MAT1A – Methionine adenosyltransferase deficiency

Methionine adenosyltransferase 1A (MAT1A) encodes the catalytic subunit of hepatic MAT I/III, the key enzyme for S-adenosylmethionine synthesis. Loss or alteration of MAT1A activity leads to persistent hypermethioninemia, known as Mudd’s disease, with clinical spectra ranging from benign biochemical findings to severe neurological injury. Both autosomal recessive (AR) and autosomal dominant (AD) inheritance have been documented in this disorder.

Genetic analyses across multiple cohorts identified 35 unrelated individuals with MAT1A variants (15 with monoallelic c.791G>A (p.Arg264His) and 20 with biallelic variants) [PMID:36704196]. The AD form, caused by the recurrent founder variant c.791G>A (p.Arg264His), was observed in 15 unrelated probands and segregated in 11 families with isolated hypermethioninemia and normal development [PMID:36704196]. The AR form was reported in 20 cases harboring compound heterozygous or homozygous loss-of-function and missense variants, of whom 10 developed neurological manifestations including brain demyelination [PMID:9042912; PMID:10674710].

Population screening estimates an incidence of approximately 1 in 26 000 in northern Portugal [PMID:23430947], 1 in 107 850 in Japan [PMID:24231718], and 1 in 116 161 in China [PMID:36704196]. Heterozygous carriers of p.Arg264His are asymptomatic, whereas patients with methionine concentrations >800 µmol/L often develop motor delay and white matter lesions (HP:0001270) or atypical behavior (HP:0000708) on imaging.

Functional and structural studies demonstrate that p.Arg264His disrupts an inter-subunit salt bridge at the dimer interface, reducing MAT activity by >99% while forming inactive heterodimers (dominant-negative) [PMID:32496220]. Enzymatic assays of 18 additional MAT1A variants confirm severely impaired MAT activity and variable tripolyphosphatase function [PMID:20675163]. Rescue of p.Arg264His activity by quinolone-based compounds or MATβ interaction highlights therapeutic potential.

Clinically, AR patients benefit from methionine-restricted diets, S-adenosylmethionine supplementation, or liver transplantation, which normalizes methionine levels and reverses neurological deficits [PMID:36704196; PMID:39511588]. The AD form typically requires only biochemical monitoring without intervention.

Key Take-home: MAT1A deficiency, with dual AR and AD inheritance, exhibits a spectrum from benign hypermethioninemia to severe neurological injury; early molecular diagnosis enables tailored dietary and pharmacological management.

References

• American Journal of Human Genetics • 1997 • Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene. PMID:9042912
• Pharmacology & Therapeutics • 2000 • Molecular genetics of hepatic methionine adenosyltransferase deficiency. PMID:10674710
• Molecular Genetics and Metabolism • 2010 • Enzymatic activity of methionine adenosyltransferase variants identified in patients with persistent hypermethioninemia. PMID:20675163
• JIMD Reports • 2012 • Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands. PMID:23430947
• Molecular Genetics and Metabolism • 2013 • Spectrum of mutations associated with methionine adenosyltransferase I/III deficiency among individuals identified during newborn screening in Japan. PMID:24231718
• Acta Crystallographica Section D • 2020 • Structural basis of the dominant inheritance of hypermethioninemia associated with the Arg264His mutation in the MAT1A gene. PMID:32496220
• Human Genetics (preprint) • 2023 • Incidence and clinical heterogeneity of MAT1A deficiency in a Chinese newborn screening cohort. PMID:36704196
• BMC Pediatrics • 2024 • Hypermethioninemia due to methionine adenosyltransferase I/III deficiency and brain damage. PMID:39511588

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