Vitamin B6-Dependent and Responsive Disorders

  • Barbara PleckoEmail author
  • Eduard A. Struys
  • Cornelis Jakobs


The importance of vitamin B6 is evident by its role as the most abundant cofactor in human metabolism. A total of six different B6 vitamers follow a complex pathway of absorption and transformation into the final active cofactor, pyridoxal 5′-phosphate (PLP), which catalyses over 100 reactions, mainly in amino acid and neurotransmitter metabolism. Over recent years a number of genetic defects have been identified as the underlying cause of vitamin B6-dependent epilepsies that need to be considered particularly in neonatal, therapy-resistant seizures of unclear aetiology. With diagnostic delay these disorders can be fatal or may lead to irreversible brain damage. Therefore, a standardised vitamin B6 trial should be part of a protocol for neonatal seizures in every institution caring for the critically ill newborn. The underlying mechanisms of vitamin B6-dependent epilepsies can be assigned to either reduced production/availability of PLP or to inactivation of PLP by accumulating compounds and formation of a Knoevenagel product. The disorders can be distinguished by specific biomarkers in urine, plasma or CSF and confirmed by molecular testing. Affected patients need a lifelong oral treatment with pyridoxine or pyridoxal 5′-phosphate and withdrawal will inevitably lead to recurrence of seizure. Due to autosomal recessive inheritance, recurrence risk for all disorders discussed here is 25 % and intrauterine treatment with vitamin B6 administered to the mother from early pregnancy may be considered in forthcoming pregnancies. Prenatal testing is available by molecular analysis.


Status Epilepticus Sulfite Oxidase Irreversible Brain Damage ALDH7A1 Gene Ohtahara Syndrome 
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.


  1. Albersen M, Groenendaal F, van der Ham M, de Koning TJ, Bosma M, Visser WF, Visser G, de Sain-van der Velden MG, Verhoeven-Duif NM (2012) Vitamin B6 vitamer concentrations in cerebrospinal fluid differ between preterm and term newborn infants. Pediatrics 130(1):e191–e198PubMedGoogle Scholar
  2. Balasubramaniam S, Bowling F, Carpenter K, Earl J, Chaitow J, Pitt J, Mornet E, Sillence D, Ellaway C (2010) Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability. J Inherit Metab Dis 33(Suppl 3):25–33CrossRefGoogle Scholar
  3. Baxter P (2003) Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta 1647:36–41PubMedCrossRefGoogle Scholar
  4. Bennett CL, Huynh HM, Chance PF, Glass IA, Gospe SM Jr (2005) Genetic heterogeneity for autosomal recessive pyridoxine-dependent seizures. Neurogenetics 6:143–149PubMedCrossRefGoogle Scholar
  5. Bok LA, Been JV, Struys EA, Jakobs C, Rijper EA, Willemsen MA (2010) Antenatal treatment in two Dutch families with pyridoxine-dependent seizures. Eur J Pediatr 169(3):297–303PubMedGoogle Scholar
  6. Bok LA, Halbertsma FJ, Houterman S, Wevers RA, Vreeswijk C, Jakobs C, Struys EA, Van Der Hoeven JH, Sival DA, Willemsen MA (2012) Long-term outcome in pyridoxine-dependent epilepsy. Dev Med Child Neurol 54:849–854PubMedCrossRefGoogle Scholar
  7. Clayton PT (2006) B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 29:317–326, ReviewPubMedCrossRefGoogle Scholar
  8. Clayton P, Plecko B (2008) Pyridoxine- and pyridoxalphosphate-dependent epilepsies. In: 40th European Metabolic Group meeting, Heidelberg. Milupa Metabolics GmbH, Friedrichsdorf, Germany. pp 31–40. ISBN 978-3-9811868-1-9Google Scholar
  9. Farrant RD, Walker V, Mills G, Mellor JM, Langley GJ (2001) Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. J Biol Chem 276:15107–15116PubMedCrossRefGoogle Scholar
  10. Flynn MP, Martin MC, Moore PT, Stafford JA, Fleming GA, Phang JM (1989) Type II hyperprolinaemia in a pedigree of Irish travellers (nomads). Arch Dis Child 64:1699–1707PubMedCentralPubMedCrossRefGoogle Scholar
  11. Footitt EJ, Heales SJ, Mills PB, Allen GF, Oppenheim M, Clayton PT (2011) Pyridoxal 5’-phosphate in cerebrospinal fluid; factors affecting concentration. J Inherit Metab DisGoogle Scholar
  12. Footitt EJ, Clayton PT, Mills K, Heales SJ, Neergheen V, Oppenheim M, Mills PB (2013) Measurement of plasma B(6) vitamer profiles in children with inborn errors of vitamin B6 metabolism using an LC-MS/MS method. J Inherit Metab Dis 36(1):139–145PubMedCrossRefGoogle Scholar
  13. Gallagher RC, Van Hove JL, Scharer G, Hyland K, Plecko B, Waters PJ, Mercimek-Mahmutoglu S, Stockler-Ipsiroglu S, Salomons GS, Rosenberg EH, Struys EA, Jakobs C (2009) Folinic acid-responsive seizures are caused by α-amino adipic semialdehyde dehydrogenase deficiency and are genetically identical to pyridoxine-dependent epilepsy. Ann Neurol 65:550–556PubMedCrossRefGoogle Scholar
  14. Gospe S (2006) Pyridoxine dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment. Curr Opin Neurol 19:148–153PubMedCrossRefGoogle Scholar
  15. Hartmann H, Fingerhut M, Jakobs C, Plecko B (2011) Status epilepticus in a neonate treated with pyridoxine because of a familial recurrence risk for antiquitin deficiency: pyridoxine toxicity? Dev Med Child Neurol 53:1150–1153PubMedCrossRefGoogle Scholar
  16. Hoffmann GF, Schmitt B, Windfuhr M, Wagner N, Strehl H, Bagci S, Franz AR, Mills PB, Clayton PT, Baumgartner MR, Steinmann B, Bast T, Wolf NI, Zschocke J (2007) Pyridoxal 5′-phosphate may be curative in early-onset epileptic encephalopathy. J Inherit Metab Dis 30:96–99PubMedCrossRefGoogle Scholar
  17. Mills PB, Surtees RA, Champion MP, Beesley CE, Dalton N, Scambler PJ, Heales SJ, Briddon A, Scheimberg I, Hoffmann GF, Zschocke J, Clayton PT (2005) Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 14:1077–1086PubMedCrossRefGoogle Scholar
  18. Mills PB, Struys EA, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT (2006) Mutations in the antiquitin (ALDH7A1) gene in patients with pyridoxine-dependent seizures. Nat Med 12:307–309PubMedCrossRefGoogle Scholar
  19. Mills PB, Footitt EJ, Mills KA, Tuschl K, Aylett S, Varadkar S, Hemingway C, Marlow N, Rennie J, Baxter P, Dulac O, Nabbout R, Craigen WJ, Schmitt B, Feillet F, Christensen E, De Lonlay P, Pike MG, Hughes MI, Struys EA, Jakobs C, Zuberi SM, Clayton PT (2010) Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 133:2148–2159PubMedCentralPubMedCrossRefGoogle Scholar
  20. Plecko B, Stöckler S (2009) Vitamin B6 dependent seizures. Can J Neurol Sci 36(Suppl 2):73–77Google Scholar
  21. Plecko B, Stöckler-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 48:121–125PubMedCrossRefGoogle Scholar
  22. Plecko B, Hikel C, Korenke GC, Schmitt B, Baumgartner M, Baumeister F, Jakobs C, Struys EA, Erwa W, Stöckler-Ipsiroglu S (2005) Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics 36:200–205PubMedCrossRefGoogle Scholar
  23. Plecko B, Paul K, Paschke E, Stoeckler-Ipsiroglu S, Struys EA, Jakobs C, Hartmann H, Luecke T, di Capua M, Korenke C, Hikel C, Reutershahn E, Freilinger M, Baumeister F, Bosch F, Erwa W (2007) Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy. Hum Mutat 28:19–26PubMedCrossRefGoogle Scholar
  24. Plecko B, Karl P, Mills Ph, Clayton P, Paschke E, Maier O, Hasselmann O, Schmiedl G, Kanz S, Connolly M, Wolf N, Struys E, Stockler S, Abela L, Hofer D (2013) Pyridoxine responsiveness in novel PNPO mutations. Neurology [in press]Google Scholar
  25. Stockler S, Plecko B, Gospe SM, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struys E, Tein I, Jakobs C, Clayton P, Van Hove JL (2011) Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 104(1–2):48–60PubMedCrossRefGoogle Scholar
  26. Struys EA, Bok LA, Emal D, Houterman S, Willemsen MA, Jakobs C (2012) The measurement of urinary Δ(1)-piperideine-6-carboxylate, the alter ego of α-aminoadipic semialdehyde, in Antiquitin deficiency. J Inherit Metab Dis 5:909–916CrossRefGoogle Scholar
  27. van Karnebeek C, Hartmann H, Jaggumantri S, Bok L, Cheng B, Connolly M, Coughlin CR II, Das A, Gospe S Jr, Jakobs C, van der Lee JH, Mercimek-Mahmutoglu S, Meyer U, Struys E, Sinclair G, Van Hove J, Collet JP, Plecko BR, Stockler S (2012) Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Genet Metab 107(3):335–344PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Barbara Plecko
    • 1
    Email author
  • Eduard A. Struys
    • 2
  • Cornelis Jakobs
    • 3
  1. 1.Department of Pediatric NeurologyChildren’s Hospital, University of ZürichZürichSwitzerland
  2. 2.Metabolic Unit, Clinical ChemistryVUmc Medical CenterAmsterdamThe Netherlands
  3. 3.Department Clinical Chemistry, PK 1X 014VU University Medical Center AmsterdamAmsterdamThe Netherlands

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