Disorders of Cobalamin and Folate Transport and Metabolism

  • David Watkins
  • David S. Rosenblatt
  • Brian Fowler

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).

References

  1. [1]
    Cooper BA, Rosenblatt DS (1987) Inherited defects of vitamin B12 metabolism. Annu Rev Nutr 7:291–320PubMedGoogle Scholar
  2. [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 244–258Google Scholar
  3. [3]
    Whitehead VM (2006) Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol 134:125–136PubMedGoogle Scholar
  4. [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 467–520Google Scholar
  5. [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 76:2057–2065PubMedGoogle Scholar
  6. [6]
    Katz M, Mehlman CS, Allen RH (1974) Isolation and characterization of an abnormal human intrinsic factor. J Clin Invest 53:1274–1283PubMedGoogle Scholar
  7. [7]
    Rothenberg SP, Quadros EV, Straus EW, Kapelner S (1984) An abnormal intrinsic factor (IF) molecule: a new cause of »pernicious anemia«. Blood 64:41aGoogle Scholar
  8. [8]
    Spurling CL, Sacks MS, Jiji RM (1964) Juvenile pernicious anemia. N Engl J Med 271:995–1003PubMedGoogle Scholar
  9. [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 10:432–440PubMedGoogle Scholar
  10. [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 103:1515–1517PubMedGoogle Scholar
  11. [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 102:4130–4133PubMedGoogle Scholar
  12. [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 144:622–624PubMedGoogle Scholar
  13. [13]
    Gräsbeck R (1972) Familial selective vitamin B12 malabsorption. N Engl J Med 287:358PubMedGoogle Scholar
  14. [14]
    Broch H, Imerslund O, Monn E, Hovig T, Seip M (1984) Imerslund- Gräsbeck anemia: a long-term follow-up study. Acta Paediatr Scand 73:248–253PubMedGoogle Scholar
  15. [15]
    El Mauhoub M, Sudarshan G, Aggarwal V, Banerjee G (1989) Imerslund-Gräsbeck syndrome in a Libyan boy. Ann Trop Paediatr 9:180–181PubMedGoogle Scholar
  16. [16]
    El Bez M, Souid M, Mebazaa R, Ben Dridi MF (1992) L’anémie d’Imerslund-Gräsbeck. A propos d’un cas. Ann Pediatr 39:305–308Google Scholar
  17. [17]
    Salameh MM, Banda RW, Mohdi AA (1991) Reversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Gräsbeck syndrome. J Neurol 238:349–350PubMedGoogle Scholar
  18. [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 133:3311–3313PubMedGoogle Scholar
  19. [19]
    Gräsbeck R (1997) Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor. Acta Biochim Polon 44:725–734PubMedGoogle Scholar
  20. [20]
    Gräsbeck R (2006) Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria). Orphanet J Rare Dis 1:17PubMedGoogle Scholar
  21. [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 18:417–421PubMedGoogle Scholar
  22. [22]
    Liang DC, Hsu HC, Huang EY, Wei KN (1991) Imerslund-Gräsbeck syndrome in two brothers: renal biopsy and ultrastructural findings. Pediatr Hematol Oncol 8:361–365PubMedGoogle Scholar
  23. [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 273:5235–5242PubMedGoogle Scholar
  24. [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 91:3593–3600PubMedGoogle Scholar
  25. [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 272:26497–26504PubMedGoogle Scholar
  26. [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 103:1573–1579PubMedGoogle Scholar
  27. [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 57:824–831PubMedGoogle Scholar
  28. [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 21:309–313PubMedGoogle Scholar
  29. [29]
    Tanner SM, Aminoff M, Wright FA et al. (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet 33:426–429PubMedGoogle Scholar
  30. [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 23:327–333PubMedGoogle Scholar
  31. [31]
    Carmel R (1983) R-binder deficiency. A clinically benign cause of cobalamin pseudodeficiency. JAMA 250:1886–1890PubMedGoogle Scholar
  32. [32]
    Carmel R (2003) Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem 49:1367–1374PubMedGoogle Scholar
  33. [33]
    Adcock BB, McKnight JT (2002) Cobalamin pseudodeficiency due to a transcobalamin I deficiency. South Med J 95:1060–1062PubMedGoogle Scholar
  34. [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 147:386–391PubMedGoogle Scholar
  35. [35]
    Frisbie SM, Chance MR (1993) Human cobalaphilin: the structure of bound methylcobalamin and a functional role in protecting methylcobalamin from photolysis. Biochemistry 32:13886–13892PubMedGoogle Scholar
  36. [36]
    Morkbak AL, Poulsen SS, Nexo E (2007) Haptocorrin in humans. Clin Chem Lab Med 45:1751–1759PubMedGoogle Scholar
  37. [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 100:145–151PubMedGoogle Scholar
  38. [38]
    Johnston J, Bollekens J, Allen RH, Berliner N (1989) Structure of the cDNA encoding transcobalamin I, a neutrophil granule protein. J Biol Chem 264:15754–15757PubMedGoogle Scholar
  39. [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 12:459–454PubMedGoogle Scholar
  40. [40]
    Schiff M, Ogier de Baulny H, Bard G et al. (2010) Should transcobalamin deficiency be treated aggressively? J Inherit Metab Dis 33:223–229PubMedGoogle Scholar
  41. [41]
    Hall CA (1992) The neurological aspects of transcobalamin II deficiency. Br J Haematol 80:117–120PubMedGoogle Scholar
  42. [42]
    Souied EH, Benhamou N, Sterkers M et al. (2001) Retinal degeneration associated with congenital transcobalamin II deficiency. Arch Ophthalmol 119:1076–1077PubMedGoogle Scholar
  43. [43]
    Haurani FI, Hall CA, Rubin R (1979) Megaloblastic anemia as a result of an abnormal transcobalamin II (Cardeza). J Clin Invest 64:1253–1259PubMedGoogle Scholar
  44. [44]
    Seligman PA, Steiner LL, Allen RH (1980) Studies of a patient with megaloblastic anemia and an abnormal transcobalamin II. N Engl J Med 303:1209–1212PubMedGoogle Scholar
  45. [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 3:1835–1840PubMedGoogle Scholar
  46. [46]
    Li N, Rosenblatt DS, Seetharam B (1994) Nonsense mutations in human transcobalamin II deficiency. Biochem Biophys Res Comm 204:1111–1118PubMedGoogle Scholar
  47. [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 123:915–920PubMedGoogle Scholar
  48. [48]
    Bibi H, Gelman-Kohan Z, Baumgartner ER, Rosenblatt DS (1999) Transcobalamin II deficiency with methylmalonic aciduria in three sisters. J Inherit Metab Dis 22:765–772PubMedGoogle Scholar
  49. [49]
    Rosenblatt D, Hosack A, Matiaszuk N (1987) Expression of transcobalamin II by amniocytes. Prenat Diagn 7:35–39PubMedGoogle Scholar
  50. [50]
    Nexo E, Christensen AL, Petersen TE, Fedosov SN (2000) Measurement of transcobalamin by ELISA. Clin Chem 46:1643–1649PubMedGoogle Scholar
  51. [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 31:924–929PubMedGoogle Scholar
  52. [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 98:122Google Scholar
  53. [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 47:677–685PubMedGoogle Scholar
  54. [54]
    Rosenblatt DS, Laframboise R, Pichette J et al. (1986) New disorder of vitamin B12 metabolism (cobalamin F) presenting as methylmalonic aciduria. Pediatrics 78:51–54PubMedGoogle Scholar
  55. [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 228:1319–1321PubMedGoogle Scholar
  56. [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 41:234–239PubMedGoogle Scholar
  57. [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 33:17–24PubMedGoogle Scholar
  58. [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 34:121–126PubMedGoogle Scholar
  59. [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 20:528–538PubMedGoogle Scholar
  60. [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 38:93–100PubMedGoogle Scholar
  61. [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 93:475–480PubMedGoogle Scholar
  62. [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 30:1072–1081PubMedGoogle Scholar
  63. [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 55:621–626PubMedGoogle Scholar
  64. [64]
    Mitchell GA, Watkins D, Melançon SB et al. (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415PubMedGoogle Scholar
  65. [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 113:269–280PubMedGoogle Scholar
  66. [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-S83PubMedGoogle Scholar
  67. [67]
    Huemer M, Simma B, Fowler B et al. (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472PubMedGoogle Scholar
  68. [68]
    Schimel AM, Mets MB (2006) The natural history of retinal degeneration in association with cobalamin C (cblC) disease. Ophthalmic Genet 27:9–14PubMedGoogle Scholar
  69. [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 98:344–348PubMedGoogle Scholar
  70. [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 60:107–108PubMedGoogle Scholar
  71. [71]
    Bodamer OAF, Rosenblatt DS, Appel SH, Beaudet AL (2001) Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 56:1113PubMedGoogle Scholar
  72. [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 111:195–201Google Scholar
  73. [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 45:588–595PubMedGoogle Scholar
  74. [74]
    Kim J, Gherasim C, Banerjee R (2008) Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci USA 105:14551–14554PubMedGoogle Scholar
  75. [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 97:260–266PubMedGoogle Scholar
  76. [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 284:33418–33424PubMedGoogle Scholar
  77. [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 86:160–171PubMedGoogle Scholar
  78. [78]
    Bartholomew DW, Batshaw ML, Allen RH et al. (1988) Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39PubMedGoogle Scholar
  79. [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 32:728–731PubMedGoogle Scholar
  80. [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 26:42Google Scholar
  81. [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 254:11847–11853PubMedGoogle Scholar
  82. [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 132:121–124PubMedGoogle Scholar
  83. [83]
    Goodman SI, Moe PG, Hammond KB, Mudd SH, Uhlendorf BW (1970) Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med 4:500–515PubMedGoogle Scholar
  84. [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 55:570–579PubMedGoogle Scholar
  85. [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 30:1–13PubMedGoogle Scholar
  86. [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;42742–42749PubMedGoogle Scholar
  87. [87]
    Coelho D, Suormala T, Stucki M et al. (2008) Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med 358:1454–1464PubMedGoogle Scholar
  88. [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 154:551–556PubMedGoogle Scholar
  89. [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 98:283–289PubMedGoogle Scholar
  90. [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 26:3361–3369Google Scholar
  91. [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 99:15554–15559PubMedGoogle Scholar
  92. [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 106:21567–21572PubMedGoogle Scholar
  93. [93]
    Banerjee R, Gherasim C, Padovani D (2009) The tinker, tailor, soldier in intracellular B12 trafficking. Curr Opin Chem Biol 13:477–484Google Scholar
  94. [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 82:329–333PubMedGoogle Scholar
  95. [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 24:509–516PubMedGoogle Scholar
  96. [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 84:317–325PubMedGoogle Scholar
  97. [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 31:55–66PubMedGoogle Scholar
  98. [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 87:219–225PubMedGoogle Scholar
  99. [99]
    Schubert HL, Hill CP (2006) Structure of ATP-bound human ATP:cobalamin adenosyltransferase. Biochemistry 45:15188–15196PubMedGoogle Scholar
  100. [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 411:1827–1829PubMedGoogle Scholar
  101. [101]
    Fowler B, Leonard JV, Baumgartner MR (2008) Causes and diagnostic approaches to methylmalonic acidurias. J Inherit Metab Dis 31:350–360PubMedGoogle Scholar
  102. [102]
    Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308:857–861PubMedGoogle Scholar
  103. [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 62:225–230PubMedGoogle Scholar
  104. [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 74:2149–2156PubMedGoogle Scholar
  105. [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 310:686–690PubMedGoogle Scholar
  106. [106]
    Watkins D, Rosenblatt DS (1988) Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG. J Clin Invest 81:1690–1694PubMedGoogle Scholar
  107. [107]
    Watkins D, Rosenblatt DS (1989) Functional methionine synthase deficiency (cblE and cblG) : clinical and biochemical heterogeneity. Am J Med Genet 34:427–434PubMedGoogle Scholar
  108. [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 318:1738–1741PubMedGoogle Scholar
  109. [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 26:361–369PubMedGoogle Scholar
  110. [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 95:3059–3064PubMedGoogle Scholar
  111. [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 8:2009–2016PubMedGoogle Scholar
  112. [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 25:239–247PubMedGoogle Scholar
  113. [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 31:437–444PubMedGoogle Scholar
  114. [114]
    Gulati S, Baker P, Li YN et al. (1996) Defects in human methionine synthase in cblG patients. Hum Mol Genet 5:1859–1865PubMedGoogle Scholar
  115. [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 5:1867–1874PubMedGoogle Scholar
  116. [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 71:143–153PubMedGoogle Scholar
  117. [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 63:409–414PubMedGoogle Scholar
  118. [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 325:1127–1129Google Scholar
  119. [119]
    Shevell MI, Rosenblatt DS (1992) The neurology of cobalamin. Can J Neurol Sci 19:472–486PubMedGoogle Scholar
  120. [120]
    Matherly LH, Goldman ID (2003) Membrane transport of folates. Vitam Horm 66:403–456PubMedGoogle Scholar
  121. [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 127:917–928PubMedGoogle Scholar
  122. [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 26:129–139PubMedGoogle Scholar
  123. [123]
    Geller J, Kronn D, Jayabose S, Sandoval C (2002) Hereditary folate malabsorption. Family report and review of the literature. Medicine 81:51–68PubMedGoogle Scholar
  124. [124]
    Urbach J, Abrahamov A, Grossowicz N (1987) Congenital isolated folic acid malabsorption. Arch Dis Childhood 62:78–80Google Scholar
  125. [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 33:301–308PubMedGoogle Scholar
  126. [126]
    Ramaekers VT, Blau N (2004) Cerebral folate deficiency. Dev Med Child Neurol 46:843–851PubMedGoogle Scholar
  127. [127]
    Ramaekers VT, Rothenberg SP, Seqeira JM et al. (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 352:1985–1991PubMedGoogle Scholar
  128. [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 85:354–363PubMedGoogle Scholar
  129. [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 73:2127–2129PubMedGoogle Scholar
  130. [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 1:375–378PubMedGoogle Scholar
  131. [131]
    Erbe RW (1979) Genetic aspects of folate metabolism. Adv Hum Genet 9:293–354PubMedGoogle Scholar
  132. [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 413–465Google Scholar
  133. [133]
    Hilton JF, Christensen KE, Watkins D et al. (2003) The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat 22:67–73PubMedGoogle Scholar
  134. [134]
    Rozen R, Ueland PM (eds) (2005) MTHFR Polymorphisms and disease. Landes Bioscience, Georgetown, TexGoogle Scholar
  135. [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 41:1313–1315Google Scholar
  136. [136]
    Haworth JC, Dilling LA, Surtees RAH et al. (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45:572–576PubMedGoogle Scholar
  137. [137]
    Fowler B(1998) Genetic defects of folate and cobalamin metabolism. Eur J Pediatr 157:S60-S66PubMedGoogle Scholar
  138. [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 41–53Google Scholar
  139. [139]
    Sewell AC, Neirich U, Fowler B (1998) Early infantile methylenetetrahydrofolate reductase deficiency: a rare cause of progressive brain atrophy. J Inherit Metab Dis 21:22Google Scholar
  140. [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 77:198–200PubMedGoogle Scholar
  141. [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 349:45–50PubMedGoogle Scholar
  142. [142]
    Goyette P, Sumner JS, Milos R et al. (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200PubMedGoogle Scholar
  143. [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 59:1268–1275PubMedGoogle Scholar
  144. [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 21:509–520PubMedGoogle Scholar
  145. [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 162:466–475PubMedGoogle Scholar
  146. [146]
    Suormala T, Koch HG, Rummel T, Haberle J, Fowler B (2004) Methylenetetrahydrofolate reductase (MTHFR) deficiency: mutations and functional abnormalities. J Inherit Metab Dis 27:231Google Scholar
  147. [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 5:135–140PubMedGoogle Scholar
  148. [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 78:441–448Google Scholar
  149. [149]
    Strauss KA, Morton DH, Puffenberger EG et al. (2007) Prevention of brain disease from severe methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175PubMedGoogle Scholar
  150. [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 47:221–225PubMedGoogle Scholar
  151. [151]
    Wendel U, Bremer HJ (1984) Betaine in the treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 142:147–150PubMedGoogle Scholar
  152. [152]
    Holme E, Kjellman B, Ronge E (1989) Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 64:1061–1064PubMedGoogle Scholar
  153. [153]
    Ronge E, Kjellman B (1996) Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency. Arch Dis Child 74:239–241PubMedGoogle Scholar
  154. [154]
    Schiff M, Benoist JF, Tilea B et al. (2011) Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34: 137–145PubMedGoogle Scholar
  155. [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 22:240–242PubMedGoogle Scholar
  156. [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 88:216–225PubMedGoogle Scholar
  157. [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 88:226–231PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • David Watkins
    • 1
  • David S. Rosenblatt
    • 1
  • Brian Fowler
    • 2
  1. 1.Division of Medical Genetics McGill University Health CentreMontreal General HospitalQuebecCanada
  2. 2.University Children’s HospitalBaselSwitzerland

Personalised recommendations