DEMYELINATION OF THE BRAIN IS ASSOCIATED WITH METHIONINE ADENOSYLTRANSFERASE I II DEFICIENCY/

Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain muta tions in the gene (MATA1) that encodes the major hepatic forms, MAT I and III, MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and, in some cases, unusual breath odor. Most indiv iduals with isolated hypermethioninemia have been free of major clinic al difficulties. Therefore a definitive diagnosis of MAT I/III deficie ncy, which requires hepatic biopsy, is not routinely made, However, tw o individuals with isolated hypermethioninemia have developed abnormal neurological problems, including brain demyelination, suggesting that MAT I/III deficiency can be deleterious, In the present study we have examined the MATA1 gene of eight hypermethioninemic individuals, incl uding the two with demyelination of the brain, Mutations that abolish or reduce the MAT activity were detected in the MATA1 gene of all eigh t individuals, Both patients with demyelination are homozygous for mut ations that alter the reading frame of the encoded protein such that t he predicted MAT alpha 1 subunits are truncated and enzymatically inac tive, The product of MAT, S-adenosylmethionine (AdoMet), is the major methyl donor for a large number of biologically important compounds in cluding the two major myelin phospholipids, phosphatidylcholine and sp hingomyelin, Both are synthesized primarily in the liver, Our findings demonstrate that isolated persistent hypermethioninemia is a marker o f MAT I/III deficiency, and that complete lack of MAT I/III activity c an lead to neurological abnormalities. Therefore, a DNA-based diagnosi s should be performed for individuals with isolated hypermethioninemia to assess if therapy aimed at the prevention of neurological manifest ations is warranted.