MAT I/III, the hepatic form of MAT, is produced by the MATAI gene. Young patients with persistent isolated hypermethioninemia due to MAT I/III deficiency appear clinically normal. The only adult with proven MAT I/III deficiency also appeared normal at age 31, suggesting that hepatic MAT deficiency is benign. In contrast, two patients with isolated hypermethioninemia displayed brain demyelination and neurological symptoms. Several hypermethioninemic patients with normal myelination have mutations in the MATAI gene. However, since the two patients with demyelination are homozygous for a gene predicted to produce a severely truncated protein, it was concluded that complete lack of hepatic MAT can lead to demyelination. Consequently, a 4-year old girl, predicted by her homozygous MATAI mutation (539insTG) to produce a truncated MAT I/III protein, was considered to be at risk for developing demyelination at a later age.

We now report that the 31-year old man with hepatic MAT deficiency, now 43, has normal brain myelination on MRI and a normal neurological exam despite elevated plasma methionines and urinary methionine transamination metabolites over 100-fold normal. SSCP analysis revealed an abnormal pattern in exon V of his MATAI gene, which sequencing verified was the 539insTG mutation. Both parents are heterozygous for the 539insTG mutation. This finding provides 40 years of natural history upon which to base a prognosis for the 4-year old girl homozygous for 539insTG, and supports the contention that MATAI mutations, even those resulting in severely truncated proteins, may be benign.