Methionine adenosyltransferase I/III deficiency: Neurological manifestations and relevance of S-adenosylmethionine

Furujo, Mahoko; Kinoshita, Masako; Nagao, Masayoshi; Kubo, Toshio

doi:10.1016/j.ymgme.2012.08.002

Cited by 23 publications

(20 citation statements)

References 26 publications

(67 reference statements)

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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: 50%

“…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%

“…The causes of hyperhomocysteinemia in MAT I/III deficiency are elusive, but hyperhomocysteinemia might be related to high Met levels that inhibit Met synthase or SAM depletion, as suggested in previous observations (1,3,24). Importantly, SAM is involved in neurotransmitter metabolism, antioxidation and myelination (11,13,26). In addition, a high homocysteine level possibly increases the long-term risk of strokes (27).…”

Section: Disclosurementioning

confidence: 89%

“…Generally, treatment is not indicated for mild or transient hypermethioninemia; monitoring plasma Met and homocysteine levels with developmental assessment may be enough as a follow-up evaluation. 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).…”

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%

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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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Section: Disclosurementioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Disclosurementioning

confidence: 89%

Section: Structural Analyses Of the Nine Mat1a Mutant Proteinsmentioning

confidence: 99%

Section: Structural Analyses Of the Nine Mat1a Mutant Proteinsmentioning

confidence: 99%

See 3 more Smart Citations

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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The functional roles of S‐adenosyl‐methionine and S‐adenosyl‐homocysteine and their involvement in trisomy 21

Caracausi,

Ramacieri,

Catapano

et al. 2024

BioFactors

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The one‐carbon metabolism pathway is involved in critical human cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. In the homocysteine‐methionine cycle S‐adenosyl‐methionine (SAM) and S‐adenosyl‐homocysteine (SAH) are synthetized, and their levels are finely regulated to ensure proper functioning of key enzymes which control cellular growth and differentiation. Here we review the main biological mechanisms involving SAM and SAH and the known related human diseases. It was recently demonstrated that SAM and SAH levels are altered in plasma of subjects with trisomy 21 (T21) but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. This review aims at providing an overview of the biological mechanisms which are altered in response to changes in the levels of SAM and SAH observed in DS.

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Methionine Is a Major Methyl Donor Whose Dietary Intake Likely Plays a Causative Role for Neurodevelopmental Disorders via Epigenomic Profile Alterations

Mubarak

Zahir

2022

Nutritional Neurosciences

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Methionine adenosyltransferase I/III deficiency: Neurological manifestations and relevance of S-adenosylmethionine

Cited by 23 publications

References 26 publications

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

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

The functional roles of S‐adenosyl‐methionine and S‐adenosyl‐homocysteine and their involvement in trisomy 21

Methionine Is a Major Methyl Donor Whose Dietary Intake Likely Plays a Causative Role for Neurodevelopmental Disorders via Epigenomic Profile Alterations

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