[A rare inborn error of intracellular processing of cobalamine presenting with microcephalus and megaloblastic anemia: a report of 3 children].

INTRODUCTION: Defects of methionine synthase or methionine synthase reductase result in an impaired remethylation of homocysteine to methionine. Patients present with megaloblastic anemia, failure to thrive and various neurological manifestations including mental retardation, cerebral atrophy, muscular hypotonia or hypertonia, ataxia, seizures, nystagmus and visual disturbances. PATIENTS: We report on three children (two girls, one boy), aged 3.5-7.5 years, who presented with severe megaloblastic anemia, micro-cephalus and partly nystagmus (2/3) due to a rare inborn error of remethylation.
RESULTS: Methionine synthase reductase deficiency, cblE type of homocystinuria (OMIM 236270), is a rare autosomal recessive inherited disorder described only in 14 patients worldwide. Metabolic hallmarks of the disease are hyperhomocysteinemia (median 98 micromol/l, normal range <15) without methylmalonic aciduria but often hypomethioninemia. The patients described here were diagnosed at ages of 2-18 months. The importance of an early recognition of this possibly underdiagnosed congenital disease is stressed. Treatment consisted of the application of hydroxocobalamine (1-2 mg weekly, i.m.), betaine (100-200 mg/kg daily, p.o.), folate (5-10 mg daily, p.o.) and intensive physical therapy.
CONCLUSION: Defects of intracellular processing of cobalamine must be considered in all patients with neurological symptoms in combination with megaloblastic anemia. Measurements of homocysteine and methionine in plasma as well as methylmalonic acid in urine is required for confirming the diagnosis. Early treatment im-proves the outcome, although mental disability may not be prevented. Treatment has a positive impact on megaloblastic anemia but only slight effect on hyperhomocysteinemia. The long-term cardiovascular risk of hyperhomocysteinemia in cblE deficient patients is not known yet.