Journal of Inherited Metabolic Disease

, Volume 34, Issue 1, pp 137–145 | Cite as

Isolated remethylation disorders: do our treatments benefit patients?

  • Manuel Schiff
  • Jean-François Benoist
  • Bogdana Tilea
  • Nicolas Royer
  • Stéphane Giraudier
  • Hélène Ogier de Baulny
Homocysteine and B-Vitamin Metabolism


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.


Betaine Folinic Acid tHCy Level Plasma tHCy Methionine Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are grateful to Dr. Patrick Boutard, Dr. Laurent Chevret, Dr. Kumaran Deiva, Dr. Emmanuelle Gondon, Dr. Shushanik Hovhannisyan, and Dr. Philippe Sachs, the pediatricians in charge of several of these patients; and to Prof. Brian Fowler who performed the enzyme activity assays for patient 4.


  1. Abeling NG, van Gennip AH, Blom H et al (1999) Rapid diagnosis and methionine administration: basis for a favourable outcome in a patient with methylene tetrahydrofolate reductase deficiency. J Inherit Metab Dis 22:240–242PubMedCrossRefGoogle Scholar
  2. Al-Essa MA, Al Amir A, Rashed M et al (1999) Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. Brain Dev 21:345–349PubMedCrossRefGoogle Scholar
  3. Baethmann M, Wendel U, Hoffmann GF et al (2000) Hydrocephalus internus in two patients with 5, 10-methylenetetrahydrofolate reductase deficiency. Neuropediatrics 31:314–317PubMedCrossRefGoogle Scholar
  4. Carmel R, Watkins D, Goodman SI, Rosenblatt DS (1988) Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 318:1738–1741PubMedCrossRefGoogle Scholar
  5. Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A, Venditti CP (2009) Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32:728–731PubMedCrossRefGoogle Scholar
  6. Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ (1986) Subacute combined degeneration of the cord, dementia and parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 49:920–927PubMedCrossRefGoogle Scholar
  7. Coelho D, Suormala T, Stucki M et al (2008) Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med 358:1454–1464PubMedCrossRefGoogle Scholar
  8. Debray FG, Boulanger Y, Khiat A et al (2008) Reduced brain choline in homocystinuria due to remethylation defects. Neurology 71:44–49PubMedCrossRefGoogle Scholar
  9. Delgado-Reyes CV, Wallig MA, Garrow TA (2001) Immunohistochemical detection of betaine-homocysteine S-methyltransferase in human, pig, and rat liver and kidney. Arch Biochem Biophys 393:184–186PubMedCrossRefGoogle Scholar
  10. Farquharson J, Adams JF (1976) The forms of vitamin B12 in foods. Br J Nutr 36:127–136PubMedCrossRefGoogle Scholar
  11. Finkelstein JD (2006) Inborn errors of sulfur-containing amino acid metabolism. J Nutr 136:1750S–1754SPubMedGoogle Scholar
  12. Fowler B (2005) Homocysteine: overview of biochemistry, molecular biology, and role in disease processes. Semin Vasc Med 5:77–86PubMedCrossRefGoogle Scholar
  13. Garlick PJ (2006) Toxicity of methionine in humans. J Nutr 136:1722S–1725SPubMedGoogle Scholar
  14. Gregory JF 3rd (1989) Chemical and nutritional aspects of folate research: analytical procedures, methods of folate synthesis, stability, and bioavailability of dietary folates. Adv Food Nutr Res 33:1–101PubMedCrossRefGoogle Scholar
  15. Harding CO, Arnold G, Barness LA, Wolff JA, Rosenblatt DS (1997) Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review. Am J Med Genet 71:384–390PubMedCrossRefGoogle Scholar
  16. Harpey JP, Rosenblatt DS, Cooper BA, Le Moel G, Roy C, Lafourcade J (1981) Homocystinuria caused by 5, 10-methylenetetrahydrofolate reductase deficiency: a case in an infant responding to methionine, folinic acid, pyridoxine, and vitamin B12 therapy. J Pediatr 98:275–278PubMedCrossRefGoogle Scholar
  17. Holme E, Kjellman B, Ronge E (1989) Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 64:1061–1064PubMedCrossRefGoogle Scholar
  18. Li D, Karp N, Wu Q et al (2008) Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 31:403–411PubMedCrossRefGoogle Scholar
  19. Malouf R, Grimley Evans J (2008) Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev CD004514Google Scholar
  20. Mellman I, Willard HF, Youngdahl-Turner P, Rosenberg LE (1979) Cobalamin coenzyme synthesis in normal and mutant human fibroblasts. Evidence for a processing enzyme activity deficient in cblC cells. J Biol Chem 254:11847–11853PubMedGoogle Scholar
  21. Miousse IR, Watkins D, Coelho D et al (2009) Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. J Pediatr 154:551–556PubMedCrossRefGoogle Scholar
  22. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157(Suppl 2):S77–S83PubMedCrossRefGoogle Scholar
  23. Pentieva K, McNulty H, Reichert R et al (2004) The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acid are equivalent in men. J Nutr 134:580–585PubMedGoogle Scholar
  24. Rosenblatt DS, Fenton WA (2001) In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) Metabolic and molecular bases of inherited disease, vol III, 8th edn. McGraw-Hill, New-York, pp 3897–3933Google Scholar
  25. Rosenblatt DS, Cooper BA, Schmutz SM, Zaleski WA, Casey RE (1985) Prenatal vitamin B12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease). Lancet 18:1127–1129CrossRefGoogle Scholar
  26. Sardharwalla IB, Fowler B, Robins AJ, Komrower GM (1974) Detection of heterozygotes for homocystinuria. Study of sulphur-containing amino acids in plasma and urine after L-methionine loading. Arch Dis Child 49:553–559PubMedCrossRefGoogle Scholar
  27. Schuh S, Rosenblatt DS, Cooper BA et al (1984) Homocystinuria and megaloblastic anemia responsive to vitamin B12 therapy. An inborn error of metabolism due to a defect in cobalamin metabolism. N Engl J Med 310:686–690PubMedCrossRefGoogle Scholar
  28. Schwahn BC, Hafner D, Hohlfeld T, Balkenhol N, Laryea MD, Wendel U (2003) Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria. Br J Clin Pharmacol 55:6–13PubMedCrossRefGoogle Scholar
  29. Schwahn BC, Laryea MD, Chen Z et al (2004) Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 382:831–840PubMedCrossRefGoogle Scholar
  30. Smulders YM, Smith DE, Kok RM et al (2006) Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap. Br J Haematol 132:623–629PubMedCrossRefGoogle Scholar
  31. Stead LM, Brosnan JT, Brosnan ME, Vance DE, Jacobs RL (2006) Is it time to reevaluate methyl balance in humans? Am J Clin Nutr 83:5–10PubMedGoogle Scholar
  32. Strauss KA, Morton DH, Puffenberger EG et al (2007) Prevention of brain disease from severe 5, 10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175PubMedCrossRefGoogle Scholar
  33. Suormala T, Gamse G, Fowler B (2002) 5, 10-Methylenetetrahydrofolate reductase (MTHFR) assay in the forward direction: residual activity in MTHFR deficiency. Clin Chem 48:835–843PubMedGoogle Scholar
  34. Suormala T, Baumgartner MR, Coelho D et al (2004) The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem 279:42742–42749PubMedCrossRefGoogle Scholar
  35. Surtees R (1998) Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 157(Suppl 2):S118–S121PubMedCrossRefGoogle Scholar
  36. Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554PubMedCrossRefGoogle Scholar
  37. Ucar SK, Koroglu OA, Berk O et al (2010) Titration of betaine therapy to optimize therapy in an infant with 5, 10-methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 169:241–243PubMedCrossRefGoogle Scholar
  38. Verlinde PH, Oey I, Hendrickx ME, Van Loey AM, Temme EH (2008) L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men. Eur J Clin Nutr 62:1224–1230PubMedCrossRefGoogle Scholar
  39. Wendel U, Bremer HJ (1984) Betaine in the treatment of homocystinuria due to 5, 10-methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 142:147–150PubMedCrossRefGoogle Scholar
  40. Whitehead VM (2006) Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol 134:125–136PubMedCrossRefGoogle Scholar
  41. Wilcken DE, Wilcken B (1997) The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis 20:295–300PubMedCrossRefGoogle Scholar
  42. Yap S, Naughten ER, Wilcken B, Wilcken DE, Boers GH (2000) Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta-synthase deficiency: effects of homocysteine-lowering therapy. Semin Thromb Hemost 26:335–340PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Manuel Schiff
    • 1
    • 2
    • 6
  • Jean-François Benoist
    • 1
    • 3
  • Bogdana Tilea
    • 4
  • Nicolas Royer
    • 1
    • 3
  • Stéphane Giraudier
    • 5
  • Hélène Ogier de Baulny
    • 1
    • 2
  1. 1.Reference Center for Metabolic DiseaseRobert Debré University Hospital, APHPParisFrance
  2. 2.Pediatric Neurology & Metabolic diseaseRobert Debré University Hospital, APHPParisFrance
  3. 3.BiochemistryRobert Debré University Hospital, APHPParisFrance
  4. 4.Pediatric RadiologyRobert Debré University Hospital, APHPParisFrance
  5. 5.Haematology LaboratoryHenri Mondor University Hospital, AP-HPCréteilFrance
  6. 6.Service de Neuropédiatrie & Maladies Métaboliques, Centre de Référence Maladies MétaboliquesHôpital Robert DebréParisFrance

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