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Exploring mitochondrial DNA abnormalities in HIV-exposed uninfected children diagnosed with autism spectrum disorder : a case control study

University of British Columbia

Background: Antiretroviral therapy has reduced mother-to-child HIV transmission from 25-40% to less than 2%. Thus, increasing numbers of HIV-exposed uninfected (HEU) children are being born with perinatal exposure to antiretrovirals. Recently, a Canadian HIV clinic noticed a high prevalence of autism spectrum disorder (ASD) in HEU children. This prompted our analysis of HEU children enrolled in the pan-Canadian Children & Women AntiRetrovirals & Markers of Aging (CARMA) cohort study. Significant differences in mitochondrial DNA to nuclear DNA ratio (mtDNA content) have been observed in ASD children and HEUs as a potential marker for mitochondrial dysfunction, which has been theorized as a possible mechanism underlying abnormal neurodevelopment. We hypothesized that HEU children with ASD would have significantly different leukocyte mtDNA content than HEU children without ASD and/or HUU children with and without ASD. Methods: CARMA HEU children with ASD (n=14) were matched 1:3 on age, sex, and ethnicity to HEU children without ASD (n=42), HUU anonymous controls (n=42), and HUU children with ASD in the BC Autism Spectrum Interdisciplinary Research (ASPIRE) program (n=42). Non-ASD HUU siblings of ASD children (n=9) were also studied and grouped with the HUU controls for the purposes of analyses (n=51 total). MtDNA content was assessed using qPCR. Results: Among 299 HEU children in CARMA, 14 (4.7%) were diagnosed with ASD, substantially (>3-fold) above North American prevalence estimates (1.5%). HEU children with ASD had higher mtDNA content (median[interquartile range]: 163[150–179]) than non-ASD HEUs (115[91–153], p=0.02), HUUs with ASD (110[99–132], p=0.0001), and HUU controls (100[73–121], p<0.0001). Non-autistic HEU children and ASD children with no HIV/cART exposure had higher mtDNA content than controls (p=0.004 and p=0.03, respectively), but did not significantly differ from each other (p=0.2). Conclusions: Our results suggest a possible cumulative association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence in our cohort. It is unclear if this effect is modulated by exposure to antiretrovirals or maternal HIV but it is consistent with studies suggesting increased mtDNA content as an adaptive mechanism to mitochondrial dysfunction.

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2016-04-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57732

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/