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Methionine adenosyltransferase I/III deficiency: novel mutations and clinical variations
M E Chamberlin1, T Ubagai, S H Mudd
1Heritable Disorders Branch, National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA.
American Journal of Human Genetics
|March 21, 2000
Summary
Methionine adenosyltransferase I/III deficiency, linked to MAT1A gene mutations, causes high methionine levels. Severe mutations correlate with neurological issues like brain demyelination, while milder ones show fewer symptoms.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Methionine adenosyltransferase (MAT) I/III deficiency results from MAT1A gene mutations, leading to hypermethioninemia.
- Clinical symptoms are diverse and not fully understood, though neurological deficits, including brain demyelination, are observed in some patients.
Purpose of the Study:
- To investigate the genotype-phenotype relationship in seven individuals with hypermethioninemia due to MAT1A mutations.
- To understand how different MAT1A mutations influence clinical manifestations and disease severity.
Main Methods:
- Genetic analysis of the MAT1A gene in seven hypermethioninemic individuals.
- Correlation of identified mutations with plasma methionine levels and clinical phenotypes, including neurological assessments.
Main Results:
- Six novel MAT1A mutations were identified.
- Patients with severe mutations (truncating, inactivating missense, aberrant splicing) exhibited significantly elevated plasma methionine (770–1,870 microM) and neurological abnormalities (gray matter issues, demyelination, cognitive impairment).
- Individuals with milder missense mutations or the R264H mutation had lower plasma methionine (105–467 microM) and remained clinically unaffected.
Conclusions:
- Elevated plasma methionine levels in MAT I/III deficiency may indicate potential clinical difficulties.
- Further research is crucial to fully elucidate the genotype-phenotype correlations and molecular mechanisms underlying the variable clinical presentations of MAT1A mutations.