Determination of Autosomal Dominant or Recessive Methionine Adenosyltransferase I/III Deficiencies Based on Clinical and Molecular Studies

Abstract

Methionine adenosyltransferase (MAT) I/III deficiency can be inherited as autosomal dominant (AD) or as recessive (AR) traits in which mono-or biallelic MAT1A mutations have been identified, respectively. Although most patients have benign clinical outcomes, some with the AR form have neurological deficits. Here we describe 16 Korean patients with MAT I/III deficiency from 15 unrelated families identified by newborn screening. Ten probands had the AD MAT I/III deficiency, while six had AR MAT I/III deficiency. Plasma methionine (145.7 μmol/L versus 733.2 μmol/L, P < 0.05) and homocysteine levels (12.3 μmol/L versus 18.6 μmol/L, P < 0.05) were lower in the AD type than in AR type. In addition to the only reported AD MAT1A mutation, p.Arg264His, we identified two novel AD mutations, p.Arg249Gln and p.Gly280Arg. In the AR type, four previously reported and two novel mutations, p.Arg163Trp and p.Tyr335*, were identified. No exonic deletions were found by quantitative genomic polymerase chain reaction (PCR). Three-dimensional structural prediction programs indicated that the AD-type mutations were located on the dimer interface or in the substrate binding site, hindering MAT I/III dimerization or substrate binding, respectively, whereas the AR mutations were distant from the interface or substrate binding site. These results indicate that the AD or AR MAT I/III deficiency is correlated with clinical findings, substrate levels and structural features of the mutant proteins, which is important for the neurological management and genetic counseling of the patients.

Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population

“…MATA1 deficiency is inherited either as autosomal-recessive or autosomal-dominant. Most MAT1A mutations give rise to autosomal recessive phenotypes, but several autosomal dominant mutations have also been observed, including c.776C > T, c.791G > A (Muriello et al, 2017), c.746G > A, and c.838G > A (Kim et al, 2016). With the exception of a few individuals with hypermethioninemia who present with abnormal neurological symptoms, most patients generally are free of major clinical manifestation.…”

Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia

“…Indeed, a case series of 9 such patients reported that none of the patients had symptoms of MATI/III deficiency, all had normal development, tolerated normal diets, and had similar patterns of methionine levels that trended downward on follow-up [12]. Similarly, 6 patients with p.Arg248Gln and 1 patient with p.Gly280Arg in the heterozygous state had methionine levels that declined over time [13]. Both of these residues are predicted to be located at the dimerization interface.…”

A New Integrated Newborn Screening Workflow Can Provide a Shortcut to Differential Diagnosis and Confirmation of Inherited Metabolic Diseases

“…However, discrepancies between the results of biochemical tests have often been observed, and biochemical enzyme assays are labor-intensive and tedious, and yield semiquantitative results. 2 17 In such cases, Sanger sequencing is the next step employed to confirm and differentiate the diagnosis. However, Sanger sequencing is also expensive and is hampered by the genetic heterogeneity of IMDs, which may result in delayed confirmation of diagnosis.…”