Journal of Inherited Metabolic Disease

, Volume 35, Issue 1, pp 91–102

Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management

  • Nuria Carrillo-Carrasco
  • Randy J. Chandler
  • Charles P. Venditti


Combined methylmalonic acidemia and homocystinuria, cblC type, is an inborn error of intracellular cobalamin metabolism with a wide spectrum of clinical manifestations that is stated to be the most common inherited disorder of cobalamin metabolism. This metabolic disease is caused by mutations in the MMACHC gene and results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, cofactors for the methylmalonyl-CoA mutase and methionine synthase enzymes. Elevated methylmalonic acid and homocysteine with decreased methionine production are the biochemical hallmarks of this disorder. Awareness of the diverse clinical presentations associated with cblC disease is necessary to provide a timely diagnosis, to guide management of affected individuals and to establish a framework for the future treatment of individuals detected through expanded newborn screening. This article reviews the biochemistry, clinical presentations, genotype-phenotype correlations, diagnosis and management of cblC disease.







Cobalamin C disease






Intrauterine growth retardation




Methylmalonic acid


Methylenetetrahydrofolate reductase






Total plasma homocysteine

Supplementary material

10545_2011_9364_MOESM1_ESM.docx (192 kb)
Supplementary Table 1Ophthalmologic complications in patients with cblC disease (DOCX 191 kb)
10545_2011_9364_MOESM2_ESM.docx (160 kb)
Supplementary Table 2Outcome of patients with cblC disease and their therapeutic regimens (DOCX 159 kb)


  1. Abels J, Kroes AC, Ermens AA, van Kapel J, Schoester M, Spijkers LJ, Lindemans J (1990) Anti-leukemic potential of methyl-cobalamin inactivation by nitrous oxide. Am J Hematol 34:128–131PubMedCrossRefGoogle Scholar
  2. Andersson HC, Marble M, Shapira E (1999) Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med 1:146–150PubMedCrossRefGoogle Scholar
  3. Andersson HC, Shapira E (1998) Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr 132:121–124PubMedCrossRefGoogle Scholar
  4. Augoustides-Savvopoulou P, Mylonas I, Sewell AC, Rosenblatt DS (1999) Reversible dementia in an adolescent with cblC disease: clinical heterogeneity within the same family. J Inherit Metab Dis 22:756–758PubMedCrossRefGoogle Scholar
  5. Banerjee R (2006) B12 trafficking in mammals: A for coenzyme escort service. ACS Chem Biol 1:149–159PubMedCrossRefGoogle Scholar
  6. Banerjee R, Gherasim C, Padovani D (2009) The tinker, tailor, soldier in intracellular B12 trafficking. Curr Opin Chem Biol 13:484–491PubMedCrossRefGoogle Scholar
  7. Bartholomew DW, Batshaw ML, Allen RH, Roe CR, Rosenblatt D, Valle DL, Francomano CA (1988) Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39PubMedCrossRefGoogle Scholar
  8. Ben-Omran TI, Wong H, Blaser S, Feigenbaum A (2007) Late-onset cobalamin-C disorder: a challenging diagnosis. Am J Med Genet A 143A:979–984PubMedCrossRefGoogle Scholar
  9. Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL (2001) Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 56:1113PubMedGoogle Scholar
  10. Boneh A, Greaves RF, Garra G, Pitt JJ (2002) Metabolic treatment of pregnancy and postdelivery period in a patient with cobalamin A disease. Am J Obstet Gynecol 187:225–226PubMedCrossRefGoogle Scholar
  11. Boxer AL, Kramer JH, Johnston K, Goldman J, Finley R, Miller BL (2005) Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology 64:1431–1434PubMedCrossRefGoogle Scholar
  12. Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type). Am J Med Genet 36:167–171PubMedCrossRefGoogle Scholar
  13. Brunel-Guitton C, Costa T, Mitchell GA, & Lambert M (2010) Treatment of cobalamin C (cblC) deficiency during pregnancy. J Inherit Metab DisGoogle Scholar
  14. Brunelli SM, Meyers KE, Guttenberg M, Kaplan P, Kaplan BS (2002) Cobalamin C deficiency complicated by an atypical glomerulopathy. Pediatr Nephrol 17:800–803PubMedCrossRefGoogle Scholar
  15. Byck S, Rosenblatt DS (1991) Metabolic cooperation among cell lines from patients with inborn errors of vitamin B12 metabolism: differential response of cblC and cblD. Clin Invest Med 14:153–159PubMedGoogle Scholar
  16. Carmel R, Bedros AA, Mace JW, Goodman SI (1980) Congenital methylmalonic aciduria–homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55:570–579PubMedGoogle Scholar
  17. 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
  18. Cerone R, Schiaffino MC, Caruso U, Lupino S, Gatti R (1999) Minor facial anomalies in combined methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism. J Inherit Metab Dis 22:247–250PubMedCrossRefGoogle Scholar
  19. Chace DH, DiPerna JC, Kalas TA, Johnson RW, Naylor EW (2001) Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. Clin Chem 47:2040–2044PubMedGoogle Scholar
  20. Chadefaux-Vekemans B, Rolland MO, Lyonnet S, Rabier D, Divry P, Kamoun P (1994) Prenatal diagnosis of combined methylmalonic aciduria and homocystinuria (cobalamin CblC or CblD mutant). Prenat Diagn 14:417–418PubMedCrossRefGoogle Scholar
  21. Chenel C, Wood C, Gourrier E, Zittoun J, Casadevall I, Ogier H (1993) Neonatal hemolytic-uremic syndrome, methylmalonic aciduria and homocystinuria caused by intracellular vitamin B 12 deficiency. Value of etiological diagnosis. Arch Fr Pediatr 50:749–754PubMedGoogle Scholar
  22. De Bie I, Nizard SD, Mitchell GA (2009) Fetal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type. Prenat Diagn 29:266–270PubMedCrossRefGoogle Scholar
  23. Deodato F, Rizzo C, Boenzi S, Baiocco F, Sabetta G, Dionisi-Vici C (2002) Successful pregnancy in a woman with mut- methylmalonic acidaemia. J Inherit Metab Dis 25:133–134PubMedCrossRefGoogle Scholar
  24. Diss E, Iams J, Reed N, Roe DS, Roe C (1995) Methylmalonic aciduria in pregnancy: a case report. Am J Obstet Gynecol 172:1057–1059PubMedCrossRefGoogle Scholar
  25. Drummond JT, Matthews RG (1994) Nitrous oxide degradation by cobalamin-dependent methionine synthase: characterization of the reactants and products in the inactivation reaction. Biochemistry 33:3732–3741PubMedCrossRefGoogle Scholar
  26. Enns GM, Barkovich AJ, Rosenblatt DS, Fredrick DR, Weisiger K, Ohnstad C, Packman S (1999) Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin. J Inherit Metab Dis 22:599–607PubMedCrossRefGoogle Scholar
  27. Felmet K, Robins B, Tilford D, Hayflick SJ (2000) Acute neurologic decompensation in an infant with cobalamin deficiency exposed to nitrous oxide. J Pediatr 137:427–428PubMedCrossRefGoogle Scholar
  28. Fowler B, Jakobs C (1998) Post- and prenatal diagnostic methods for the homocystinurias. Eur J Pediatr 157(Suppl 2):S88–S93PubMedCrossRefGoogle Scholar
  29. Fowler B, Leonard JV, Baumgartner MR (2008) Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis 31:350–360PubMedCrossRefGoogle Scholar
  30. Francis PJ, Calver DM, Barnfield P, Turner C, Dalton RN, Champion MP (2004) An infant with methylmalonic aciduria and homocystinuria (cblC) presenting with retinal haemorrhages and subdural haematoma mimicking non-accidental injury. Eur J Pediatr 163:420–421PubMedCrossRefGoogle Scholar
  31. Frattini D, Fusco C, Ucchino V, Tavazzi B, Della Giustina E (2010) Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. Pediatr Neurol 43:135–138PubMedCrossRefGoogle Scholar
  32. Freehauf CLJ, Wilman E, Wright JL, Van Hove E, Spector R. Gallagher & Thomas JA (2011) Use and benefit of a subcutaneous indwelling catheter for cobalamin administration in B12 responsive methylmalonic acidemia. In SIMD Annual Meeting, 16. Asilomar, Pacific Grove, CAGoogle Scholar
  33. Froese DS, Healy S, McDonald M, Kochan G, Oppermann U, Niesen FH, Gravel RA (2010) Thermolability of mutant MMACHC protein in the vitamin B12-responsive cblC disorder. Mol Genet Metab 100:29–36PubMedCrossRefGoogle Scholar
  34. Froese DS, Zhang J, Healy S, Gravel RA (2009) Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab 98:338–343PubMedCrossRefGoogle Scholar
  35. Gerth C, Morel CF, Feigenbaum A, Levin AV (2008) Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS 12:591–596PubMedCrossRefGoogle Scholar
  36. Gold R, Bogdahn U, Kappos L, Toyka KV, Baumgartner ER, Fowler B, Wendel U (1996) Hereditary defect of cobalamin metabolism (homocystinuria and methylmalonic aciduria) of juvenile onset. J Neurol Neurosurg Psychiatry 60:107–108PubMedCrossRefGoogle Scholar
  37. Gravel RA, Mahoney MJ, Ruddle FH, Rosenberg LE (1975) Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism. Proc Natl Acad Sci U S A 72:3181–3185PubMedCrossRefGoogle Scholar
  38. Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, Mougenot B, Rosenblatt DS, Deschenes G (2005) Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 45:588–595PubMedCrossRefGoogle Scholar
  39. Hannibal L, Kim J, Brasch NE, Wang S, Rosenblatt DS, Banerjee R, Jacobsen DW (2009) Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Mol Genet Metab 97:260–266PubMedCrossRefGoogle Scholar
  40. Harding CO, Pillers DA, Steiner RD, Bottiglieri T, Rosenblatt DS, Debley J, Michael Gibson K (2003) Potential for misdiagnosis due to lack of metabolic derangement in combined methylmalonic aciduria/hyperhomocysteinemia (cblC) in the neonate. J Perinatol 23:384–386PubMedCrossRefGoogle Scholar
  41. Houeto P, Borron SW, Sandouk P, Imbert M, Levillain P, Baud FJ (1996) Pharmacokinetics of hydroxocobalamin in smoke inhalation victims. J Toxicol Clin Toxicol 34:397–404PubMedCrossRefGoogle Scholar
  42. Huemer M, Simma B, Fowler B, Suormala T, Bodamer OA, Sass JO (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472PubMedCrossRefGoogle Scholar
  43. Kim J, Gherasim C, Banerjee R (2008) Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci U S A 105:14551–14554PubMedCrossRefGoogle Scholar
  44. Kim J, Hannibal L, Gherasim C, Jacobsen DW, Banerjee R (2009) A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem 284:33418–33424PubMedCrossRefGoogle Scholar
  45. Kind T, Levy J, Lee M, Kaicker S, Nicholson JF, Kane SA (2002) Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol 24:327–329PubMedCrossRefGoogle Scholar
  46. Kinsella LJ, Green R (1995) 'Anesthesia paresthetica': nitrous oxide-induced cobalamin deficiency. Neurology 45:1608–1610PubMedGoogle Scholar
  47. Laframboise R, Cooper BA, Rosenblatt DS (1992) Malabsorption of vitamin B12 from the intestine in a child with cblF disease: evidence for lysosomal-mediated absorption. Blood 80:291–292PubMedGoogle Scholar
  48. Lawson-Yuen A, Levy HL (2006) The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab 88:201–207PubMedCrossRefGoogle Scholar
  49. Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum Mutat 30:1072–1081PubMedCrossRefGoogle Scholar
  50. Lerner-Ellis JP, Tirone JC, Pawelek PD, Dore C, Atkinson JL, Watkins D, Morel CF, Fujiwara TM, Moras E, Hosack AR, Dunbar GV, Antonicka H, Forgetta V, Dobson CM, Leclerc D, Gravel RA, Shoubridge EA, Coulton JW, Lepage P, Rommens JM, Morgan K, Rosenblatt DS (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93–100PubMedCrossRefGoogle Scholar
  51. Levy HL, Mudd SH, Schulman JD, Dreyfus PM, Abeles RH (1970) A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia and methylmalonic aciduria. Am J Med 48:390–397PubMedCrossRefGoogle Scholar
  52. Linnell JC, Miranda B, Bhatt HR, Dowton SB, Levy HL (1983) Abnormal Cobalamin Metabolism in a Megaloblastic Child with Homocystinuria, Cystathioninuria and Methylmalonic Aciduria. J Inher Metab Dis 6:137–139CrossRefGoogle Scholar
  53. Mamlok RJ, Isenberg JN, Rassin DK, Norcross K, Tallan HH (1986) A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anemia. Neuropediatrics 17:94–99PubMedCrossRefGoogle Scholar
  54. Mansoor MA, Ueland PM, Aarsland A, Svardal AM (1993) Redox status and protein binding of plasma homocysteine and other aminothiols in patients with homocystinuria. Metabolism 42:1481–1485PubMedCrossRefGoogle Scholar
  55. Martinelli D, Dotta A, Massella L, Picca S, Di Pede A, Boenzi S, Aiello C, & Dionisi-Vici C (2010) Cobalamin C defect presenting as severe neonatal hyperammonemia. Eur J PediatrGoogle Scholar
  56. McNeely JK, Buczulinski B, Rosner DR (2000) Severe neurological impairment in an infant after nitrous oxide anesthesia. Anesthesiology 93:1549–1550PubMedCrossRefGoogle Scholar
  57. 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
  58. Merke DP, Bornstein SR (2005) Congenital adrenal hyperplasia. Lancet 365:2125–2136PubMedCrossRefGoogle Scholar
  59. Mitchell GA, Watkins D, Melancon SB, Rosenblatt DS, Geoffroy G, Orquin J, Homsy MB, Dallaire L (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415PubMedCrossRefGoogle Scholar
  60. Morel CF, Lerner-Ellis JP, Rosenblatt DS (2006) Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab 88:315–321PubMedCrossRefGoogle Scholar
  61. Morel CF, Watkins D, Scott P, Rinaldo P, Rosenblatt DS (2005) Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport. Mol Genet Metab 86:160–171PubMedCrossRefGoogle Scholar
  62. Mudd SH, Levy HL, Abeles RH, Jennedy JP Jr (1969) A derangement in B 12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun 35:121–126PubMedCrossRefGoogle Scholar
  63. Nogueira C, Aiello C, Cerone R, Martins E, Caruso U, Moroni I, Rizzo C, Diogo L, Leao E, Kok F, Deodato F, Schiaffino MC, Boenzi S, Danhaive O, Barbot C, Sequeira S, Locatelli M, Santorelli FM, Uziel G, Vilarinho L, Dionisi-Vici C (2008) Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab 93:475–480PubMedCrossRefGoogle Scholar
  64. 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
  65. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123PubMedCrossRefGoogle Scholar
  66. Patton N, Beatty S, Lloyd IC, Wraith JE (2000) Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 21:151–154PubMedGoogle Scholar
  67. Pexa A, Fischer K, Deussen A, Henle T (2008) Homocysteine in food. Eur Food Res Technol 226:933–935CrossRefGoogle Scholar
  68. Pierre G, Gissen P, Chakrapani A, McDonald A, Preece M, Wright J (2006) Successful treatment of pyridoxine-unresponsive homocystinuria with betaine in pregnancy. J Inherit Metab Dis 29:688–689PubMedCrossRefGoogle Scholar
  69. Plesa M, Kim J, Paquette SG, Gagnon H, Ng-Thow-Hing C, Gibbs BF, Hancock MA, Rosenblatt DS, Coulton JW (2011) Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B metabolism. Mol Genet Metab 102:139–148PubMedCrossRefGoogle Scholar
  70. Powers JM, Rosenblatt DS, Schmidt RE, Cross AH, Black JT, Moser AB, Moser HW, Morgan DJ (2001) Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol 49:396–400PubMedCrossRefGoogle Scholar
  71. Profitlich L, Kirmse B, Wasserstein MP, Diaz G, Srivastava S (2009a) Resolution of cor pulmonale after medical management in a patient with cblC-type methylmalonic aciduria and homocystinuria: a case report. Cases J 2:8603PubMedCrossRefGoogle Scholar
  72. Profitlich LE, Kirmse B, Wasserstein MP, Diaz GA, Srivastava S (2009b) High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Mol Genet Metab 98:344–348PubMedCrossRefGoogle Scholar
  73. Ribes A, Briones P, Vilaseca MA, Lluch M, Rodes M, Maya A, Campistol J, Pascual P, Suormala T, Baumgartner R (1990) Methylmalonic aciduria with homocystinuria: biochemical studies, treatment, and clinical course of a Cbl-C patient. Eur J Pediatr 149:412–415PubMedCrossRefGoogle Scholar
  74. Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Perez-Cerda C, Ribes A, Ugarte M, Perez B (2009) Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 30:1558–1566PubMedCrossRefGoogle Scholar
  75. Robb RM, Dowton SB, Fulton AB, Levy HL (1984) Retinal degeneration in vitamin B12 disorder associated with methylmalonic aciduria and sulfur amino acid abnormalities. Am J Ophthalmol 97:691–696PubMedGoogle Scholar
  76. Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538PubMedCrossRefGoogle Scholar
  77. Rosenblatt DS, Cooper BA (1987) Inherited disorders of vitamin B12 metabolism. Blood Rev 1:177–182PubMedCrossRefGoogle Scholar
  78. Rossi A, Cerone R, Biancheri R, Gatti R, Schiaffino MC, Fonda C, Zammarchi E, Tortori-Donati P (2001) Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol 22:554–563PubMedGoogle Scholar
  79. Roze E, Gervais D, Demeret S, Ogier de Baulny H, Zittoun J, Benoist JF, Said G, Pierrot-Deseilligny C, Bolgert F (2003) Neuropsychiatric disturbances in presumed late-onset cobalamin C disease. Arch Neurol 60:1457–1462PubMedCrossRefGoogle Scholar
  80. Schilling RF (1986) Is nitrous oxide a dangerous anesthetic for vitamin B12-deficient subjects? JAMA 255:1605–1606PubMedCrossRefGoogle Scholar
  81. Selzer RR, Rosenblatt DS, Laxova R, Hogan K (2003) Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45–50PubMedCrossRefGoogle Scholar
  82. Shinnar S, Singer HS (1984) Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence. A treatable cause of dementia and myelopathy. N Engl J Med 311:451–454PubMedCrossRefGoogle Scholar
  83. Smith DL, Bodamer OA (2002) Practical management of combined methylmalonicaciduria and homocystinuria. J Child Neurol 17:353–356PubMedCrossRefGoogle Scholar
  84. Smith SE, Kinney HC, Swoboda KJ, Levy HL (2006) Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab 88:138–145PubMedCrossRefGoogle Scholar
  85. Smulders YM, Smith DE, Kok RM, Teerlink T, Swinkels DW, Stehouwer CD, Jakobs C (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
  86. Spada M, Fowler B, Bonetti G, Battistoni G, Baglieri S, Perfetto F, Peduto A, & Ponzone A (1999) Fetal therapy in combined methylmalonic aciduria and homocystinuria. In SSIEM, 91. JIMDGoogle Scholar
  87. Spector R (1979) Cerebrospinal fluid folate and the blood brain barrier. In: Botez M, Reynolds E (eds) Folic acid in neurology, psychiatry, and internal medicine. Reven Press, New York, pp 187–194Google Scholar
  88. Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, Stabler SP, Allen RH, Chwatko G, Jakubowski H, Niculescu MD, Mudd SH (2007) Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175PubMedCrossRefGoogle Scholar
  89. Surtees R (1998) Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 157(Suppl 2):S118–S121PubMedCrossRefGoogle Scholar
  90. Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L (2008) The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 79:725–728PubMedCrossRefGoogle Scholar
  91. Tomaske M, Bosk A, Heinemann MK, Sieverding L, Baumgartner ER, Fowler B, Trefz FK (2001) CblC/D defect combined with haemodynamically highly relevant VSD. J Inherit Metab Dis 24:511–512PubMedCrossRefGoogle Scholar
  92. Tortorelli S, Turgeon CT, Lim JS, Baumgart S, Day-Salvatore DL, Abdenur J, Bernstein JA, Lorey F, Lichter-Konecki U, Oglesbee D, Raymond K, Matern D, Schimmenti L, Rinaldo P, Gavrilov DK (2010) Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other remethylation disorders with tandem mass spectrometry. J Pediatr 157:271–275PubMedCrossRefGoogle Scholar
  93. Urbon Artero A, Aldana Gomez J, Reig Del Moral C, Nieto Conde C, Merinero Cortes B (2002) Neonatal onset methylmalonic aciduria and homocystinuria:Biochemical and clinical improvement with betaine therapy. An Esp Pediatr 56:337–341PubMedGoogle Scholar
  94. Van Hove JL, Van Damme-Lombaerts R, Grunewald S, Peters H, Van Damme B, Fryns JP, Arnout J, Wevers R, Baumgartner ER, Fowler B (2002) Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet 111:195–201PubMedCrossRefGoogle Scholar
  95. Waclawik AJ, Luzzio CC, Juhasz-Pocsine K, Hamilton V (2003) Myeloneuropathy from nitrous oxide abuse: unusually high methylmalonic acid and homocysteine levels. WMJ 102:43–45PubMedGoogle Scholar
  96. Wang F, Han LS, Hu YH, Yang YL, Ye J, Qiu WJ, Zhang YF, Gao XL, Wang Y, Gu XF (2009) Analysis of gene mutations in Chinese patients with methylmalonic acidemia and homocysteinemia. Zhonghua Er Ke Za Zhi 47:189–193PubMedGoogle Scholar
  97. Weisfeld-Adams JD, Morrissey MA, Kirmse BM, Salveson BR, Wasserstein MP, McGuire PJ, Sunny S, Cohen-Pfeffer JL, Yu C, Caggana M, Diaz GA (2010) Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab 99:116–123PubMedCrossRefGoogle Scholar
  98. Wiley VC, Dudman NP, Wilcken DE (1988) Interrelations between plasma free and protein-bound homocysteine and cysteine in homocystinuria. Metabolism 37:191–195PubMedCrossRefGoogle Scholar
  99. Willard HF, Ambani LM, Hart AC, Mahoney MJ, Rosenberg LE (1976) Rapid prenatal and postnatal detection of inborn errors of propionate, methylmalonate, and cobalamin metabolism: a sensitive assay using cultured cells. Hum Genet 34:277–283PubMedCrossRefGoogle Scholar
  100. Yap S, Barry-Kinsella C, Naughten ER (2001) Maternal pyridoxine non-responsive homocystinuria: the role of dietary treatment and anticoagulation. BJOG 108:425–428PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer (outside the USA) 2011

Authors and Affiliations

  • Nuria Carrillo-Carrasco
    • 1
  • Randy J. Chandler
    • 1
    • 2
  • Charles P. Venditti
    • 1
  1. 1.Organic Acid Research Section, Genetics and Molecular Biology BranchNational Human Genome Research Institute, National Institutes of HealthBethesdaUSA
  2. 2.Institute for Biomedical SciencesThe George Washington UniversityWashington, DCUSA

Personalised recommendations