AUTHOR=Al-Kafaji Ghada , Jahrami Haitham Ali , Alwehaidah Materah Salem , Alshammari Yasmeen , Husni Mariwan 

TITLE=Mitochondrial DNA copy number in autism spectrum disorder and attention deficit hyperactivity disorder: a systematic review and meta-analysis

JOURNAL=Frontiers in Psychiatry

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1196035

DOI=10.3389/fpsyt.2023.1196035

ISSN=1664-0640

ABSTRACT=<sec id="sec1"><title>Background</title><p>Several reports suggest that altered mitochondrial DNA copy number (mtDNA-cn), a common biomarker for aberrant mitochondrial function, is implicated in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), but the results are still elusive.</p></sec><sec id="sec2"><title>Methods</title><p>A meta-analysis was performed to summarize the current indication and to provide a more precise assessment of the mtDNA-cn in ASD and ADHD. A search in the MEDLINE-PubMed, Scopus, and EMBASE databases was done to identify related studies up to the end of February 2023. The meta-analysis was conducted according to recommendations of the Cochrane Handbook of Systematic Reviews.</p></sec><sec id="sec3"><title>Results</title><p>Fourteen studies involving 666 cases with ASD and ADHD and 585 controls were collected and judged relevant for the systematic review and meta-analysis. The pooled results by a random effects meta-analysis was reported as a geometric mean of the estimated average response ratio and 95% confidence interval. Overall analysis of studies reported differences in mtDNA-cn in blood samples (<italic>k</italic> = 10) and non-blood samples (brain tissues and oral samples; <italic>k</italic> = 4) suggested significantly higher mtDNA-cn in patients compared to controls (<italic>p</italic> = 0.0275). Sub-analysis by stratifying studies based on tissue type, showed no significant increase in mtDNA-cn in blood samples among patients and controls (<italic>p</italic> = 0.284). Conversely, higher mtDNA-cn was observed in non-blood samples in patients than in controls (<italic>p</italic> = 0.0122). Further stratified analysis based on blood-cell compositions as potential confounds showed no significant difference in mtDNA-cn in peripheral blood samples of patients comparted to controls (<italic>p</italic> = 0.074). In addition, stratified analysis of aged-matched ASD and ADHD patients and controls revealed no significant difference in mtDNA-cn in blood samples between patients and controls (<italic>p</italic> = 0.214), whereas a significant increase in mtDNA-cn was observed in non-blood samples between patients and controls (<italic>p</italic> &lt; 0.001). Finally, when the mtDNA-cn was analyzed in blood samples of aged-matched patients with ASD (peripheral blood, leukocytes, and PBMCs) or ADHD (peripheral blood), no significant difference in mtDNA-cn was observed between ASD patients and controls (<italic>p</italic> = 0.385), while a significant increase in mtDNA-cn was found between ADHD patients and controls (<italic>p</italic> = 0.033).</p></sec><sec id="sec4"><title>Conclusion</title><p>In this first meta-analysis of the evaluation of mtDNA-cn in ASD/ADHD, our results show elevated mtDNA-cn in ASD and ADHD, further emphasizing the implication of mitochondrial dysfunction in neurodevelopmental disorders. However, our results indicate that the mtDNA-cn in blood is not reflected in other tissues in ASD/ADHD, and the true relationship between blood-derived mtDNA-cn and ASD/ADHD remains to be defined in future studies. The importance of blood-cell compositions as confounders of blood-based mtDNA-cn measurement and the advantages of salivary mtDNA-cn should be considered in future studies. Moreover, the potential of mtDNA-cn as a biomarker for mitochondrial malfunction in neurodevelopmental disorders deserves further investigations.</p></sec>