Homocysteine and B-Vitamin Metabolism

Journal of Inherited Metabolic Disease

, Volume 34, Issue 1, pp 137-145

Isolated remethylation disorders: do our treatments benefit patients?

  • Manuel SchiffAffiliated withReference Center for Metabolic Disease, Robert Debré University Hospital, APHPPediatric Neurology & Metabolic disease, Robert Debré University Hospital, APHPService de Neuropédiatrie & Maladies Métaboliques, Centre de Référence Maladies Métaboliques, Hôpital Robert Debré Email author 
  • , Jean-François BenoistAffiliated withReference Center for Metabolic Disease, Robert Debré University Hospital, APHPBiochemistry, Robert Debré University Hospital, APHP
  • , Bogdana TileaAffiliated withPediatric Radiology, Robert Debré University Hospital, APHP
  • , Nicolas RoyerAffiliated withReference Center for Metabolic Disease, Robert Debré University Hospital, APHPBiochemistry, Robert Debré University Hospital, APHP
  • , Stéphane GiraudierAffiliated withHaematology Laboratory, Henri Mondor University Hospital, AP-HP
  • , Hélène Ogier de BaulnyAffiliated withReference Center for Metabolic Disease, Robert Debré University Hospital, APHPPediatric Neurology & Metabolic disease, Robert Debré University Hospital, APHP

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Abstract

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.