AHCY was first reported in relation to autosomal recessive hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase in 2004 (Baric I, et al., 2004, PMID: 15024124). Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, with biochemical abnormalities of marked elevations in plasma SAH, SAM, methionine and creatine kinase accompanied by a significant decrease in the SAM/SAH ratio (however several cases had normal methionine levels at the initial evaluation). At least 13 variants (mostly missense but also nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Biallelic variants in this gene have been reported in at least 12 probands in 12 publications (PMIDs: 15024124, 16736098, 20852937, 22959829, 30121674, 26527160, 26095522, 27848944, 31957987, 35463910, 39512434, 39634240). Variants in this gene segregated with disease in three additional family members. This gene-disease relationship is supported by its biochemical function (PMID: 13641268). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 06/29/2020. It was reevaluated on 10/14/2022 with identification of one additional proband in PMID: 31957987. It was agin reevaluated on 12/6/2024 with identification of two additional probands and a C. elegans model in PMIDs: 39512434, 39634240, 38052822. As a result of this reevaluation, the classification moved from Moderate to Definitive.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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