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Congenital Abnormalities and Multiple Sclerosis Ramagopalan, Sreeram V; Guimond, Colleen; Criscuoli, Maria; Dyment, David A; Orton, Sarah-Michelle; Yee, Irene M; Ebers, George C; Sadovnick, Dessa Nov 16, 2010

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RESEARCH ARTICLE Open AccessCongenital Abnormalities and Multiple SclerosisSreeram V Ramagopalan1,2, Colleen Guimond3, Maria Criscuoli3, David A Dyment1,2, Sarah-Michelle Orton1,2,Irene M Yee3, George C Ebers1,2, Dessa Sadovnick3,4*AbstractBackground: There is a strong maternal parent-of-origin effect in determining susceptibility to multiple sclerosis(MS). One hypothesis is that an abnormal intrauterine milieu leading to impaired fetal development could plausiblyalso result in increased susceptibility to MS. A possible marker for this intrauterine insult is the presence of a non-fatal congenital anomaly.Methods: We investigated whether or not congenital anomalies are associated with MS in a population-basedcohort. We identified 7063 MS index cases and 2655 spousal controls with congenital anomaly information fromthe Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS).Results: The frequency of congential anomalies were compared between index cases and controls. No significantdifferences were found.Conclusions: Congenital anomalies thus do not appear to be associated with MS. However, we did not havecomplete data on types and severity of congenital anomalies or on maternal birth history and thus this studyshould be regarded as preliminary.BackgroundMultiple sclerosis (MS) is an inflammatory disease ofthe central nervous system (CNS) characterized by mye-lin loss, varying degrees of axonal pathology and pro-gressive neurological dysfunction [1]. Autoimmunemechanisms are thought to have major roles in thepathogenesis of MS [2] but the cause of the disease isnot yet conclusively understood [1]. A maternal parent-of-origin effect in MS [3,4] has now been well demon-strated but the biological basis underlying this remainsunknown [5].Approximately 3% of babies born in North Americahave a congenital anomaly [6]. A congenital anomaly isan abnormality of structure, function or body metabo-lism that is present at birth and results in physical ormental disability, with varying degrees of severity [7].Purely genetic factors (chromosomes, single gene muta-tions) are believed to account for 15-25% of all congeni-tal anomalies leaving up to 80% due to multifactorialinheritance or environmental exposures [6]. These lattertwo categories may be affected by factors such as fetalexposures to infection (e.g. cytomegalovirus, varicella,rubella), toxins (e.g. alcohol, cocaine, accutane) ormaternal medical conditions (diabetes, epilepsy, phe-nylketonuria) [6]. It is possible that a compromisedintrauterine environment underlies the maternal effectseen in MS. One hypothesis is that an abnormal intrau-terine milieu leading to impaired fetal developmentcould plausibly also result in increased susceptibility toMS. A possible marker for this intrauterine insult is thepresence of a “non-fatal” congenital anomaly (hereafterreferred to simply as a “congenital anomaly”). If thiswere true, one would expect an excess of congenitalanomalies in MS patients compared to gender and eth-nicity-matched controls.MethodsThe population-based Canadian Collaborative Project onGenetic Susceptibility to Multiple Sclerosis (CCPGSMS)has been collecting perinatal data on MS index casesand spousal controls using structured telephone inter-views with appropriate consents [7]. Data specific forthe question of congenital anomalies were collectedfrom mothers of index cases and mothers of controls.Each participating CCPGSMS site has obtained ethical* Correspondence: dessa.sadovnick@gmail.com3Department of Medical Genetics, University of British Columbia, G920,Detwiller Pavilion, VCHA - UBC Hospital, 2211 Wesbrook Mall, Vancouver,British Columbia, V6T 2B5, CanadaFull list of author information is available at the end of the articleRamagopalan et al. BMC Neurology 2010, 10:115http://www.biomedcentral.com/1471-2377/10/115© 2010 Ramagopalan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.approval from the relevant institutional review board.The entire project was reviewed and approved by theUniversity of British Columbia in compliance with theHelsinki Declaration.Statistical analysesThe Chi squared test was used to assess significancewhen comparing the frequency of congenital anomaliesin index cases and controls. The effect of congenitalanomalies and sex on the risk of MS was assessed bylogistic regression using the R statistical package.ResultsMaternal information on congenital anomalies could becollected for 7063 MS index cases and 2655 spousalcontrols. The clinical and demographic details of theindex cases and controls are shown in Table 1.Two hundred and seventy (3.8%) MS index casesreported a congenital anomaly, not significantly different(p = 0.97) from controls (n = 101, 3.8%). As there is apreponderance of females with MS [8], there is by defini-tion a corresponding over-representation of male spousalcontrols. If the trait of interest is sex-limited, then analy-sis by sex stratified cases and controls is important [9].When we compared male index cases and female con-trols separately from male index case and male controls,there were again no significant differences. Logisticregression confirmed this showing an effect of female sexon the risk of MS (p < 1 × 10-16) but no effect of having acongenital abnormality (p = 0.92).DiscussionEnvironmental risk factors are known to be responsiblefor 8-12% of congenital anomalies and are a likely con-tributing factor in an additional 20-25% of anomalies aspart of multifactorial inheritance [10,11] If the same riskfactors acting in utero contribute to both congenitalanomalies and future MS risk, then congenital anoma-lies could be used as biomarkers for MS. The large MSindex case and control sample size used in this studydid not support this hypothesis. It may well be possiblethat congenital anomalies are not good markers forintrauterine risk factors specific to MS or that the effectis too small to observe, given that only a small propor-tion of anomalies are attributed solely to environmentalfactors.Our study does have limitations. Maternal recall ofcongenital anomalies is likely influenced by the timeelapsed from the child’s birth and by the severity of thecondition and may not be as reliable as clinical records.For example, a mother would more likely recall a conge-nital anomaly needing medical intervention (e.g. cleft lipor palate, talipes) than one that may not (e.g. minor car-diac septal defect, spina bifida occulta). Conversely, amother may over-report minor afflictions as congenitalanomalies or they may report anomalies not detected atbirth. The latter would help to explain the relatively highrate of anomalies observed compared to expected rates.As part of the CCPGSMS to date, we did not ask specifi-cally for information on the type and severity of the con-genital abnormality, which maybe important for MS risk.We also did not ask about the maternal history of fatalcongenital abnormalities in previous pregnancies; thisinformation would be missing from the family historyespecially if an affected pregnancy resulted in a termina-tion, miscarriage, stillbirth, or perinatal death. We antici-pate conducting a more focused questionnaire interviewin the future as part of the ongoing CCPGSMS.ConclusionsThe maternal effect in MS is substantial. Risk for MS inmaternal half-siblings compared with the risk for fullsiblings does not differ significantly indicating thatmaternal effects might even be the major component offamilial aggregation of the disease [4]. Our data suggeststhat congenital anomalies are not more prevalent amongthose who develop MS and seems to reduce the likeli-hood that there is a strong association between risk fac-tors common to MS and congenital anomalies. Howeverour study is a preliminary investigation as we did nothave detailed data on congenital anomalies or maternalbirth history. Further investigations are needed toexplain the mechanisms underlying the increased MSrisk conferred maternally.Compenting interestsThe authors declare that they have no competing interests.Authors’ contributionsGCE and ADS conceived and designed the experiments. SVR, CG, MC, DAD,SMO, IMY, GCE and ADS analyzed the data and wrote the paper. All authorsread and approved the final manuscript.AcknowledgementsThis study was funded by the Multiple Sclerosis Society of Canada ScientificResearch Foundation. The authors would like to thank all patients whogenerously participated in this study and physicians constituting theCanadian Collaborative Group: CCPGSMS: Vancouver, BC (A Traboulsee VTable 1 Clinical and demographic details of MS indexcases and controlsMS Index Cases Spousal Controlsn 7063 2655mean age in years (SD) 50.2 (10.1) 52.3 (9.6)n (females) 5319 807n (males) 1744 1848sex ratio (f:m) 3:1 0.4:1% relapsing remitting MS 82.3 /SD = standard deviation, (f:m) = female to male sex ratioRamagopalan et al. BMC Neurology 2010, 10:115http://www.biomedcentral.com/1471-2377/10/115Page 2 of 3Devonshire, S A Hashimoto, J Hooge, L Kastrukoff, J J F Oger); Calgary, AB (LMetz); Edmonton, AB (S Warren); Saskatoon, SK (W Hader, K Knox); Winnipeg(R.A. Marrie), London, ON (M Kremenchutzky); Ottawa, ON (M Freedman);Kingston, ON (D Brunet); Toronto, ON (P O’Connor, T Gray, M Hohol);Montreal, QC (P Duquette, Y Lapierre); Halifax, NS (T J Murray, V Bhan, CMaxner); and St John’s, NL (M Stefanelli).Author details1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford,OX3 7BN, UK. 2Department of Clinical Neurology, University of Oxford, TheWest Wing, The John Radcliffe Hospital, Oxford, OX3 9DU, UK. 3Departmentof Medical Genetics, University of British Columbia, G920, Detwiller Pavilion,VCHA - UBC Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia, V6T2B5, Canada. 4Faculty of Medicine, Division of Neurology, University of BritishColumbia, G920, Detwiller Pavilion, VCHA - UBC Hospital, 2211 WesbrookMall, Vancouver, British Columbia, V6T 2B5, Canada.Received: 7 August 2010 Accepted: 16 November 2010Published: 16 November 2010References1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG: Multiplesclerosis. N Engl J Med 2000, 343(13):938-952.2. McFarland HF, Martin R: Multiple sclerosis: a complicated picture ofautoimmunity. Nat Immunol 2007, 8(9):913-919.3. Hoppenbrouwers IA, Liu F, Aulchenko YS, Ebers GC, Oostra BA, vanDuijn CM, Hintzen RQ: Maternal transmission of multiple sclerosis in adutch population. Arch Neurol 2008, 65(3):345-348.4. Ebers GC, Sadovnick AD, Dyment DA, Yee IM, Willer CJ, Risch N: Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet2004, 363(9423):1773-1774.5. Ramagopalan SV, Dyment DA, Ebers GC: Genetic epidemiology: the use ofold and new tools for multiple sclerosis. Trends Neurosci 2008,31(12):645-652.6. Rasmussen SA, Erickson JD, Reef SE, Ross DS: Teratology: from science tobirth defects prevention. Birth Defects Res A Clin Mol Teratol 2009,85(1):82-92.7. Petrini J, Damus K, Johnston RB Jr: An overview of infant mortality andbirth defects in the United States. Teratology 1997, 56(1-2):8-10.8. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD,Ebers GC: Sex ratio of multiple sclerosis in Canada: a longitudinal study.Lancet Neurol 2006, 5(11):932-936.9. Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M, Yee IM,Sadovnick AD, Ebers GC: Autoimmune disease in families with multiplesclerosis: a population-based study. Lancet Neurol 2007, 6(7):604-610.10. Stevenson RE, Hall JG, Goodman RM: Human malformations and relatedanomalies New York; Oxford: Oxford University Press; 1993.11. Nelson K, Holmes LB: Malformations due to presumed spontaneousmutations in newborn infants. N Engl J Med 1989, 320(1):19-23.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/115/prepubdoi:10.1186/1471-2377-10-115Cite this article as: Ramagopalan et al.: Congenital Abnormalities andMultiple Sclerosis. BMC Neurology 2010 10:115.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitRamagopalan et al. BMC Neurology 2010, 10:115http://www.biomedcentral.com/1471-2377/10/115Page 3 of 3


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