Methionine Adenosyltransferase I/III Deficiency: Novel Mutationsand Clinical Variations

Chamberlin, Margaret E.; Ubagai, Tsuneyuki; Mudd, S. Harvey; Thomas, Janet A.; Pao, Vivian Y.; Nguyen, Thien Khanh; Levy, Harvey L.; Greene, Carol L.; Freehauf, Cynthia; Chou, Janice Y.

doi:10.1086/302752

Cited by 71 publications

(84 citation statements)

References 23 publications

(50 reference statements)

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“…At least 37 mutations have so far been reported in MAT1A gene (Mudd 2011), R264H exceptionally behaves as a dominant mutation and causes relatively mild hypermethioninemia, even in heterozygotes. This behavior is explained by the fact that the R264H mutated subunit can form inactive dimers with the normal subunit (Chamberlin et al 2000;Pérez Mato et al 2001). R264H heterozygosity seems to be relatively frequent among the patients identified by screening for methionine (Chien et al 2005;Couce et al 2008), and it is usually considered to be clinically benign (Pérez Mato et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Martins

Marcão²,

Bandeira

et al. 2012

JIMD Reports

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Methionine adenosyltransferase deficiency (MAT I/III deficiency) is an inborn error of metabolism resulting in isolated hypermethioninemia, and usually inherited as an autosomal recessive trait, although a dominant form has been reported in several families.During the last 6 years, approximately 520,000 newborns were screened in the Portuguese Newborn Screening Laboratory by MS/MS, and 21 cases of persistent hypermethioninemia were found. One case was confirmed to be a deficiency of cystathionine b-synthase and 20 cases were confirmed by MAT1A gene analysis to have an elevation of methionine due to MAT I/III deficiency, which indicates an incidence for this condition of 1/26,000. Twelve of the MAT I/III deficient newborns, belonging to 11 families, were identified in the northern region of Portugal and sent to the same treatment center, where they are under follow-up. Clinical, biochemical, and genetic characteristics of individuals from these 11 families are presented. Plasma methionine and homocysteine concentrations were found to be moderately increased in all newborns, and molecular analysis revealed that they all were heterozygous for R264H mutation. Normal growth, development, and neurological examination were observed in all cases, and cerebral MRI performed in six cases revealed myelination abnormalities in one case. Plasma methionine concentration for all 12 cases was always below 300 mM, and they are all on a normal diet for their age. AbbreviationsAdoMet S-adenosylmethionine CNS Central nervous system MAT Methionine adenosyltransferase MRI Magnetic resonance imaging MS/MS Tandem mass spectrometry

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Section: Discussionmentioning

confidence: 99%

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Martins

Marcão²,

Bandeira

et al. 2012

JIMD Reports

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“…For example, p.Arg264Cys, located on the same residue as p.Arg264His, has been found in AR inheritance (13,14). In addition, one of the new AD-type mutations suggested in our study, p.Gly280Arg, was identified only in one patient, in whom parental study was not available.…”

Section: Disclosurementioning

confidence: 51%

“…The AD type has been considered a benign condition, although its long-term prognosis remains unknown (1,4,5,7,11). However, some patients with the AR type may have developmental delay, intellectual disability or brain demyelination (7,(11)(12)(13)(14). Thus, determination of the inheritance pattern of MAT I/III deficiency is important for the optimal care of the patients as well as for genetic counseling of affected families.…”

Section: Resultsmentioning

confidence: 99%

“…It should be noted, however, that a novel nonsense mutation, p.Tyr335*, was also found in the AR type. 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).…”

Section: Structural Analyses Of the Nine Mat1a Mutant Proteinsmentioning

confidence: 99%

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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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“…Subsequent investigation identified the cause of elevated methionine to be due to a deficiency of methionine adenosyltransferase, expressed in the liver, which is encoded by the MAT1A gene (Ubagai and Lei 1995). Following the discovery of this enzyme deficiency and gene, it was noted that there were two main inheritance patterns for this condition: (1) a less common autosomal recessive form, which in addition to persistently elevated methionine, in some cases, is also characterized by developmental delay and progressive brain demyelization, and (2) an autosomal dominant form, characterized by the R264H mutation, which is clinically benign (Mato et al 2001;Ubagai and Lei 1995;Chamberlin et al 1997Chamberlin et al , 2000.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Background: Methionine adenosyltransferase I/III (MATI/III) deficiency is the most common genetic cause of persistent isolated hypermethioninemia.Patients and Methods: This is a retrospective data analysis of 62 newborns with elevated methionine detected by newborn screening between January 2000 and June 2013. The clinical, biochemical, and molecular findings of a subset of these children with MAT1A mutations associated with MATI/III deficiency are presented.Results: Of the 62 newborns with elevated methionine, 12 were identified as having classical homocystinuria; 37 were false-positives; and 13 were found to have isolated persistent hypermethioninemia in the absence of biochemical markers of homocystinuria, abnormal liver function studies, or other causes of elevated methionine. These 13 individuals underwent genetic testing for changes in the MAT1A gene, associated with MATI/III deficiency. Three of 13 were found to have the common autosomal dominant R264H mutation, one was found to be a compound heterozygote for two novel pathogenic mutations, and three were found to be heterozygotes for previously reported mutations shown to cause autosomal recessive MATI/III deficiency when present in homozygous or a compound heterozygous configuration. The remaining six patients had variants of unknown clinical significance or novel mutations. For the majority of individuals, methionine persisted above the normal range but trended downward over time. None of these 13 individuals was started on a lowmethionine diet, and all have age-appropriate growth and development.Conclusion: These cases show that individuals with even single changes in the MAT1A gene may have elevations in methionine identified by newborn screening, which may persist for months after birth without any clinical consequences.

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Methionine Adenosyltransferase I/III Deficiency: Novel Mutationsand Clinical Variations

Cited by 71 publications

References 23 publications

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

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

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

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