Clinical and metabolic findings in patients with methionine adenosyltransferase I/III deficiency detected by newborn screening.

Persistent hypermethioninemia due to mutations in the MAT1A gene is often found during newborn screening (NBS) for homocystinuria due to cystathionine beta-synthase deficiency, however, outcomes and optimal management for these patients are not well established. We carried out a multicenter study of MAT I/III-deficient patients detected by NBS in four of the Spanish regional NBS programs. Data evaluated during NBS and follow-up for 18 patients included methionine and total homocysteine levels, clinical presentation parameters, genotypes, and development quotients. The birth prevalence was 1:1:22,874. At detection 16 of the 18 patients exhibited elevations of plasma methionine above 60 μmol/L (mean 99.9 ± 38 μmol/L) and the mean value in confirmation tests was 301 μmol/L (91–899) μmol/L. All patients were asymptomatic. In four patients with more markedly elevated plasma methionines (> 450 μmol/L) total homocysteine values were slightly elevated (about 20 μmol/L). The average follow-up period was 3 years 7 months (range: 2–123 months). Most patients (83%) were heterozygous for the autosomal dominant Arg264His mutation and, with one exception, presented relatively low circulating methionine concentrations (< 400 μM). Additional mutations identified in patients with mean confirmatory plasma methionines above 400 μM were Arg199Cys, Leu355Arg, and a novel mutation, Thr288Ala. During continued follow-up, the patients have been asymptomatic, and, to date, no therapeutic interventions have been utilized. Therefore, the currently available evidence shows that hypermethioninemia due to heterozygous MAT1A mutations such as Arg264His is a mild condition for which no treatment is necessary.