There are multiple lines of evidence for an impaired sulfur amino acid (SAA) metabolism in autism spectrum disorder (ASD). For instance, the concentrations of 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 melatonin deficiency and hypomethylation of a number of biomolecules such as DNA, RNA and histones. 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 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.

Silver-Russell syndrome (SRS) and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are described in isolation. However, their co-occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation-dependent probe amplification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer-reviewed publications (original articles and reviews) using the key words Silver-Russell syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms.