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

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