Journal of Inherited Metabolic Disease

, Volume 29, Issue 2–3, pp 317–326 | Cite as

B6-responsive disorders: A model of vitamin dependency

  • Peter T. ClaytonEmail author


Pyridoxal phosphate is the cofactor for over 100 enzyme-catalysed reactions in the body, including many involved in the synthesis or catabolism of neurotransmitters. Inadequate levels of pyridoxal phosphate in the brain cause neurological dysfunction, particularly epilepsy. There are several different mechanisms that lead to an increased requirement for pyridoxine and/or pyridoxal phosphate. These include: (i) inborn errors affecting the pathways of B6 vitamer metabolism; (ii) inborn errors that lead to accumulation of small molecules that react with pyridoxal phosphate and inactivate it; (iii) drugs that react with pyridoxal phosphate; (iv) coeliac disease, which is thought to lead to malabsorption of B6 vitamers; (v) renal dialysis, which leads to increased losses of B6 vitamers from the circulation; (vi) drugs that affect the metabolism of B6 vitamers; and (vii) inborn errors affecting specific pyridoxal phosphate-dependent enzymes. The last show a very variable degree of pyridoxine responsiveness, from 90% in X-linked sideroblastic anaemia (δ-aminolevulinate synthase deficiency) through 50% in homocystinuria (cystathionine β-synthase deficiency) to 5% in ornithinaemia with gyrate atrophy (ornithine δ-aminotransferase deficiency). The possible role of pyridoxal phosphate as a chaperone during folding of nascent enzymes is discussed. High-dose pyridoxine or pyridoxal phosphate may have deleterious side-effects (particularly peripheral neuropathy with pyridoxine) and this must be considered in treatment regimes. None the less, in some patients, particularly infants with intractable epilepsy, treatment with pyridoxine or pyridoxal phosphate can be life-saving, and in other infants with inborn errors of metabolism B6 treatment can be extremely beneficial.


Inborn Error Pyridoxal Phosphate Hypophosphatasia Pipecolic Acid Xanthurenic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. An SJ, Park SK, Hwang IK, et al (2004) Vigabatrin inhibits pyridoxine-5′-phosphate oxidase, not pyridoxal kinase in the hippocampus of seizure prone gerbils. Neurochem Int 44: 133–137.PubMedCrossRefGoogle Scholar
  2. Aoki Y, Muranaka S, Nakabayashi K, Ueda Y (1979) delta-Aminolevulinic acid synthetase in erythroblasts of patients with pyridoxine-responsive anemia. Hypercatabolism caused by the increased susceptibility to the controlling protease. J Clin Invest 64: 1196–1203.PubMedGoogle Scholar
  3. Apeland T, Mansoor MA, Pentieva K, McNulty H, Seljeflot I, Strandjord RE (2002) The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs. Epilepsy Res 51: 237–247.PubMedCrossRefGoogle Scholar
  4. Barber GW, Spaeth GL (1969) The successful treatment of homocystinuria with pyridoxine. J Pediatr 75: 463–478.PubMedCrossRefGoogle Scholar
  5. Baxter P (2001) Pyridoxine dependent/responsive seizures. In: Baxter P, ed. Vitamin Responsive Conditions in Paediatric Neurology. London: MacKeith Press, 109–165.Google Scholar
  6. Been JV, Bok LA, Andriessen P, Renier WO (2005) Epidemiology of pyridoxine-dependent seizures in The Netherlands. Arch Dis Child 90: 1293–1296.PubMedCrossRefGoogle Scholar
  7. Bender DA (1999) Non-nutritional uses of vitamin B6. Br J Nutr 81: 7–20.PubMedGoogle Scholar
  8. Berson EL, Schmidt SY, Shih VE (1978) Ocular and biochemical abnormalities in gyrate atrophy of the choroid and retina. Ophthalmology 85: 1018–1027.PubMedGoogle Scholar
  9. Berson EL, Shih VE, Sullivan PL (1981) Ocular findings in patients with gyrate atrophy on pyridoxine and low-protein, low-arginine diets. Ophthalmology 88: 311–315.PubMedGoogle Scholar
  10. Biehl JP, Vilter RW (1954) Effects of isoniazid on pyridoxine metabolism. J Am Med Assoc 156: 1549–1552.PubMedGoogle Scholar
  11. Bilski P, LiMY, Ehrenshaft M, Daub ME, Chignell CF (2000) Vitamin B6 (pyridoxine) and its derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants. Photochem Photobiol 71: 129–134.PubMedCrossRefGoogle Scholar
  12. Cormier-Daire V, Dagoneau N, Nabbout R, et al (2000) A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31. Am J Hum Genet 67: 991–993.PubMedCrossRefGoogle Scholar
  13. Cotter PD, May A, Fitzsimons EJ, et al (1995) Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest 96: 2090–2096.PubMedGoogle Scholar
  14. Coursin DB (1954) Convulsive seizures in infants with pyridoxine-deficient diet. J Am Med Assoc 154: 406–408.PubMedGoogle Scholar
  15. Dalton K, Dalton MJ (1987) Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 76: 8–11.PubMedCrossRefGoogle Scholar
  16. Ebinger M, Schultze C, Konig S (1999) Demographics and diagnosis of pyridoxine-dependent seizures. J Pediatr 134: 795–796.PubMedGoogle Scholar
  17. Ehrenshaft M, Bilski P, Li MY, Chignell CF, Daub ME (1999) A highly conserved sequence is a novel gene involved in de novo vitamin B6 synthesis. Proc Natl Acad Sci USA 96: 9374–9378.PubMedCrossRefGoogle Scholar
  18. Eliot AC, Kirsch JF (2004) Pyridoxal phosphate enzymes: mechanistic, structural and evolutionary considerations. Annu Rev Biochem 73: 383–415.PubMedCrossRefGoogle Scholar
  19. Erlandsen H, Pey AP, Gámez A, et al (2004) Correction of kinetic and stability defects by terahydrobiopterin in phenylketonuria with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci USA 101: 16903–16908.PubMedCrossRefGoogle Scholar
  20. Farrant RD, Walker V, Mills GA, Mellor JM, Langley GJ (2001) Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. J Biol Chem 276: 15107–15116.PubMedCrossRefGoogle Scholar
  21. Fouts PJ, Lepkovsky S (1942) A green pigment-producing compound in urine of pyridoxine-deficient dogs. Proc Soc Exp Biol Med 50: 221–222.Google Scholar
  22. Furuyama K, Fujita H, Nagai T, et al (1997) Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene. Blood 90: 822–830.PubMedGoogle Scholar
  23. Glenn GM, Krober MS, Kelly P, McCarty J, Weir M (1995) Pyridoxine as therapy in theophylline-induced seizures. Vet Hum Toxicol 37: 342–345.PubMedGoogle Scholar
  24. Greengard O, Gordon M (1963) The cofactor-mediated regulation of apoenzyme levels in animal tissues. I. The pyridoxine-induced rise of rat liver tyrosine transaminase level in vivo. J Biol Chem 238: 3708–3710.PubMedGoogle Scholar
  25. Gross-Mesilaty S, Hargrove JL, Ciechanover A (1997) Degradation of tyrosine aminotransferase (TAT) via the ubiquitin-proteasome pathway. FEBS Lett 405: 175–180.PubMedCrossRefGoogle Scholar
  26. Hallert C, Grant C, Grehn S, et al (2002) Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years. Aliment Pharmacol Ther 16: 1333–1339.PubMedCrossRefGoogle Scholar
  27. Hammen A, Wagner B, Berkhoff M, Donati F (1998) A paradoxical rise of neonatal seizures after treatment with vitamin B6. Eur J Paediatr Neurol 2: 319–322.PubMedCrossRefGoogle Scholar
  28. Hunt AD Jr, Stokes J Jr, McCrory WW, Stroud HH (1954) Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics 13: 140–145.PubMedGoogle Scholar
  29. Iqbal SJ, Brain A, Reynolds TM, Penny M, Holland S (1998) Relationship between serum alkaline phosphatase and pyridoxal-5′-phosphate levels in hypophosphatasia. Clin Sci (Lond) 94: 203–206.Google Scholar
  30. Kennaway NG, Weleber RG, Buist NRM (1980) Gyrate atrophy of the choroid and retina with hyperornithinaemia: biochemical and histological studies and response to vitamin B6. Am J Hum Genet 32: 529–541.PubMedGoogle Scholar
  31. Kowlessar OD, Haefner LJ, Benson GD (1964) Abnormal tryptophan metabolism in patients with adult celiac disease, with evidence for deficiency of vitamin B6. J Clin Invest 43: 894–903.PubMedGoogle Scholar
  32. Kretsch MJ, Sauberlich HE, Newbrun E (1991) Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women. Am J Clin Nutr 53: 1266–1274.PubMedGoogle Scholar
  33. Lee P, Kuhl W, Gelbart T, et al (1994) Homology between a human protein and a protein of the green garden pea. Genomics 21: 371–378.PubMedCrossRefGoogle Scholar
  34. Levine S, Saltzman A (2004) Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet. J Appl Toxicol 24: 497–500.PubMedCrossRefGoogle Scholar
  35. Litmanovitz I, Reish O, Dolfin T, et al (2002) Glu274Lys/Gly309Arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions. J Inherit Metab Dis 25: 35–40.PubMedCrossRefGoogle Scholar
  36. Mackey AD, Lieu SO, Carman C, Gregory JF (2003) Hydrolytic activity towards pyridoxine-5-β-d-glucoside in rat intestinal mucosa is not increased by vitamin B-6 deficiency: effect of basal diet composition and pyridoxine intake. J Nutr 133: 1362–1367.PubMedGoogle Scholar
  37. McCormick DB, Snell EE (1961) Pyridoxal phosphokinases. II. Effects of inhibitors. J Biol Chem 236: 2085–2088.PubMedGoogle Scholar
  38. McKinley MC, McNulty H, McPartlin J, et al (2001) Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. Am J Clin Nutr 73: 759–764.PubMedGoogle Scholar
  39. Mills PB, Surtees RAH, Champion MP, et al (2005) Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 14: 1077–1086.PubMedCrossRefGoogle Scholar
  40. Mills PB, Struys E, Jakobs C, et al (2006) Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nature Medicine 12: 307–309.PubMedCrossRefGoogle Scholar
  41. Morrison LA, Driskell JA (1985) Quantities of B6 vitamers in human milk by high-performance liquid chromatography. Influence of maternal vitamin B6 status. J Chromatogr 337: 249–258.PubMedGoogle Scholar
  42. Mudd SH, Levy HL, Kraus JP (2001) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2007–2056.Google Scholar
  43. Namazi MR (2003) Pyridoxal 5′-phosphate as a novel weapon against autoimmunity and transplant rejection. FASEB J 17: 2184–2186.PubMedCrossRefGoogle Scholar
  44. ParkYK, Linkswiler H (1971) Effect of vitamin B6 depletion in man on the plasma concentration and the urinary excretion of free amino acids. J Nutr 101: 185–191.PubMedGoogle Scholar
  45. Perez-Llarena, FJ, Rodriguez-Garcia A, Enguita FJ, et al (1998) The pcd gene encoding piperideine 6-carboxylate dehydrogenase involved in biosynthesis of alpha-aminoadipic acid is located in the cephamycin cluster of Streptomyces clavuligerus. J Bacteriol 180: 4753–4756.PubMedGoogle Scholar
  46. Plecko B, Stockler-Ipsiroglu S, Paschke E, Erwa W, Struys EA, Jakobs C (2000) Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol 48: 121–125.PubMedCrossRefGoogle Scholar
  47. Rathbun JC (1948) Hypophosphatasia: a new developmental anomaly. Am J Dis Child 75: 822–831.PubMedGoogle Scholar
  48. Salazar P, Tapia R (2001) Seizures induced by intracerebral injection of pyridoxal-5′-phosphate: effect of GABAergic drugs and glutamate receptor antagonists. Neuropharmacology 41: 546–553.PubMedCrossRefGoogle Scholar
  49. Salhany JM, Schopfer LM (1993) Pyridoxal 5′-phosphate binds specifically to soluble CD4 protein, the HIV-1 receptor. J Biol Chem 268: 7643–7645.PubMedGoogle Scholar
  50. Sauberlich HE (1999) Vitamin B-6 (pyridoxine). In: Sauberlich HE, ed. Laboratory Tests for the Assessment of Nutritional Status, 2nd ed. Boca Raton: CRC Press, 71–102.Google Scholar
  51. Skvorak AB, Robertson NG, Yin Y, et al (1997) An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1). Genomics 46: 191–199.PubMedCrossRefGoogle Scholar
  52. Takagi M, Fukui T, Shimomura S (1982) Catalytic mechanism of glycogen phosphorylase: pyridoxal(5′)diphospho(1)-α-d-glucose as a transition-state analogue. Proc Natl Acad Sci USA 79: 3716–3719.PubMedCrossRefGoogle Scholar
  53. Tully DB, Allgood VE, Cidlowski JA (1994) Modulation of steroid receptor-mediated gene expression by vitamin B6. FASEB J 8: 343–349.PubMedGoogle Scholar
  54. Ubbink JB, Bissbort S, Vermaak WJ, Delport R (1990a) Inhibition of pyridoxal kinase by methylxanthines. Enzyme 43: 72–79.Google Scholar
  55. Ubbink JB, Delport R, Bissbort S, Vermaak WJ, Becker PJ (1990b) Relationship between vitamin B-6 status and elevated pyridoxal kinase levels induced by theophylline therapy in humans. J Nutr 120: 1352–1359.Google Scholar
  56. Veresova S, Kabova R, Velisek L (1998) Proconvulsant effects induced by pyridoxine in young rats. Epilepsy Res 29: 259–264.PubMedCrossRefGoogle Scholar
  57. Walker V, Mills GA, Peters SA, Merton WL (2000) Fits, pyridoxine, and hyperprolinaemia type II. Arch Dis Child 82: 236–237.PubMedCrossRefGoogle Scholar
  58. Wang HS, Kuo MF, Chou ML, et al (2005) Pyridoxal phosphate is better than pyridoxine for controlling idiopathic intractable epilepsy. Arch Dis Child 90(5): 512–515.PubMedCrossRefGoogle Scholar
  59. Waymire KG, Mahuren JD, Jaje JM, Guilarte TR, Coburn SP, MacGregor GR (1995) Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nature Genetics 11: 45–51.PubMedCrossRefGoogle Scholar
  60. Weleber RG, Kennaway NG, Buist NR (1978) Vitamin B6 in management of gyrate atrophy of the choroids and retina. Lancet 2: 1213.PubMedCrossRefGoogle Scholar
  61. Weleber RG, Kennaway NG (1981) Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology 88: 316–324.PubMedGoogle Scholar
  62. Whyte MP, Mahuren JD, Fedde KN, Cole FS, McCabe ER, Coburn SP (1988) Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5′-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase. J Clin Invest 81: 1234–1239.PubMedCrossRefGoogle Scholar
  63. Yoshida I, Sakaguchi Y, Nakano M, Yamashita F, Hitoshi T (1985) Pyridoxal phosphate-induced liver injury in a patient with homocystinuria. J Inherit Metab Dis 8: 91.PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  1. 1.Biochemistry, Endocrinology and MetabolismInstitute of Child HealthLondonUK

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