Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with 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 a medically based 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 and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels—a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). 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, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. 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...

Microbiome Disturbances and Autism Spectrum Disorders

“…The MD observed in autistic cases is thought to be acquired rather than genetic in origin. The SCFAs, especially PPA, which are increased in ASD-associated gut microbes (Clostridia, Desulfovibrio, Sutterella, and Bacteroidetes), might contribute to mitochondrial dysfunction (MacFabe, 2012(MacFabe, , 2013Frye et al, 2013). One mechanism by which the bacterial metabolite PPA may disrupt mitochondria is through alteration of the tricarboxylic acid cycle via conversion of PPA to propionyl-CoA.…”

Emerging Clues and Altered Metabolic Findings in Autism: Breakthroughs and Prospects from Omics Studies

“…Consequently, it turned out that patients with ASD showed reduced proportions of poly-unsaturated fatty acids (PUFA) in brain tissues and RBCmembranes, thereby reducing fluidity of membranes in these cells [105,106]. Likewise, in ASD, there has been a rise in ω6/ω3 FA ratio, indicative of erroneous FA synthesis, elongation and metabolism [107]. Such FA anomalies correlated positively with the incidence and extent of ASD mal-behavior and aggression, and were found mostly of nongenetic origin.…”

“…It is noteworthy also that FA-evoked glitches with ASD patients can turn more serious when the mitochondrial membranes are affected [108]. To assess altered FA composition and membrane fluidity, analysis of RBC FA-composition and unsaturation (double bond) sites has been a useful tool and a diagnostic marker to judge the integrity and stability of cellular membranes in vital tissues, including the brain [105][106][107][108].…”

Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats

“…While the causal factors of ASD remain unknown, there is strong evidence for a multi-genetic role in ASD [2]. However, research also indicates that environmental and gut-related factors may be important, and that autism may be a multisystem disorder affecting metabolic, immune and gastrointestinal systems [3,[5][6][7][8]. As it is difficult to address questions surrounding causality and interactions between genetic and environmental factors in the ASD patient setting, the use of animal models may provide insight into these potential relationships.…”

“…Propionic acid (PPA) is a short chain fatty acid (SCFA) that has been implicated as a possible gut-derived environmental factor in ASD [5,9,10]. PPA is produced as a fermentation product by many autism associated gut bacteria, and is also a common preservative in food products that may exacerbate ASD symptoms [9,10].…”