Methionine Adenosyltransferase I/III Deficiency Detected by Newborn Screening

Methionine adenosyltransferase I/III deficiency is an inborn error of metabolism due to mutations in the MAT1A gene. It is the most common cause of hypermethioninemia in newborn screening. Heterozygotes are often asymptomatic. In contrast, homozygous or compound heterozygous individuals can develop severe neurological symptoms. Less than 70 cases with biallelic variants have been reported worldwide. A methionine-restricted diet is recommended if methionine levels are above 500-600 mu mol/L. In this study, we report on a female patient identified with elevated methionine concentrations in a pilot newborn screening program. The patient carries a previously described variant c.1132G>A (p.Gly378Ser) in homozygosity. It is located at the C-terminus of MAT1A. In silico analysis suggests impaired protein stability by beta-turn disruption. On a methionine-restricted diet, her serum methionine concentration ranged between 49-605 mu mol/L (median 358 mu mol/L). Her clinical course was characterized by early-onset muscular hypotonia, mild developmental delay, delayed myelination and mild periventricular diffusion interference in MRI. At 21 months, the girl showed age-appropriate neurological development, but progressive diffusion disturbances in MRI. Little is known about the long-term outcome of this disorder and the necessity of treatment. Our case demonstrates that neurological symptoms can be transient and even patients with initial neurologic manifestations can show normal development under dietary management.

Automated summary

Methionine adenosyltransferase I/III deficiency, caused by mutations in the MAT1A gene, can lead to hypermethioninemia in newborns. This study reports on a female patient with elevated methionine concentrations in newborn screening. With dietary management, her neurological development was age-appropriate.