Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism

Abstract 

Autism is a neurological disorder that manifests as noticeable behavioral and developmental abnormalities predominantly in males between the ages of 2 and 10. Although the genetics, biochemistry and neuropathology of this disease have been extensively studied, underlying causal factors to this disease have remained elusive. Using a longitudinal trial design in which three plasma samples were collected from 15 autistic and 12 non-autistic age-matched controls over the course of 1 year, universal and unambiguous alterations in lipid metabolism were observed. Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects. In all 8 of the affected/non-affected sibling pairs, the affected sibling had higher levels of these biomarkers than the unaffected sibling. Exposure of neurons, astrocytes and hepatocytes in vitro to elevated extracellular glutamate levels resulted in lipid biomarker changes indistinguishable from those observed in autistic subjects. Glutamate stress also resulted in in vitro decreased levels of reduced glutathione (GSH), methionine and cysteine, in a similar way to the decreases we observed in autism plasma. Impaired mitochondrial fatty acid oxidation, elevated plasma VLCFAs, and glutamate toxicity as putative causal factors in the biochemistry, neuropathology, and gender bias in autism are discussed.

Keywords: Autism, Very long chain fatty acid (VLCFA), Plasmalogen, Mitochondria, Carnitine, Glutamate, Glutathione

Abbreviation: Cys, cysteine, CNS, central nervous system, DHA, docosahexaenoic acid, EtOAc, ethyl acetate, GSH, reduced glutathione, Hcy, homocysteine, 1-HG, 1-hexadecylglycerol, Met, methionine, PlsEtn, ethanolamine plasmalogen, PtdEtn, phosphatidylethanolamine, TCA, tricarboxylic acid