Intractable Epilepsy due to MTR Deficiency: Importance of Homocysteine Analysis

Abstract

Background Methionine synthase deficiency is a rare inborn error of intracellular cobalamin metabolism caused by mutations in the MTR (5-methyltetrahydrofolate-homocysteine S-methyltransferase) gene, resulting in megaloblastic anemia and neurologic symptoms.

Methods and Results We describe for the first time a homozygous MTR gene c.3518C > T (p.P1173L) mutation in a patient with severe megaloblastic anemia, developmental delay, and drug-resistant seizures associated with hyperhomocysteinemia and hypomethioninemia. Methionine synthase activity was only 9% of the reference value, and MTR protein expression was decreased in the fibroblasts of the patient. The clinical features of our patient are similar to previously published patients with the complementation type G disorder of methionine synthase deficiency with the exception of drug-resistant seizures. However, intramuscular injections of hydroxocobalamin (OHCbl) in conjunction with betaine and folic acid provided verified clinical and electrophysiological treatment response.

Conclusion This study emphasizes the importance of early diagnosis of patients having neurologic symptoms due to methionine synthase deficiency where early treatment has significant effects on the clinical outcome of the patients. Elevated level of plasma homocysteine together with low methionine in plasma amino acid analysis should raise a suspicion of remethylation disorder.

Keywords

drug-resistant epilepsy - methionine synthase deficiency - cblG - MTR gene - plasma homocysteine

Funding

This work was supported by grants from the Research Council for Health of the Academy of Finland (JU, Decision number 138566; RH, Decision number 266498 and 273790), the Foundation for Pediatric Research, Special State Grants for Health Research in the Department of Pediatrics and Adolescence at Oulu University Hospital, Oulu, Finland, The Alma and K. A. Snellman Foundation, Oulu, Finland, and Finnish Cultural Foundation, North Ostrobothnia Regional Fund.

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