic intervention; Prolonged-Release Melatonin Sleep latency decreased by 44%, sleep duration increased by 10.1%, number of awakenings decreased by 75% Dodge 2001116 RCT Unspecified developmental disabilities 20 Sleep diary Pharmacologic intervention; Melatonin Difference in sleep latency and duration of sleep not significantly greater than baseline.  Ellaway 2001117 Cross-sectional Rett syndrome 83 Sleep diary Describes trajectory or characteristics Sleep characteristics did not change with age and did not show age related decreases in total and daytime sleep. Evans 2016118 Cross-sectional Mowat-Wilson syndrome 34 SDSC, DBC Describes trajectory or characteristics High level of sleep disturbance was found, with 44% scoring in the clinical disorder range; sleep disorders should be screened for in children with MWS. Fraser 2002119 Survey MPSIII 11 clinicians who treat MPSIII - Describes trajectory or characteristics Sleep problems almost universal in this population and there is no single treatment that is viewed by all as beneficial. Fraser 2005120 Cross-sectional, Survey MPSIII 141 + 61 controls Questionnaire validated for the study Describes trajectory or characteristics 91.5% of children had sleep disturbance and melatonin and benzodiazepines were reported by parents as the most efficacious treatments. Freeman 2016121 Cross-sectional Smith-Lemli-Opitz syndrome 20 CSHQ Describes trajectory or characteristics Most markers of cholesterol synthesis defect severity were associated with severity of sleep disturbance. Gringras 2012122 RCT Unspecified Q3 conditions 146 Sleep diaries, CSDI, ABC, ESS Pharmacologic intervention; Melatonin Melatonin increased total sleep time and was most affective for children with the longest sleep latency. Hancock 2005123 Case-control Tuberous sclerosis 7 (6 children) + 21 healthy controls - Describes trajectory or characteristics Normal patterns of melatonin excretion seen in TS patients who are responders to melatonin. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Hancock 2005124 RCT Tuberous sclerosis 7 (5 children) Quine sleep index score, Sleep diary, Actigraphy Pharmacologic intervention; Melatonin No statistically significant improvements in sleep latency and sleep time on 10 mg of melatonin compared to 5 mg. Hatonen 1999125 RCT NCL3 3 + 2 with other types of NCL Sleep log, wrist Actigraphy Pharmacologic intervention; Melatonin No change in activity rhythms resulting from melatonin, but families reported that sleep quality was slightly improved.  Heikkil 1995126 Cross-sectional NCL3 7 + 15 with other types of NCL Actigraphy Describes trajectory or characteristics In most patients sleep was fragmented and sleep phase was irregular. Ingram 2017127 Cross-sectional Agenesis of the corpus callosum 66 CSHQ Describes trajectory or characteristics 78% of children had clinically significant sleep problems and children with more sleep problems had a worse quality of life. Kirveskari 2000128 Cross-sectional NCL3 28 (25 children) + healthy controls Visual assessment of sleep Describes trajectory or characteristics In most patients the total sleep time and efficiency were significantly lower than in healthy controls. Kirveskari 2001129 Case-series, Cross-sectional NCL5 12 (at least 4 children) Sleep Questionnaire, Actigraphy Describes trajectory or characteristics Patients under 20 years of age had excess of sleep at night and frequent daytime naps. Laakso 1993120 Cross-sectional Congenital hydrocephalus, Lennox-Gastaut syndrome, West syndrome 18 (10 children) - Describes trajectory or characteristics More participants with LGS and sleep disturbance had disruptions in their temperature, cortisol or melatonin rhythms than LGS with normal sleep patterns.   Lehwald 2016131 Cross-sectional NCL3 54 CSHQ Describes trajectory or characteristics 96.3% had scores consistent with sleep disturbance; onset of sleep disturbance was associated with both onset of seizures and loss of vision. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Lindblom 2006132 Cross-sectional Aspartylglucosaminuria 81 (27 children) + 49 controls (23 children) BNSQ Describes trajectory or characteristics 61% of children with AGU reported daily sleep-related problems and showed more setting difficulties and snored more often than controls. Maas 2008133 Cross-sectional Jacobsen syndrome 43 (6 patients 18 years or older) Adapted sleep questionnaire Describes trajectory or characteristics 10 of the 43 participants had a sleep problem and 22 had a history of sleep problems.  Maas 2009134 Cross-sectional Cri-du-chat 30 + 60 controls  Adapted sleep questionnaire Describes trajectory or characteristics Night waking problems, sleep disorder breath and poor-quality sleep more common in CDC compared to controls. Maas 2011135 Tool / Scale Development Rett syndrome, cri-du-chat, Jacobsen syndrome 345 (number of children with Q3 conditions  unknown) SQ-SP, CSI, SDSC Tool or scale development The SQ-SP is a valid tool for assessing sleep and sleep disturbance in this population. Maas 2012136 Case-control Cri-du-chat, Jacobsen syndrome 50 + 50 with other conditions SQ-SP Describes trajectory or characteristics Snoring most prevalent sleep disturbance in CDC and JS, but no difference in severity of sleep problems between groups. Mahon 2014137 Longitudinal, Survey MPSIIIA, MPSIIIB 8 + 8 matched controls CSHQ, Actigraphy, sleep diary Describes trajectory or characteristics Children with MPSIII have longer sleep latencies and greater daytime sleep compared to controls, but night sleep duration did not differ. In MPSIII, sleep efficiency declined and sleep latency increased with age. McArthur 1998138 Longitudinal, RCT Rett syndrome 9 Sleep diary, Actigraphy Pharmacologic intervention; Melatonin Melatonin decreased sleep latency and appeared to improve total sleep time and efficiency in patients who had the worse baseline sleep quality. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Miyamoto 1999139 Case-series, Longitudinal Rett syndrome 2 Sleep diary Pharmacologic intervention; Melatonin Melatonin improved sleep in both patients, and effect was maintained over 2 years without adverse effects. Moser 2017140 Cross-sectional Juvenile Huntington disease 33 Survey created for study Describes trajectory or characteristics 87% of participants had disrupted sleep. Mumford 2015141 Longitudinal MPSIIIA, MPSIIIB 8 + 8 matched controls Actigraphy Describes trajectory or characteristics MPS group showed significant fragmentation of circadian rhythm compared to controls. Niakan 1979142 Case-series Pelizaeus-Merzbacher disease 3 - Describes trajectory or characteristics Lower percentage of REM sleep seen than normal values. O’Callaghan 1999143 Longitudinal, RCT Tuberous sclerosis 7 Sleep diaries, Quine sleep index score Pharmacologic intervention; Melatonin Children treated with melatonin had a small improvement in total sleep time, but no effect on sleep fragmentation. Phillips 2004144 Systematic review Rett syndrome (and other ID) - - Pharmacologic intervention; Melatonin Melatonin treatment reduced time to sleep, but no significant effect on total sleep time, night awakenings and parental report. Piazza 1990145 Cross-sectional Rett syndrome 20 Momentary time sampling procedure Describes trajectory or characteristics RS girls had more total sleep, less night sleep and more daytime sleep than peers; night sleep was correlated with age. Piazza 1991146 Case-series Rett syndrome 3 Momentary time sampling procedure Psychological intervention; Fading procedure Intervention resulted in more regular sleep patterns by increasing night sleep and decreasing day sleep. Rajan 2002147 Cross-sectional De Lange syndrome 31 (19 children)  PSQ, PDSS, OSA18 Describes trajectory or characteristics Children showed difficulties with falling asleep and staying asleep. Ross 2002148 Open-label Lennox-Gastaut syndrome, leukodystrophy, MPSII, MPSIII 46 Sleep diaries Pharmacologic intervention; Melatonin 34 of the 46 patients showed improvement in sleep. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Segawa 1990149 Cross-sectional Rett syndrome 8 - Describes trajectory or characteristics The sleep-wake cycle is abnormal in RS. Tietze 2014150 Cross-sectional, Tool / Scale Development Unclear Q3 conditions 224 HOST, ESS, PSQI Describes trajectory or characteristics, Tool or scale development Sleep-related difficulties impact daily life of children and caregivers; the HOST is a valid tool for sleep-related difficulties. Zambrelli 2016151  Cross-sectional De Lange syndrome 46 SDSC Describes trajectory or characteristics Abnormal total sleep score for at least one SDSC factor found in 39% of participants and 15% had an abnormal total score.  Temperature Regulation     Svedberg 2001152 Case-series Smith-Lemli-Opitz syndrome, progressive encephaolopathia 6 Skin temperature measurements  Physical intervention; Acupuncture 3 children had a brief rise in temperature in the hand and one foot, with a tendency toward cumulative effect in additional sessions. Svedberg 2005153 Case-control Chromosome 22q11.2 deletion, SMA1 15 + 25 healthy controls Infrared radiation to measure skin temperature Describes trajectory or characteristics Significant lower mean skin temperature in all measurement points compared to controls. Tone and Motor Problems     Abbruzzese 2016154 Case control Cri-du-Chat  14 + 14 controls - Describes trajectory or characteristics Participants with CdCS had more frequent and smaller steps than controls, but on average had a comparable gait speed. Aberg 2001155 Open-label NCL 3, NCL 6 16 + 5 controls UPDRS Pharmacological intervention; Levodopa or Selegiline Mean UPDRS score decreased in the levodopa group Air 2011156 Retrospective Chart Review Glutaric acidemia type I, Lesch-Nyhan syndrome 31 BFMDRS, BADS, BPI, UPDRS Deep Brain Stimulation Those with secondary dystonia only had a small improvement in BFMDRS score 1 year later First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Beaulieu-Boire 2016157 Open Label Ataxia telangectasia, MCM deficiency, NCL, Nemaline myopathy 11  BFMDRS Surgical intervention; Deep Brain Stimulation At one year follow-up Ataxia Telangectasia patient had deterioration of symptoms, Nemaline Myopathy patient had no change, and other patients had non-significant improvement Boy 2015158 Cross-sectional Glutaric acidemia type I 226 BADS Describes trajectory or characteristics BADS scores correlated with speed, but not test of stability or higher cognitive function. Buizer 2017159 Retrospective Chart Review Lipidoses 24 GMFCS, Caregiver Questionnaire, SPAT Surgical intervention; Selective dorsal rhizotomy Reduction in spasticity in legs, most reported improvements in dressing, washing and comfort Bumin 2002160 Case Series Rett syndrome 4 Number of stereotypical movements in 5 minutes of video, functional hand use (ability to eat a cracker) in 5 minutes of video Physical intervention; Hand splints, elbow restraint All subjects showed decrease in stereotypic behavior Bürk 2009161 Tool / Scale Development Friedrich’s ataxia 96 SARA, FARS, ICARS Describes trajectory or characteristics SARA is valid and reliable to measure afferent ataxia in FA.  Cak 2014162 Case Series NPC 3 - Pharmacologic intervention; Imipramine 2 patients with cataplexy successfully treated Cano 2005163 Tool / Scale Development Friedrich’s ataxia  77 ICARS Tool or scale development ICARS total score can be used to measure FA, but more studies are necessary to further test validity of all the subscales. Carter 2010164 Cross-sectional Rett syndrome 144 - Describes trajectory or characteristics Hand stereotypies seen in most subjects, with a median of 2 types stereotypies per subject but this decreased with age.  First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Castelnau 2005165 Case Series IND 6 BFMDRS Surgical intervention; Pallidal Stimulation Sustained decrease in dystonia in all patients and global motor improvement  Castilhos 2012166 Open label, Tool / Scale Development MPS I, MPSIV, Adreno-myeloneuropathy, Mucolipidosis  38  SSPROM Tool or scale development SSPROM is a valid scale for children with progressive myelopathies secondary to inborn errors of the metabolism. Corben 2010167 Longitudinal Study Friedrich’s ataxia  20 9HPT, BBT, JTHFT, FARS Describes trajectory or characteristics 9HPT and BBT using the non-dominate hand can be used to show disease progression in FA. Croarkin 2009168 Cross-sectional Friedrich’s ataxia 38 FARS Describes trajectory or characteristics FARS score is associated with gait velocity, stride length and cadence, and may be a useful screening tool de Lattre 2013169  Tool / Scale Development, Prospective Cohort  SMA1 88 + 194 healthy controls MFM Tool or scale development The MFM-20 can be used to assess motor function in young children with neuromuscular disease Detweiler 2013170 Retrospective Chart Review Costello syndrome 43 - Describes trajectory or characteristics Most children with Costello Syndrome have orthopedic manifestations and should be routinely referred to orthopedics.  Downs 2008171 Cross-sectional Rett syndrome 99 (70 under 19 years) Coding scheme developed for study Describes trajectory or characteristics General gross motor skills decline with age while complex motor skills do not. Downs 2010172 Cross-sectional Rett syndrome 144 (101 under 19 years of age) WeeFIM, Hand Apraxia Scale, Level of hand function Describes trajectory or characteristics Hand function deteriorates with age and level of hand function is associated with the type of MECP2 mutation. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Downs 2011173 Longitudinal  Rett syndrome 72 (54 under 19 years) Hand Apraxia Scale, Level of hand function, ARSD Family Questionnaire Describes trajectory or characteristics Over time participants with RS and some grasping abilities lost skills, with those who were younger than 8 years more likely to lose skill. Downs 2012174 Tool / Scale Development Rett syndrome 12 StepWatch Activity Monitor, Rett Syndrome Gross Motor Scale Tool or scale development The StepWatch is an accurate tool to measure activity in RS, no matter the level of gross motor ability. Downs 2015175 Tool / Scale Development Rett syndrome 26 Actigraphs, Rett Syndrome Gross Motor Scale Tool or scale development The StepWatch is an accurate tool to measure activity in RS, no matter the level of gross motor ability. Downs 2016176 Tool / Scale Development Rett syndrome 293 (190 under 19 years) RSGMS Tool or scale development The RSGMS may be a valid measure of gross motor skills in RS. Downs 2017177 Cross-sectional Rett syndrome 64 StepWatch Activity Monitor Describes trajectory or characteristics Adolescents led less active lives than children. Dusing 2006178 Case-series MPSI 4 Peabody Developmental Motor Scales Describes trajectory or characteristics There are early gross motor delays in MPSI and children with the condition should be referred to a physical therapist. Dy 2017179 Tool/ Scale Development Rett syndrome 24 Operational definitions of hand stereotypies Tool or scale development Achieved 50% level of agreement, so need more objective measures to evaluate hand stereotypies. Elian 1996180 Cross-sectional Rett syndrome 25 Unspecified questionnaire Describes trajectory or characteristics Hand movements are asymmetrical and appear to change with emotional or mental states. Finkel 2008181 Tool/ Scale Development SMA1 11 TIMP Tool or scale development The TIMP is a reliable measure of motor problems in SMA1.  FitzGerald 1990182 Longitudinal Rett syndrome 32 Motor-Behavioral Assessment Scale Describes trajectory or characteristics The most common movement problems were stereotypy and gait disturbance.  First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Foley 2011183 Longitudinal Rett syndrome 77 (44 children) RSGMS Describes trajectory or characteristics There is evidence of general stability in gross motor function over a 3 to 4 year period in girls and women with RS. Freeman 2007184 Cross-sectional IND 16 (6 children) VABS, Adaptive Behavior Assessment Scale, Care and Comfort Hypertonicity Questionnaire Describes trajectory or characteristics There is variability in adaptive behavior functioning in this population. Germanotta 2015185 Tool/ Scale Development Friedrich’s ataxia 14 + 18 control SARA, InMotion Arm Robot Tool or scale development The InMotion Arm Robot was highly discriminative between subjects with FA and health controls. Gimeno 2012186 Case-series, Tool/ Scale Development Glutaric acidemia type I 5 BFMDRS, Canadian Occupational Performance Measure,  Goal Attainment Scaling, CPCHILD questionnaire Surgical intervention; Deep brain stimulation No change in the BFMDRS after deep brain stimulation, which shows the limitations of impairment-focused measures. Glanzman 2010187 Tool/ Scale Development SMA1 26 CHOP INTEND Tool or scale development The CHOP INTEND is a reliable measure, but more validation is needed. Glanzman 2011188 Tool/ Scale Development SMA1 27 CHOP INTEND Tool or scale development The CHOP INTEND reflects disease severity measures. Goldman 2012189 Case-control Rett syndrome 20 with RS + 20 controls with autism Coding system developed for hand stereotypies Describes trajectory or characteristics In RS the hand stereotypies are complex, continuous, at the body midline and involved mouthing, which is different from those seen in autism. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Haddad 1997190 Cross-sectional MLIII, MPSI, MPSII, MPSIII, MPSVI 48 Assessment of functional level - 5 item scale Surgical and physical interventions; Surgery, physiotherapy, exercises After early decompression functional improvement was seen with some benefit form simultaneous tendon release. Hjartarson 2017191 Case-series X-linked adrenoleukodystrophy 2 Modified Ashworth Scale Pharmacologic interventions; Intrathecal baclofen Intrathecal baclofen significantly reduced muscle tone.  Holloway 2006192 Systematic Review IND - BFMDRS, UDRS, Abnormal Involuntary Movement Scale,  Toronto Western Spasmodic Torticollis Rating, Tsui Scale for Cervical Dystonia, Truong and Fahn Myoclonus Scale Surgical intervention; Deep brain stimulation Mean changed in BFMDRS was 51.8%, with IND having no difference in outcomes in comparison to other dystonic etiology.   Humphreys 2016193 Cross-sectional Rett syndrome 51 (at least 9 children) RTT rigidity distribution score Describes trajectory or characteristics Rigidity found in 43 of 51 participants, starting as early as age 3 and started in the ankle region. Ilg 2012194 Cohort study Friedrich’s ataxia 10 (7 children) SARA, dynamic gait index, Activity-specific Balance Confidence Scale Physical intervention; Video game-based coordinative training Ataxia significantly reduced and balance improved after intervention. Krosschell 2006195 Tool/ Scale Development SMA1 44 HFMS Tool or scale development HFMS is a reliable and stable tool to assess motor function over a 6 month period. Krosschell 2013196 Tool/ Scale Development SMA1 38 TIMP Tool or scale development The TIMP is a reliable tool for assessing motor function in infants with SMA1. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Kuhlen 2016197 Retrospective Chart Review Chromosome 18q deletion, Lissencephaly Type 1, Metachromatic Leukodystrophy, NCL 3 16 (2 children) - Pharmacologic intervention; dronabinol Improvements in severe treatment resistant spasticity in 12 patients. Kwon 2011198 Longitudinal, Tool/ Scale Development NCL3 82 UBDRS Tool or scale development The UBDRS is a valid tool for measuring clinical progression, including motor function. Kyllerman 1994199 Case-series Glutaric acidemia type I 12 - Describes trajectory or characteristics 10 participants had severe dystonic-dyskinesia disorder, 1 had mild hyperkinetic disorder. Iannaccone 1993200 Longitudinal SMA1 58 Functional Motor Scale Describes trajectory or characteristics 56% showed tongue fasciculation and 22% facial weakness. Lim 2012201 Cross-sectional, Retrospective Chart Review IND 12 BFMDRS Surgical intervention; Pallidal deep brain stimulation Outcome of deep brain stimulation is dependent on mutation. Liow 2016202 Case-series, Longitudinal IND 69 GMFCS, Dystonia Severity Assessment Plan, ICF-CY Pharmacologic intervention; Gabapentin Significant improvement in general muscle tone and involuntary muscle contractions. Liu 2017203 Case-series IND 3 BFMDRS Surgical intervention; Subthalamic Nuclei Stimulation BFMDRS scores improved in all a patients. Lotan 2004204 Case-series, Longitudinal, N of 1 Rett syndrome 3 Rett Functional Evaluation Scale, RSGMS Psychological intervention; Daily conductive educational program Gross motor function improvements seen at the end of training. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Lotan 2012205 Case-series, Longitudinal Rett syndrome 4 Scale developed and validated for study Physical intervention; Daily training program on a treadmill General functional abilities improved considerably after training. Mazzone 2014206 Longitudinal, Tool/ Scale Development SMA1 74 HFMS, MFM Tool or scale development HMFS worked better in non-ambulant patients where the MFM worked better in very weaker patients. Naganuma 1988207 Case-series, Longitudinal Rett syndrome 3 Duration of stereotypic movements and duration of functional hand use Physical intervention; Thumb abduction splints Decrease in amount of time spent in stereotypic hand behavior and 1 patient had an increase in finger-feeding skills after hand splints. Nava 2012208 Case-series MPSII 2 - Pharmacologic and physical interventions; Botulinum toxin type A, followed by serial casting and intensified physical therapy Passive range of motion, muscle tone and gait performance improved significantly. Nelson 2006209 Tool/ Scale Development SMA1 40 GMFM Tool or scale development The GMFM is a valid tool in SMA. Nissenkorn 2013210 Longitudinal, Open-label  Ataxia telangectasia 17 ICARS, UNDRS, AIMS Pharmacologic intervention; Amantadine Sulfate 76.6% of participants had at least a 20% improvement in sum of all scales. Nissenkorn 2016211 Tool/ Scale Development Ataxia telangectasia 63 ICARS, SARA, Brief Ataxia Rating Scale Tool or scale development Both scales showed positive correlation between severity and age. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Park 2016212 Retrospective Chart Review IND 5 with IND BFMDRS Surgical intervention; Deep brain stimulation Mean movement and disability scores decreased significantly at 60 month follow up. Qvarfordt 2009213 Case-series, N of 1 Rett syndrome 3 Video analysis by coding system Psychological intervention; Guided eating vs being fed Guided eating improved mouth and spoon coordination, involvement in meal and cooperation in arm movements.  Sansare 2018214 Case-control NPC 10 + 15 healthy controls 6-meter long electronic walkway, NIH NPC Neurologic Severity Scale, NeuroCom Balance SMART Equitest System, Kinematic assessment of the finger-to-nose test Describes trajectory or characteristics Participants showed significant deficits gait, balance and upper limb coordination. Shaikh 2013215 Cross-sectional Ataxia telangectasia 80 + 19 healthy controls Accelerometer Describes trajectory or characteristics 79 of 80 participants had abnormal involuntary movements and had both kinetic and postural tremor; 48 also had resting tremor. Sharpe 1992216 N of 1 Rett syndrome 2 Stereotypic hand movements and hand-to-toy contact recorded in 10 second time samples Physical intervention; Elbow orthosis and thumb abduction splints Both subjects had a decrease in stereotypic hand movements and increase in toy contact with elbow orthosis, but not difference with thumb abduction splints. Stahlhut 2017217 Tool/ Scale Development Rett syndrome 42  Modified two-minute walk test, Rett syndrome specific functional mobility scale, RSGMS Tool or scale development Rett syndrome specific functional mobility scale and the modified two-minute walk test may be valid measures. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Stasolla 2013218 Case-series Rett syndrome 2 Measured intervals with stereotyped behavior and indices of happiness Physical intervention; Wobble microswitch and optic sensors Participants showed increase in performance, indices of happiness and decreased stereotyped movements. Stasolla 2014219 Case-series Rett syndrome 3 Number of items requested / chosen, Indices of happiness Physical intervention; Picture exchange communication systems, Vocal output communication aid  Participants showed increase in requested and chosen items and indices of happiness. Stasolla 2015220 Case-series Rett syndrome 3 Measured intervals with stereotyped behavior and indices of happiness Physical intervention; Assistive technology (photocells, interface  and personal computer) Participants showed increase in adaptive responses items and indices of happiness and decreased stereotyped movements. Subramony 2005221 Tool/ Scale Development Friedrich’s ataxia 14 Friedrich's Ataxia Scale Tool or scale development Friedrich's Ataxia Scale may be a valid measure in FA. Susatia 2010222 Tool/ Scale Development Unspecified Q3 conditions 25 (4 children) UDRS, BFMDRS Tool or scale development, Surgical intervention; Deep brain stimulation Blinded outcome assessments result in lower outcome scores and may be a more realistic assessment tool after deep brain stimulation. Temuno 2007223 Cross-sectional Rett syndrome 83 Pineda general severity scale Describes trajectory or characteristics RS participants with the MECP2 mutation showed more frequent hair pulling and more varied stereotypies. First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Temudo 2008224 Cross-sectional Rett syndrome 60 Pineda general severity scale, Motor-behavioral assessment scale Describes trajectory or characteristics Movement disorders in RS seem to reflect the rate of progression and severity of the syndrome. Timmermann 2010225 Retrospective Chart Review IND 23 BFMDRS, BADS Surgical intervention; Bilateral pallidal stimulation 66.7% of patients showed improvement of 20% or better in severity of dystonia. Tsering 2017226 Retrospective Chart Review IND 4 BFMDRS, BADS Surgical intervention; Deep brain stimulation All participants experienced reductions in severity of dystonia. Tuten 1989227 Case-series Rett syndrome 2 Coding of videotapes of amount of stereotypic behavior Physical intervention; Hand splints No increase in feeding skills or hand wringing when splits where removed. van Capelle 2012228 Tool/ Scale Development Glycogen storage disease type II 91 (19 were 20 years or younger) GMFM, Quick Motor Function Test Tool or scale development Quick Motor Function Test can reliably rate motor function in children with GSDII. van Heest 1998229 Retrospective Chart Review MPSI, MPSIII, MPSVI 22 Hand function questionnaire Surgical intervention; Annular pulley release or Annular pulley release and partial flexor digitorum superficialis tendon resection All patients had improved hand function. Vasco 2016230 Case-control, Longitudinal  Friedrich’s ataxia 11 + 13 controls Gait analysis. SARA Describes trajectory or characteristics Gait analysis proved more sensitive measure of motor function than SARA.  First Author Year of Publication Study Design Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Vignoli 2009231 Longitudinal Rett syndrome 12 (7 children) Stereotypies rated on a 1-3 scale Describes trajectory or characteristics Over time RS participants maintained stereotypies into adolescence. Vuillerot 2012232 Longitudinal, Tool/ Scale Development SMA1, Other unspecified Q3 conditions 152 (87 children) Motor Function Measure Tool or scale development MFM showed good responsiveness, but needs to be validated. Wales 2004233 Case-series Rett syndrome 8 Videotaped, system of event coding used Psychological intervention; Continuous adult attention vs no stimulation vs demands vs stimulation Environmental conditions have limited effect on repetitive hand movements. Wong 2017234 Cross-sectional Rett syndrome 58 Stereotypies classification checklist from the literature Describes trajectory or characteristics Participants with atypical RS have more varied stereotypies; hair pulling, bruxism, retropulsion and protrusion of lips are more common in atypical RS. Zannolli 2012235 RCT Ataxia telangectasia 13 ICARS Pharmacologic intervention; Betamethasone Betamethasone reduced ICARS total score by a median of 16 points. Zweije-Horman 1982236 RCT NCL3 8 List of 30 observations of motor function, scored 1-5 Pharmacologic intervention; Orfenadrine, Amantadine, Madopar  None of the drugs led to a significant improvement in motor function.  Urinary Incontinence   von Gontard 2001237 Case-control SMA1 96 + 45 unaffected siblings + 59 healthy controls CBC Describes trajectory or characteristics There is a high rate of urinary incontinence in this population that is often overlooked and not treated. Table 2: Characteristics of included studies with multiple symptoms First Author Year of Publication Study Design Symptom(s) Q3 Condition(s) Number of participants Tools or Scales Used Study Objective; Intervention(s) Primary Outcome(s) / Conclusion(s) Abraham 2015238 Cross-sectional Feeding Difficulties, Tone and motor Rett Syndrome 23 VDS, Penetration-Aspiration Scale Describes traj