Methionine adenosyltransferase I/III deficiency: Novel mutations and clinical variations

Methionine adenosyltransferase (MAT) I/III deficiency, caused by mutations in the MAT1A gene, is characterized by persistent hypermethioninemia withou t elevated homocysteine or tyrosine. Clinical manifestations are variable a nd poorly understood, although a number of individuals with, homozygous nul l mutations in MAT1A have neurological problems, including brain demyelinat ion. We analyzed MAT1A in seven hypermethioninemic individuals, to provide insight into the relationship between genotype and phenotype. We identified six novel mutations and demonstrated that mutations resulting in high plas ma methionines may signal clinical difficulties. Two patients-a compound he terozygote for truncating and severely inactivating missense mutations and a homozygote for an aberrant splicing MAT1A mutation-have plasma methionine in the 1,226-1,870 mu M range (normal 5-35 mu M) and manifest abnormalitie s of the brain gray matter or signs of brain demyelination. Another compoun d heterozygote for truncating and inactivating missense mutations has 770-1 ,240 mu M plasma methionine and mild cognitive impairment. Four individuals carrying either two inactivating missense mutations or the single-allelic R264H mutation have 105-467 mu M plasma methionine and are clinically unaff ected. Our data underscore the necessity of further studies to firmly estab lish the relationship between genotypes in MAT I/III deficiency and clinica l phenotypes, to elucidate the molecular bases of variability in manifestat ions of MAT1A mutations.