Thirteen Patients with MAT1A Mutations Detected Through Newborn Screening: 13 Years´ Experience

Background: Methionine adenosyltransferase I/III (MATI/III) deficiency is the most common genetic cause of persistent isolated hypermethioninemia. Patients and Methods: This is a retrospective data analysis of 62 newborns with elevated methionine detected by newborn screening between January 2000 and June 2013. The clinical, biochemical, and molecular findings of a subset of these children with MAT1A mutations associated with MATI/III deficiency are presented. Results: Of the 62 newborns with elevated methionine, 12 were identified as having classical homocystinuria; 37 were false-positives; and 13 were found to have isolated persistent hypermethioninemia in the absence of biochemical markers of homocystinuria, abnormal liver function studies, or other causes of elevated methionine. These 13 individuals underwent genetic testing for changes in the MAT1A gene, associated with MATI/III deficiency. Three of 13 were found to have the common autosomal dominant R264H mutation, one was found to be a compound heterozygote for two novel pathogenic mutations, and three were found to be heterozygotes for previously reported mutations shown to cause autosomal recessive MATI/III deficiency when present in homozygous or a compound heterozygous configuration. The remaining six patients had variants of unknown clinical significance or novel mutations. For the majority of individuals, methionine persisted above the normal range but trended downward over time. None of these 13 individuals was started on a low-methionine diet, and all have age-appropriate growth and development. Conclusion: These cases show that individuals with even single changes in the MAT1A gene may have elevations in methionine identified by newborn screening, which may persist for months after birth without any clinical consequences.