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.