There are multiple lines of evidence for an impaired sulfur amino acid (SAA) metabolism in autism spectrum disorder (ASD). For instance, the concentrations of the methionine, cysteine and S-adenosylmethionine (SAM) in body fluids of individuals with ASD is significantly lower while the concentration of S-adenosylhomocysteine (SAH) is significantly higher as compared to healthy individuals. Reduced methionine and SAM may reflect impaired remethylation pathway whereas increased SAH may reflect reduced S-adenosylhomocysteine hydrolase activity in the catabolic direction. Reduced SAM/SAH ratio reflects an impaired methylation capacity. We hypothesize multiple mechanisms to explain how the interplay of oxidative stress, neuroinflammation, mercury exposure, maternal use of valproate, altered gut microbiome and certain genetic variants may lead to these SAA metabotypes. Furthermore, we also propose a number of mechanisms to explain the metabolic consequences of abnormal SAA metabotypes. For instance in the brain, reduced SAM/SAH ratio will result in hypomethylation of a number of biomolecules such as DNA, RNA, histones, and N-acetylserotonin. In addition to previously proposed mechanisms, we propose that impaired activity of “radical SAM” enzymes will result in reduced endogenous lipoic acid synthesis, reduced molybdenum cofactor synthesis and impaired porphyrin metabolism leading to mitochondrial dysfunction, porphyrinuria and impaired sulfation capacity. Furthermore depletion of SAM may also lead to the disturbed mTOR signaling pathway in a subgroup of individuals with ASD. The proposed “SAM-depletion hypothesis” is an inclusive model to explain the relationship between heterogeneous risk factors and metabotypes observed in a subset of children with ASD.
Copyright © 2021. Published by Elsevier B.V.