Inherited disorders in the conversion of methionine to homocysteine

Abstract

During the last decade much important new information relating to the metabolic pathway from methionine to homocysteine has been gained. Interest has been stimulated by the discovery of two novel disorders, glycine N-methyltransferase deficiency and S-adenosylhomocysteine hydrolase deficiency. Another disorder in this pathway, methionine adenosyltransferase deficiency, has been increasingly detected, thanks to the expansion of newborn screening programmes by tandem mass spectrometry technology. These significant steps allow important insight into the pathogenesis of these three disorders, as well as into the mechanisms of damage to various organs (liver, brain, muscle) and point to the relevance of these disorders for crucial biological processes such as methylation, transsulfuration or carcinogenesis in mammals, the pathogenesis of numerous pathological conditions, in particular those associated with hyperhomocysteinaemia, the action and possible toxicity of some drugs or consequences of nutritional variations. This review summarizes current knowledge of three inherited disorders in this metabolic pathway and draws attention to their much broader significance for human health and understanding of important biological processes.

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

“…Most reports of this condition are recent since they are subsequent to the introduction of the MS/MS technology in newborn-screening programs. Its true incidence worldwide is not known, but it is surely under diagnosed (Baric 2009). The frequency found in our population (1:26,000) is similar to the one reported in Galicia (Couce et al 2008), which may indicate a similar frequency in the whole Iberian Peninsula.…”

Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

“…The transmethylation of methionine to homocysteine is present in all mammalian cells and its disruption can lead to severe clinical phenotypes (Baric 2009). Defects of the single steps of the methionine cycle are MAT I/III deficiency (OMIM #250850) (Chien et al 2015), GNMT deficiency (OMIM #606664) (Mudd et al 2001) and SAHH deficiency (OMIM #613752) (Baric et al 2004).…”

Methionine adenosyltransferase I/III deficiency: Neurological manifestations and relevance of S-adenosylmethionine

“…Methionine adenosyltransferase I/III (MAT I/III) deficiency, caused by mutations in the MAT1A gene, is an inherited metabolic disorder characterized by persistent hypermethioninemia without elevated tyrosine [1]. The present review article on MAT I/III deficiency describes genetic and metabolic aspects, neurological problems associated with brain demyelination, and therapeutic issues, with special emphasis on role of S-adenosylmethionine (SAM), the metabolic product of methionine catalyzed by MAT.…”