Methionine adenosyltransferase I/III deficiency

Methionine adenosyltransferase I/III deficiency (MAT I/III deficiency), also known as hypermethioninemia due to MAT1A deficiency or glycine N-methyltransferase deficiency-related hypermethioninemia, is an inborn error of methionine metabolism caused by mutations in the MAT1A gene. This gene encodes the hepatic isoforms (I and III) of methionine adenosyltransferase, the enzyme responsible for converting methionine to S-adenosylmethionine (AdoMet or SAMe), a critical methyl donor in numerous biochemical reactions. The deficiency leads to persistent isolated hypermethioninemia, meaning elevated levels of methionine in the blood. The condition primarily affects methionine metabolism in the liver, as MAT1A is predominantly expressed in hepatic tissue. In the autosomal recessive (homozygous or compound heterozygous) form, methionine levels can be markedly elevated, and some patients may develop neurological manifestations including demyelination of the brain, cognitive difficulties, and unusual breath odor (due to dimethylsulfide). However, many individuals — particularly those with the more common autosomal dominant form (heterozygous mutations) — remain clinically asymptomatic and are identified incidentally through newborn screening programs that detect elevated methionine. The clinical spectrum is broad, ranging from completely benign hypermethioninemia to rare cases with neurological involvement. Most patients with the dominant form require no treatment. For those with the more severe recessive form, dietary methionine restriction may be considered, and S-adenosylmethionine supplementation has been explored in some cases to compensate for reduced SAMe production. Regular monitoring of plasma methionine levels and neurological assessment is recommended. Long-term prognosis is generally favorable, especially for heterozygous individuals, though patients with very high methionine levels warrant closer clinical follow-up.

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