SFN: Unique acyl-carnitine profiles in the propionic acid rat model of autism predict potential biomarkers for mitochondrial dysfunction in autistic patients

 Autism spectrum disorder (ASD) may occur with mitochondrial disease (MD), and unique enteric bacterial populations. Specific genetic mutations to explain MD are rare, suggesting that MD in some ASD patients may be environmentally acquired. Acquired MD occurs in an ASD model in
which propionic acid (PPA), an enteric bacterial fermentation product of ASD associated bacteria (i.eclostridia, desulfovibrio), is given to rodents. This animal model demonstrates many behavioral and brain changes associated with ASD, including a unique pattern of elevated short-chain
and long-chain acyl-carnitines, suggesting abnormalities in fatty-acid
metabolism. To determine if these biomarkers are present in ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in an autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal short and long chain acyl-carnitine panels- consistent with the PPA rodent ASD model. Examination of electron transport chain function (muscle, fibroblast culture), histological and electron microscopy examination of muscle and other mitochondrial biomarkers suggest that PPA could be interfering with mitochondrial tricarboxylic acid metabolism. The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, suggesting that the fatty-acid metabolic abnormalities were secondary to tricarboxylic acid cycle abnormalities. Glutathione metabolism was abnormal in the ASD subset with acyl-carnitine panel abnormalities, similar to that found in the PPA rodent model. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction. Future studies need to identify additional parallels between the PPA rodent model of ASD and this subset of ASD individuals with this unique pattern of acyl-carnitine and glutathione abnormalities. Use of this animal model with ASD patients should lead to better insight in mechanisms behind environmentally induced ASD pathophysiology and should provide guidance for developing preventive and symptomatic treatments.

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