Isolated remethylation disorders: do our treatments benefit patients?

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), the very rare methionine synthase reductase (CblE) and methionine synthase (CblG) defects, and the recently identified CblD-variant-1 defect are primary remethylation defects characterized by an isolated defect in methionine synthesis without methylmalonic aciduria. The clinical signs are mainly neurological, and hematological signs are seen in CblE, CblG, and CblD-variant-1 defects. Patients with neonatal or early-onset disease exhibit acute neurological distress. Infants and children have unspecific mental retardation, often with acquired microcephaly. Without appropriate therapy, they may experience acute or rapidly progressive neurological deterioration, which may be fatal. Adolescents and adults show normal development or mild developmental delay initially and then experience rapid neurological or behavioral deterioration. A few patients may have signs of subacute combined degeneration of the spinal cord. Adults may be asymptomatic or present with isolated thromboembolism. All patients with suspected remethylation disorders should receive emergency treatment with parenteral administration of hydroxocobalamin and folate supplements combined with betaine orally. The long-term treatment of CblE, CblG, and CblD-variant-1 defects consists of parenterally administered hydroxocobalamin and orally administered folate and betaine supplements, whereas patients with MTHFR deficiency require long-term oral folate and betaine supplements. Long-term oral methionine therapy should also be considered. Early treatment may lead to a favorable outcome with developmental recovery and prevention of further neurological deterioration. In contrast, most late-treated patients have severe and irreversible neuromotor impairments. Hematological abnormalities are easily corrected.