Thirteen Patients with MAT1A Mutations Detected Through Newborn Screening: 13 Years’ Experience

Chadwick, Sara L.; Fitzgerald, K.; Weiss, Brendan M.; Fıçıcıoğlu, Can

doi:10.1007/8904_2013_286

Cited by 14 publications

(20 citation statements)

References 9 publications

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“…Blood methionine measurements in parents can help to identify dominant hypermethioninemia although sometimes this may only be slightly elevated. Strong evidence indicates that heterozygotes, in particular c.791G > A (p.R264H) heterozygotes will be clinically unaffected (Couce et al 2013; Chadwick et al 2014). See further under ‘differential diagnosis’ above.…”

Section: Methionine Adenosyltransferase I/iii Deficiencymentioning

confidence: 99%

Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders

Barić

Staufner

Augoustides‐Savvopoulou

et al. 2016

J of Inher Metab Disea

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Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient’s age, severity of the disease, clinical and laboratory findings.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9972-7) contains supplementary material, which is available to authorized users.

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Section: Methionine Adenosyltransferase I/iii Deficiencymentioning

confidence: 99%

Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders

Barić

Staufner

Augoustides‐Savvopoulou

et al. 2016

J of Inher Metab Disea

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“…These findings provide evidence that heterozygosity for the p.Ala259Val mutation in MAT1A accounts for a second variant causative of autosomal dominant hypermethioninemia. The common p.Arg264His mutation has been shown to have less marked elevations in methionine with age [3], [11], a pattern that has since been shown in patients with other heterozygous mutations [12]. 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].…”

Section: Discussionmentioning

confidence: 87%

Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia

Muriello

Viall

Cusmano‐Ozog

et al. 2017

Molecular Genetics and Metabolism Reports

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Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in MAT1A, encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance. We report a case of hypermethioninemia caused by the p.Ala259Val substitution and provide evidence of autosomal dominant inheritance by showing both maternal inheritance of the mutation and concomitant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by means of interference with subunits encoded by the wild-type allele.

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“…Notably, the severe types of mutations, including nonsense, frameshift and splicing mutations, have been found exclusively in patients with the AR type (7,11,14,17,(21)(22)(23)(24). Because MAT I/III functions as a dimer, these types of mutations appear be p.Gly257Arg and p.Asp258Gly (7,(17)(18)(19)(20). It was suggested that a mutation in the other allele would exist; however, any mutation in other alleles was not identified by sequence analysis.…”

Section: Structural Analyses Of the Nine Mat1a Mutant Proteinsmentioning

confidence: 99%

“…However, diet modification such as a low Met diet can be considered for patients with persistent severe hypermethioninemia considering high risk for a neurologic deficit and cardiovascular event (13,17,24). However, there is controversy over Met restriction because it can deplete SAM, affecting neurological outcomes, and only a small number of patients have been treated previously (13,18,21,24). The comprehensive analyses of the overall activities of the enzymes and their cofactors involved in the homocysteine-Met cycle with measurement of their metabolites would give more information regarding the biochemical pathology and treatment options such as SAM or betaine supplementation.…”

Section: Structural Analyses Of the Nine Mat1a Mutant Proteinsmentioning

confidence: 99%

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

Kim

Choi

et al. 2016

Mol Med

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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.

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Thirteen Patients with MAT1A Mutations Detected Through Newborn Screening: 13 Years’ Experience

Cited by 14 publications

References 9 publications

Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders

Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders

Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia

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

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