Skip to main content
SpringerLink
Log in
Book cover

Inborn Metabolic Diseases pp 385–402Cite as

Disorders of Cobalamin and Folate Transport and Metabolism

  • Chapter

Abstract

The serum cobalamin (Cbl) level is usually low in patients with disorders affecting absorption and transport of Cbl, with the exception of transcobalamin (TC) deficiency. Patients with disorders of intracellular Cbl metabolism typically have normal serum Cbl levels, although levels may be reduced in the cblF disorder. Homocystinuria and hyperhomocysteinaemia, as well as megaloblastic anaemia and neurological disorders, are major clinical findings in patients with disorders of cobalamin absorption and transport, as well as those with defects of cellular metabolism that affect synthesis of methylcobalamin (MeCbl). Methylmalonic aciduria and acidaemia, resulting in metabolic acidosis, are seen in disorders that result in decreased synthesis of adenosylcobalamin (AdoCbl).

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   159.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Cooper BA, Rosenblatt DS (1987) Inherited defects of vitamin B12 metabolism. Annu Rev Nutr 7:291–320

    PubMed  CAS  Google Scholar 

  2. Rosenblatt DS (2001) Inborn errors of folate and cobalamin metabolism. In: Carmel R, Jacobsen DW (eds) Homocysteine in health and disease. Cambridge University Press, Cambridge, pp 244–258

    Google Scholar 

  3. Whitehead VM (2006) Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol 134:125–136

    PubMed  CAS  Google Scholar 

  4. Watkins D, Whitehead VM, Rosenblatt DS (2009) Megaloblastic anemia. In: Orkin SH, Ginsburg D, Nathan DA, Look AT, Fisher DE (eds) Nathan and Oski’s Hematology of infancy and childhood, 7th edn. Saunders Elsevier, Philadelphia, pp 467–520

    Google Scholar 

  5. Yang Y-M, Ducos R, Rosenberg AJ et al. (1985) Cobalamin malabsorption in three siblings due to an abnormal intrinsic factor that is markedly susceptible to acid and proteolysis. J Clin Invest 76:2057–2065

    PubMed  CAS  Google Scholar 

  6. Katz M, Mehlman CS, Allen RH (1974) Isolation and characterization of an abnormal human intrinsic factor. J Clin Invest 53:1274–1283

    PubMed  CAS  Google Scholar 

  7. Rothenberg SP, Quadros EV, Straus EW, Kapelner S (1984) An abnormal intrinsic factor (IF) molecule: a new cause of »pernicious anemia«. Blood 64:41a

    Google Scholar 

  8. Spurling CL, Sacks MS, Jiji RM (1964) Juvenile pernicious anemia. N Engl J Med 271:995–1003

    PubMed  CAS  Google Scholar 

  9. Hewitt JE, Gordon MM, Taggart RT, Mohandas TK, Alpers DH (1991) Human intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11. Genomics 10:432–440

    PubMed  CAS  Google Scholar 

  10. Yassin F, Rothenberg SP, Rao S et al. (2004) Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency. Blood 103:1515–1517

    PubMed  CAS  Google Scholar 

  11. Tanner SM, Li Z, Perko JD et al. (2005) Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci USA 102:4130–4133

    PubMed  CAS  Google Scholar 

  12. Ament AE, Li Z, Sturm AC et al. (2009) Juvenile cobalamin deficiency in individuals of African ancestry is caused by a founder mutation in the intrinsic factor gene GIF. Br J Haematol 144:622–624

    PubMed  Google Scholar 

  13. Gräsbeck R (1972) Familial selective vitamin B12 malabsorption. N Engl J Med 287:358

    PubMed  Google Scholar 

  14. Broch H, Imerslund O, Monn E, Hovig T, Seip M (1984) Imerslund- Gräsbeck anemia: a long-term follow-up study. Acta Paediatr Scand 73:248–253

    PubMed  CAS  Google Scholar 

  15. El Mauhoub M, Sudarshan G, Aggarwal V, Banerjee G (1989) Imerslund-Gräsbeck syndrome in a Libyan boy. Ann Trop Paediatr 9:180–181

    PubMed  CAS  Google Scholar 

  16. El Bez M, Souid M, Mebazaa R, Ben Dridi MF (1992) L’anémie d’Imerslund-Gräsbeck. A propos d’un cas. Ann Pediatr 39:305–308

    CAS  Google Scholar 

  17. Salameh MM, Banda RW, Mohdi AA (1991) Reversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Gräsbeck syndrome. J Neurol 238:349–350

    PubMed  CAS  Google Scholar 

  18. Kulkey O, Reusz G, Sallay P, Miltenyi M (1992) Selective vitamin B12 absorption disorder (Imerslund-Gräsbeck syndrome) (in Hungarian with English abstract). Orv Hetil 133:3311–3313

    PubMed  CAS  Google Scholar 

  19. Gräsbeck R (1997) Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor. Acta Biochim Polon 44:725–734

    PubMed  Google Scholar 

  20. Gräsbeck R (2006) Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria). Orphanet J Rare Dis 1:17

    PubMed  Google Scholar 

  21. Wahlstedt-Fröberg V, Pettersson T, Aminoff M, Dugué B, Gräsbeck R (2003) Proteinuria in cubilin-deficient patients with selective vitamin B12 malabsorption. Pediatr Nephrol 18:417–421

    PubMed  Google Scholar 

  22. Liang DC, Hsu HC, Huang EY, Wei KN (1991) Imerslund-Gräsbeck syndrome in two brothers: renal biopsy and ultrastructural findings. Pediatr Hematol Oncol 8:361–365

    PubMed  Google Scholar 

  23. Moestrup SK, Kozyraki R, Kristiansen M et al. (1998) The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral protein with homology to developmental proteins. J Biol Chem 273:5235–5242

    PubMed  CAS  Google Scholar 

  24. Kozyraki R, Kristiansen M, Silahtaroglu A et al. (1998) The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood 91:3593–3600

    PubMed  CAS  Google Scholar 

  25. Birn H, Verroust PJ, Nexo E et al. (1997) Characterization of an epithelial ~460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein. J Biol Chem 272:26497–26504

    PubMed  CAS  Google Scholar 

  26. Fyfe JC, Madsen M, Hojrup P et al. (2004) The functional cobalamin (vitamin B12) -intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103:1573–1579

    PubMed  CAS  Google Scholar 

  27. Aminoff M, Tahvainen E, Gräsbeck R et al. (1995) Selective intestinal malabsorption of vitamin B12 displays recessive mendelian inheritance: assignment of a locus to chromosome 10 by linkage. Am J Hum Genet 57:824–831

    PubMed  CAS  Google Scholar 

  28. Aminoff M, Carter JE, Chadwick RB et al. (1999) Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21:309–313

    PubMed  CAS  Google Scholar 

  29. Tanner SM, Aminoff M, Wright FA et al. (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet 33:426–429

    PubMed  CAS  Google Scholar 

  30. Tanner SM, Li Z, Bisson R et al. (2004) Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain the aggregations in Scandinavia and the Middle East. Hum Mutat 23:327–333

    PubMed  CAS  Google Scholar 

  31. Carmel R (1983) R-binder deficiency. A clinically benign cause of cobalamin pseudodeficiency. JAMA 250:1886–1890

    PubMed  CAS  Google Scholar 

  32. Carmel R (2003) Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem 49:1367–1374

    PubMed  CAS  Google Scholar 

  33. Adcock BB, McKnight JT (2002) Cobalamin pseudodeficiency due to a transcobalamin I deficiency. South Med J 95:1060–1062

    PubMed  Google Scholar 

  34. Carmel R, Parker J, Kelman Z (2009) Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels. Br J Haematol 147:386–391

    PubMed  CAS  Google Scholar 

  35. Frisbie SM, Chance MR (1993) Human cobalaphilin: the structure of bound methylcobalamin and a functional role in protecting methylcobalamin from photolysis. Biochemistry 32:13886–13892

    PubMed  CAS  Google Scholar 

  36. Morkbak AL, Poulsen SS, Nexo E (2007) Haptocorrin in humans. Clin Chem Lab Med 45:1751–1759

    PubMed  CAS  Google Scholar 

  37. Lin JC, Borregaard N, Liebman HA, Carmel R (2001) Deficiency of specific granule proteins R binder/transcobalamin I and lactoferrin, in plasma and saliva: a new disorder. Am J Med Genet 100:145–151

    PubMed  CAS  Google Scholar 

  38. Johnston J, Bollekens J, Allen RH, Berliner N (1989) Structure of the cDNA encoding transcobalamin I, a neutrophil granule protein. J Biol Chem 264:15754–15757

    PubMed  CAS  Google Scholar 

  39. Johnston J, Yang-Feng T, Berliner N (1992) Genomic structure and mapping of the chromosomal gene for transcobalamin I (TCN1) : comparison to human intrinsic factor. Genomics 12:459–454

    PubMed  CAS  Google Scholar 

  40. Schiff M, Ogier de Baulny H, Bard G et al. (2010) Should transcobalamin deficiency be treated aggressively? J Inherit Metab Dis 33:223–229

    PubMed  Google Scholar 

  41. Hall CA (1992) The neurological aspects of transcobalamin II deficiency. Br J Haematol 80:117–120

    PubMed  CAS  Google Scholar 

  42. Souied EH, Benhamou N, Sterkers M et al. (2001) Retinal degeneration associated with congenital transcobalamin II deficiency. Arch Ophthalmol 119:1076–1077

    PubMed  CAS  Google Scholar 

  43. Haurani FI, Hall CA, Rubin R (1979) Megaloblastic anemia as a result of an abnormal transcobalamin II (Cardeza). J Clin Invest 64:1253–1259

    PubMed  CAS  Google Scholar 

  44. Seligman PA, Steiner LL, Allen RH (1980) Studies of a patient with megaloblastic anemia and an abnormal transcobalamin II. N Engl J Med 303:1209–1212

    PubMed  CAS  Google Scholar 

  45. Li N, Rosenblatt DS, Kamen BA, Seetharam S, Seetharam B (1994) Identification of two mutant alleles of transcobalamin II in an affected family. Hum Molec Genet 3:1835–1840

    PubMed  CAS  Google Scholar 

  46. Li N, Rosenblatt DS, Seetharam B (1994) Nonsense mutations in human transcobalamin II deficiency. Biochem Biophys Res Comm 204:1111–1118

    PubMed  CAS  Google Scholar 

  47. Namour F, Helfer AC, Quadros EV et al. (2003) Transcobalamin deficiency due to activation of an intra exonic cryptic splice set. Br J Haematol 123:915–920

    PubMed  CAS  Google Scholar 

  48. Bibi H, Gelman-Kohan Z, Baumgartner ER, Rosenblatt DS (1999) Transcobalamin II deficiency with methylmalonic aciduria in three sisters. J Inherit Metab Dis 22:765–772

    PubMed  CAS  Google Scholar 

  49. Rosenblatt D, Hosack A, Matiaszuk N (1987) Expression of transcobalamin II by amniocytes. Prenat Diagn 7:35–39

    PubMed  CAS  Google Scholar 

  50. Nexo E, Christensen AL, Petersen TE, Fedosov SN (2000) Measurement of transcobalamin by ELISA. Clin Chem 46:1643–1649

    PubMed  CAS  Google Scholar 

  51. Quadros EV, Lai SC, Nakayama Y et al. (2010) Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalaminbound vitamin B12. Hum Mutat 31:924–929

    PubMed  CAS  Google Scholar 

  52. Anastasio N, Watkins D, Vezina L et al. (2009) Mutations in TCBLR, the gene for the transcobalamin receptor, results in decreased cellular uptake of vitamin B12 and methylmalonic aciduria. Mol Genet Metab 98:122

    Google Scholar 

  53. Pangilinan F, Mitchell A, VanderMeer, et al. (2010) Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects. J Med Genet 47:677–685

    PubMed  CAS  Google Scholar 

  54. Rosenblatt DS, Laframboise R, Pichette J et al. (1986) New disorder of vitamin B12 metabolism (cobalamin F) presenting as methylmalonic aciduria. Pediatrics 78:51–54

    PubMed  CAS  Google Scholar 

  55. Rosenblatt DS, Hosack A, Matiaszuk NV, Cooper BA, Laframboise R (1985) Defect in vitamin B12 release from lysosomes: newly described inborn error of vitamin B12 metabolism. Science 228:1319–1321

    PubMed  CAS  Google Scholar 

  56. Rutsch F, Gailus S, Miousse IR et al. (2009) Identification of a putative lysosomal cobalamin exporter mutated in the cblF inborn error of vitamin B12 metabolism. Nat Genet 41:234–239

    PubMed  CAS  Google Scholar 

  57. Gailus S, Suormala T, Gül Malerczyk-Aktas A et al. (2010) A novel mutation in LMBRD1 causes the cblF defect of vitamin B12 metabolism in a Turkish patient. J Inherit Metab Dis 33:17–24

    PubMed  CAS  Google Scholar 

  58. Rutsch F, Gailus S, Suormala T, Fowler B (2011) LMBRD1: the gene for the cblF defect of vitamin B12 metabolism. J Inherit Metab Dis 34:121–126

    PubMed  CAS  Google Scholar 

  59. Rosenblatt DS, Aspler AL, Shevell MI et al. (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inher Metab Dis 20:528–538

    PubMed  CAS  Google Scholar 

  60. Lerner-Ellis JP, Tirone JC, Pawelek PD et al. (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93–100

    PubMed  CAS  Google Scholar 

  61. Nogueira C, Aiello C, Cerone R et al. (2008) Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab 93:475–480

    PubMed  CAS  Google Scholar 

  62. Lerner-Ellis JP, Anastasio N, Liu J et al. (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotypephenotype correlations. Hum Mutat 30:1072–1081

    PubMed  CAS  Google Scholar 

  63. Liu MY, Yang YL, Chang YC et al. (2010) Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. J Hum Genet 55:621–626

    PubMed  CAS  Google Scholar 

  64. Mitchell GA, Watkins D, Melançon SB et al. (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415

    PubMed  CAS  Google Scholar 

  65. Traboulsi EI, Silva JC, Geraghty MT et al. (1992) Ocular histopathologic characteristics of cobalamin C type vitamin B12 defect with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 113:269–280

    PubMed  CAS  Google Scholar 

  66. Ogier de Baulny H, Gérard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157:S77-S83

    PubMed  Google Scholar 

  67. Huemer M, Simma B, Fowler B et al. (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472

    PubMed  CAS  Google Scholar 

  68. Schimel AM, Mets MB (2006) The natural history of retinal degeneration in association with cobalamin C (cblC) disease. Ophthalmic Genet 27:9–14

    PubMed  CAS  Google Scholar 

  69. Profitlich LE, Kirmse B, Wasserstein MP, Diaz GA, Srivastava S (2009) High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Mol Genet Metab 98:344–348

    PubMed  CAS  Google Scholar 

  70. Gold R, Bogdahn U, Kappos L et al. (1996) Hereditary defect of cobalamin metabolism (homocystinuria and methylmalonic aciduria) of juvenile onset. J Neurol Neurosurg Psychiatry 60:107–108

    PubMed  CAS  Google Scholar 

  71. Bodamer OAF, Rosenblatt DS, Appel SH, Beaudet AL (2001) Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 56:1113

    PubMed  CAS  Google Scholar 

  72. Hove v JLK, Damme-Lombaerts v R, Grünewald S et al. (2002) Cobalamin disorder cbl-C presenting with late-onset thrombocytic microangiopathy. Am J Med Genet 111:195–201

    Google Scholar 

  73. Guigonis V, Frémeaux-Bacchi V, Giraudier S et al. (2005) Lateonset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 45:588–595

    PubMed  CAS  Google Scholar 

  74. Kim J, Gherasim C, Banerjee R (2008) Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci USA 105:14551–14554

    PubMed  CAS  Google Scholar 

  75. Hannibal L, Kim J, Brasch NE et al. (2009) Processing of alkylcobalamins in mammalian cells: a role for the MMACHC (cblC) gene product. Mol Genet Metab 97:260–266

    PubMed  CAS  Google Scholar 

  76. Kim J, Hannibal L, Gherasim C, Jacobsen DW, Banerjee R (2009) A human B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem 284:33418–33424

    PubMed  CAS  Google Scholar 

  77. 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 86:160–171

    PubMed  CAS  Google Scholar 

  78. Bartholomew DW, Batshaw ML, Allen RH et al. (1988) Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39

    PubMed  CAS  Google Scholar 

  79. Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A, Venditti CP (2009) Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32:728–731

    PubMed  CAS  Google Scholar 

  80. Bain MD, Jones MG, Besley GTN, Boxer LA, Chalmers RA (2003) Oral B12 treatment in Cbl C/D methylmalonic aciduria. J Inherit Metab Dis 26:42

    Google Scholar 

  81. Mellman I, Willard HF, Youngdahl-Turner P, Rosenberg LE (1979) Cobalamin coenzyme synthesis in normal and mutant fibroblasts. Evidence for a processing enzyme activity deficient in cblC cells. J Biol Chem 254:11847–11853

    PubMed  CAS  Google Scholar 

  82. Andersson HC, Shapira E (1998) Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr 132:121–124

    PubMed  CAS  Google Scholar 

  83. Goodman SI, Moe PG, Hammond KB, Mudd SH, Uhlendorf BW (1970) Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med 4:500–515

    PubMed  CAS  Google Scholar 

  84. 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 55:570–579

    PubMed  CAS  Google Scholar 

  85. Willard HF, Mellman IS, Rosenberg LE (1978) Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity: evidence for a new class of human cobalamin mutant. Am J Hum Genet 30:1–13

    PubMed  CAS  Google Scholar 

  86. 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;42742–42749

    PubMed  CAS  Google Scholar 

  87. Coelho D, Suormala T, Stucki M et al. (2008) Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med 358:1454–1464

    PubMed  CAS  Google Scholar 

  88. Miousse IR, Watkins D, Coelho D et al. et al. (2009) Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. J Pediatr 154:551–556

    PubMed  CAS  Google Scholar 

  89. Fenton WA, Rosenberg LE (1981) The defect in the cbl B class of human methylmalonic acidemia: deficiency of cob(I) alamin adenosyltransferase activity in extracts of cultured fibroblasts. Biochem Biophys Res Commun 98:283–289

    PubMed  CAS  Google Scholar 

  90. Dobson CM, Wai T, Leclerc D et al. (2002) Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum Mol Genet 26:3361–3369

    Google Scholar 

  91. Dobson CM, Wai T, Leclerc D et al. (2002) Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. Proc Natl Acad Sci USA 99:15554–15559

    PubMed  CAS  Google Scholar 

  92. Padovani D, Banerjee R (2009) A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria. Proc Natl Acad Sci USA 106:21567–21572

    PubMed  CAS  Google Scholar 

  93. Banerjee R, Gherasim C, Padovani D (2009) The tinker, tailor, soldier in intracellular B12 trafficking. Curr Opin Chem Biol 13:477–484

    Google Scholar 

  94. Yang X, Sakamoto O, Matsubara Y et al. (2004) Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B12-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation. Mol Genet Metab 82:329–333

    PubMed  CAS  Google Scholar 

  95. Lerner-Ellis JP, Dobson CM, Wai T et al. (2004) Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism. Hum Mutat 24:509–516

    PubMed  CAS  Google Scholar 

  96. Martinez MA, Rincon A, Desviat LR et al. (2005) Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants. Mol Genet Metab 84:317–325

    PubMed  CAS  Google Scholar 

  97. Merinero B, Pérez B, Pérez-Cerdá C et al. (2008) Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. J Inherit Metab Dis 31:55–66

    PubMed  CAS  Google Scholar 

  98. Lerner-Ellis JP, Gradinger AB, Watkins D et al. (2006) Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Mol Genet Metab 87:219–225

    PubMed  CAS  Google Scholar 

  99. Schubert HL, Hill CP (2006) Structure of ATP-bound human ATP:cobalamin adenosyltransferase. Biochemistry 45:15188–15196

    PubMed  CAS  Google Scholar 

  100. Erdogan E, Nelson GJ, Rockwood AL, Frank EL (2010) Evaluation of reference intervals for methylmalonic acid in plasma/serum and urine. Clin Chim Acta 411:1827–1829

    PubMed  CAS  Google Scholar 

  101. Fowler B, Leonard JV, Baumgartner MR (2008) Causes and diagnostic approaches to methylmalonic acidurias. J Inherit Metab Dis 31:350–360

    PubMed  CAS  Google Scholar 

  102. Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308:857–861

    PubMed  CAS  Google Scholar 

  103. Hörster F, Baumgartner MR, Viardot C et al. (2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res 62:225–230

    PubMed  Google Scholar 

  104. Rosenblatt DS, Cooper BA, Pottier A et al. (1984) Altered vitamin B12 metabolism in fibroblasts from a patient with megaloblastic anemia and homocystinuria due to a new defect in methionine biosynthesis. J Clin Invest 74:2149–2156

    PubMed  CAS  Google Scholar 

  105. 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 310:686–690

    PubMed  CAS  Google Scholar 

  106. Watkins D, Rosenblatt DS (1988) Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG. J Clin Invest 81:1690–1694

    PubMed  CAS  Google Scholar 

  107. Watkins D, Rosenblatt DS (1989) Functional methionine synthase deficiency (cblE and cblG) : clinical and biochemical heterogeneity. Am J Med Genet 34:427–434

    PubMed  CAS  Google Scholar 

  108. 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 318:1738–1741

    PubMed  CAS  Google Scholar 

  109. Vilaseca MA, Vilarinho L, Zavadakova P et al. (2003) CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. J Inherit Metab Dis 26:361–369

    PubMed  CAS  Google Scholar 

  110. Leclerc D, Wilson A, Dumas R et al. (1998) Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci USA 95:3059–3064

    PubMed  CAS  Google Scholar 

  111. Wilson A, Leclerc D, Rosenblatt DS, Gravel RA (1999) Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism. Hum Mol Genet 8:2009–2016

    PubMed  CAS  Google Scholar 

  112. Zavadakova P, Fowler B, Suormala T et al. (2005) cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum Mutat 25:239–247

    PubMed  CAS  Google Scholar 

  113. Homolova K, Zavadakova P, Doktor TK et al. (2010) The deep intronic c.903002B;469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria. Hum Mutat 31:437–444

    PubMed  CAS  Google Scholar 

  114. Gulati S, Baker P, Li YN et al. (1996) Defects in human methionine synthase in cblG patients. Hum Mol Genet 5:1859–1865

    PubMed  CAS  Google Scholar 

  115. Leclerc D, Campeau E, Goyette P et al. (1996) Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum Mol Genet 5:1867–1874

    PubMed  CAS  Google Scholar 

  116. Watkins D, Ru M, Hwang HY et al. (2002) Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet 71:143–153

    PubMed  CAS  Google Scholar 

  117. Wilson A, Leclerc D, Saberi F et al. (1998) Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. Am J Hum Genet 63:409–414

    PubMed  CAS  Google Scholar 

  118. 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 325:1127–1129

    Google Scholar 

  119. Shevell MI, Rosenblatt DS (1992) The neurology of cobalamin. Can J Neurol Sci 19:472–486

    PubMed  CAS  Google Scholar 

  120. Matherly LH, Goldman ID (2003) Membrane transport of folates. Vitam Horm 66:403–456

    PubMed  CAS  Google Scholar 

  121. Qiu A, Jansen M, Sakaris A et al. (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127:917–928

    PubMed  CAS  Google Scholar 

  122. Zhao R, Goldman ID (2007) The molecular identity and characterization of a proton-coupled folate transporter – PCFT; biological ramifications and impact on the activity of pemetrexed. Cancer Metastasis Rev 26:129–139

    PubMed  CAS  Google Scholar 

  123. Geller J, Kronn D, Jayabose S, Sandoval C (2002) Hereditary folate malabsorption. Family report and review of the literature. Medicine 81:51–68

    PubMed  CAS  Google Scholar 

  124. Urbach J, Abrahamov A, Grossowicz N (1987) Congenital isolated folic acid malabsorption. Arch Dis Childhood 62:78–80

    CAS  Google Scholar 

  125. Ramaekers VT, Häusler M, Opladen T, Heimann G, Blau N (2002) Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 33:301–308

    PubMed  CAS  Google Scholar 

  126. Ramaekers VT, Blau N (2004) Cerebral folate deficiency. Dev Med Child Neurol 46:843–851

    PubMed  Google Scholar 

  127. Ramaekers VT, Rothenberg SP, Seqeira JM et al. (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 352:1985–1991

    PubMed  CAS  Google Scholar 

  128. Steinfeld R, Grapp M, Kraetzner R et al. (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85:354–363

    PubMed  CAS  Google Scholar 

  129. Cario H, Bode H, Debatin KM, Opladen T, Schwarz K (2009) Congenital null mutations of the FOLR1 gene; a progressive neurologic disease and its treatment. Neurology 73:2127–2129

    PubMed  CAS  Google Scholar 

  130. Nishimura M, Yoshino K, Tomita Y et al. (1985) Central and peripheral nervous system pathology of homocystinuria due to 5,10-methylenentetrahydrofolate reductase deficiency. Pediatr Neurol 1:375–378

    PubMed  CAS  Google Scholar 

  131. Erbe RW (1979) Genetic aspects of folate metabolism. Adv Hum Genet 9:293–354

    PubMed  CAS  Google Scholar 

  132. Erbe RW (1986) Inborn errors of folate metabolism. In: Blakley RL, Benkovic SJ (eds) Folates and pterins, vol 3: Nutritional, pharmacological and physiological aspects. Wiley, New York, pp 413–465

    Google Scholar 

  133. Hilton JF, Christensen KE, Watkins D et al. (2003) The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat 22:67–73

    PubMed  CAS  Google Scholar 

  134. Rozen R, Ueland PM (eds) (2005) MTHFR Polymorphisms and disease. Landes Bioscience, Georgetown, Tex

    Google Scholar 

  135. Visy JM, Le Coz P, Chadefaux B et al. (1991) Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings. Neurobiology 41:1313–1315

    CAS  Google Scholar 

  136. Haworth JC, Dilling LA, Surtees RAH et al. (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45:572–576

    PubMed  CAS  Google Scholar 

  137. Fowler B(1998) Genetic defects of folate and cobalamin metabolism. Eur J Pediatr 157:S60-S66

    PubMed  CAS  Google Scholar 

  138. Thomas MA, Rosenblatt DS (2005) Severe methylenetetrahydrofolate reductase deficiency. In: Rozen R, Ueland PM (eds) MTHFR Polymorphisms and disease. Landes Bioscience, Georgetown, Tex, pp 41–53

    Google Scholar 

  139. Sewell AC, Neirich U, Fowler B (1998) Early infantile methylenetetrahydrofolate reductase deficiency: a rare cause of progressive brain atrophy. J Inherit Metab Dis 21:22

    Google Scholar 

  140. Arn PH, Williams CA, Zori RT, Driscoll DJ, Rosenblatt DS (1998) Methyltetrahydrofolate reductase deficiency in a patient with phenotypic findings of Angelman syndrome. Am J Med Genet 77:198–200

    PubMed  CAS  Google Scholar 

  141. 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 349:45–50

    PubMed  Google Scholar 

  142. Goyette P, Sumner JS, Milos R et al. (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200

    PubMed  CAS  Google Scholar 

  143. Goyette P, Christensen B, Rosenblatt DS, Rozen R (1996) Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet 59:1268–1275

    PubMed  CAS  Google Scholar 

  144. Sibani S, Leclerc D, Weisberg I et al. (2003) Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation. Hum Mutat 21:509–520

    PubMed  CAS  Google Scholar 

  145. Tonetti C, Saudubray JM, Echenne B et al. (2003) Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 162:466–475

    PubMed  Google Scholar 

  146. Suormala T, Koch HG, Rummel T, Haberle J, Fowler B (2004) Methylenetetrahydrofolate reductase (MTHFR) deficiency: mutations and functional abnormalities. J Inherit Metab Dis 27:231

    Google Scholar 

  147. Yano H, Nakaso K, Yasui K et al. (2004) Mutations of the MTHFR gene (428C>T and [458G>T002B;459C>T]) markedly decrease MTHFR activity. Neurogenetics 5:135–140

    PubMed  CAS  Google Scholar 

  148. Urreitzi R, Moya-Garcia A, Pino-Angeles A et al. (2010) Molecular characterization of five patients with homocystinuria due to severe MTHFR deficiency. Clin Genet 78:441–448

    Google Scholar 

  149. Strauss KA, Morton DH, Puffenberger EG et al. (2007) Prevention of brain disease from severe methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175

    PubMed  CAS  Google Scholar 

  150. Rosenblatt D, Lue-Shing H, Arzoumanian A, Low-Nang L, Matiaszuk N (1992) Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts. Biochem Med Metab Biol 47:221–225

    PubMed  CAS  Google Scholar 

  151. Wendel U, Bremer HJ (1984) Betaine in the treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 142:147–150

    PubMed  CAS  Google Scholar 

  152. Holme E, Kjellman B, Ronge E (1989) Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 64:1061–1064

    PubMed  CAS  Google Scholar 

  153. Ronge E, Kjellman B (1996) Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency. Arch Dis Child 74:239–241

    PubMed  CAS  Google Scholar 

  154. Schiff M, Benoist JF, Tilea B et al. (2011) Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34: 137–145

    PubMed  CAS  Google Scholar 

  155. Abeling NGGM, Gennip v AH, Blom HJ 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 22:240–242

    PubMed  CAS  Google Scholar 

  156. Banka S, Blom HJ, Walter J et al. (2011) Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet 88:216–225

    PubMed  CAS  Google Scholar 

  157. Cario H, Smith DEC, Blom H et al. (2011) Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet 88:226–231

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Medical Genetics McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, H3G 1A4, Quebec, Canada

    David Watkins & David S. Rosenblatt

  2. University Children’s Hospital, Romergasse 8, 4005, Basel, Switzerland

    Brian Fowler

Authors
  1. David Watkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David S. Rosenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian Fowler
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Neurology Neurometabolic Unit, Hôpital Pitié Salpêtrière 47–83 Boulevard de l’Hôpital, Paris Cedex 13, 75651, Paris, France

    Jean-Marie Saudubray

  2. Laboratory of Physiological Chemistry de Duve Institute, University of Louvain Medical School, Avenue Hippocrate 75/39, 1200, Brussels, Belgium

    Georges van den Berghe

  3. Biochemical Genetics Unit Manchester Academic Health Science Centre, Central Manchester University Hospitals St Mary’s Hospital, Oxford Road, M13 9WL, Manchester, UK

    John H. Walter

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Watkins, D., Rosenblatt, D.S., Fowler, B. (2012). Disorders of Cobalamin and Folate Transport and Metabolism. In: Saudubray, JM., van den Berghe, G., Walter, J.H. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-15720-2_28

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-15720-2_28

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-15719-6

  • Online ISBN: 978-3-642-15720-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation