B6-responsive disorders: A model of vitamin dependency
- Peter T. Clayton
- … show all 1 hide
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
Presented at the 42nd Annual Meeting of the SSIEM, Paris, 6–9 September 2005
Competing interests: None declared
Communicating editor: Jean-Marie Saudubray
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.PubMed
Baxter P (2001) Pyridoxine dependent/responsive seizures. In: Baxter P, ed. Vitamin Responsive Conditions in Paediatric Neurology. London: MacKeith Press, 109–165.
Bender DA (1999) Non-nutritional uses of vitamin B6. Br J Nutr 81: 7–20.PubMed
Berson EL, Schmidt SY, Shih VE (1978) Ocular and biochemical abnormalities in gyrate atrophy of the choroid and retina. Ophthalmology 85: 1018–1027.PubMed
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.PubMed
Biehl JP, Vilter RW (1954) Effects of isoniazid on pyridoxine metabolism. J Am Med Assoc 156: 1549–1552.PubMed
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.PubMed
Coursin DB (1954) Convulsive seizures in infants with pyridoxine-deficient diet. J Am Med Assoc 154: 406–408.PubMed
Ebinger M, Schultze C, Konig S (1999) Demographics and diagnosis of pyridoxine-dependent seizures. J Pediatr 134: 795–796.PubMed
Fouts PJ, Lepkovsky S (1942) A green pigment-producing compound in urine of pyridoxine-deficient dogs. Proc Soc Exp Biol Med 50: 221–222.
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.PubMed
Glenn GM, Krober MS, Kelly P, McCarty J, Weir M (1995) Pyridoxine as therapy in theophylline-induced seizures. Vet Hum Toxicol 37: 342–345.PubMed
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.PubMed
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.PubMed
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.
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.PubMed
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.PubMed
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.PubMed
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.PubMed
McCormick DB, Snell EE (1961) Pyridoxal phosphokinases. II. Effects of inhibitors. J Biol Chem 236: 2085–2088.PubMed
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.PubMed
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.PubMed
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.
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.PubMed
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.PubMed
Rathbun JC (1948) Hypophosphatasia: a new developmental anomaly. Am J Dis Child 75: 822–831.PubMed
Salhany JM, Schopfer LM (1993) Pyridoxal 5′-phosphate binds specifically to soluble CD4 protein, the HIV-1 receptor. J Biol Chem 268: 7643–7645.PubMed
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.
Tully DB, Allgood VE, Cidlowski JA (1994) Modulation of steroid receptor-mediated gene expression by vitamin B6. FASEB J 8: 343–349.PubMed
Ubbink JB, Bissbort S, Vermaak WJ, Delport R (1990a) Inhibition of pyridoxal kinase by methylxanthines. Enzyme 43: 72–79.
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.
Weleber RG, Kennaway NG (1981) Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology 88: 316–324.PubMed
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.PubMedCrossRef
- B6-responsive disorders: A model of vitamin dependency
Journal of Inherited Metabolic Disease
Volume 29, Issue 2-3 , pp 317-326
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers
- Additional Links
- Industry Sectors
- Peter T. Clayton (1)
- Author Affiliations
- 1. Biochemistry, Endocrinology and Metabolism, Institute of Child Health, 30 Guilford St, London, WC1N 1 EH, UK