Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

Abstract

A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (≈ 0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.

Figure 1

Mitochondrial function and the electron transport chain (ETC). Abbreviations: ADP, adenosine diphosphate; AKA, α-ketoglutarate; ATP, adenosine triphosphate; CoQ, co-enzyme Q; Cyt C, cytochrome c; e, electron; FAD, flavin adenine dinucleotide; FADH₂, reduced FAD; H, hydrogen; LCFA, long chain fatty acid; MCFA, medium chain fatty acid; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; OXPHOS, oxidative phosphorylation; PDC, pyruvate dehydrogenase complex; SCFA, short chain fatty acid; TCA, tricarboxylic acid; I, complex I; II, complex II; III, complex III; IV, complex IV; V, complex V. The red arrows denote the flow of electrons in the ETC. The color reproduction of this figure is available on the html full text version of the article.

Figure 2

Study flow chart. Abbreviation: ASD, autism spectrum disorder.

Figure 3

Suggested screening for mitochondrial dysfunction in ASD. Abbreviations: ASD, autism spectrum disorder; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; GI, gastrointestinal; MD, mitochondrial disease; mtDNA, mitochondrial DNA; nDNA, nuclear DNA.