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Vitamin B6-Dependent and Responsive Disorders

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Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

Abstract

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.

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References

  • 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–e198

    PubMed  Google Scholar 

  • 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):25–33

    Article  Google Scholar 

  • Baxter P (2003) Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta 1647:36–41

    Article  CAS  PubMed  Google Scholar 

  • Bennett CL, Huynh HM, Chance PF, Glass IA, Gospe SM Jr (2005) Genetic heterogeneity for autosomal recessive pyridoxine-dependent seizures. Neurogenetics 6:143–149

    Article  CAS  PubMed  Google Scholar 

  • 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):297–303

    PubMed  Google Scholar 

  • 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 54:849–854

    Article  PubMed  Google Scholar 

  • Clayton PT (2006) B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 29:317–326, Review

    Article  CAS  PubMed  Google Scholar 

  • 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 978-3-9811868-1-9

    Google Scholar 

  • Farrant RD, Walker V, Mills G, Mellor JM, Langley GJ (2001) Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. J Biol Chem 276:15107–15116

    Article  CAS  PubMed  Google Scholar 

  • 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 64:1699–1707

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 Dis

    Google Scholar 

  • 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):139–145

    Article  CAS  PubMed  Google Scholar 

  • 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 65:550–556

    Article  CAS  PubMed  Google Scholar 

  • Gospe S (2006) Pyridoxine dependent seizures: new genetic and biochemical clues to help with diagnosis and treatment. Curr Opin Neurol 19:148–153

    Article  CAS  PubMed  Google Scholar 

  • 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 53:1150–1153

    Article  PubMed  Google Scholar 

  • 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 30:96–99

    Article  CAS  PubMed  Google Scholar 

  • 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 14:1077–1086

    Article  CAS  PubMed  Google Scholar 

  • 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 12:307–309

    Article  CAS  PubMed  Google Scholar 

  • 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 133:2148–2159

    Article  PubMed Central  PubMed  Google Scholar 

  • Plecko B, Stöckler S (2009) Vitamin B6 dependent seizures. Can J Neurol Sci 36(Suppl 2):73–77

    Google Scholar 

  • 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 48:121–125

    Article  CAS  PubMed  Google Scholar 

  • 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 36:200–205

    Article  CAS  PubMed  Google Scholar 

  • 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 28:19–26

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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):48–60

    Article  CAS  PubMed  Google Scholar 

  • 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 5:909–916

    Article  Google Scholar 

  • 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):335–344

    PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pediatric Neurology, Children’s Hospital, University of Zürich, Steinwiesstrasse 75, Zürich, 8032, Switzerland

    Barbara Plecko

  2. Metabolic Unit, Clinical Chemistry, VUmc Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands

    Eduard A. Struys

  3. Department Clinical Chemistry, PK 1X 014, VU University Medical Center Amsterdam, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands

    Cornelis Jakobs

Authors
  1. Barbara Plecko
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  2. Eduard A. Struys
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  3. Cornelis Jakobs
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Corresponding author

Correspondence to Barbara Plecko .

Editor information

Editors and Affiliations

  1. Department of General Pediatrics, University Children's Hospital, Division of Inborn Metabolic Diseases, Heidelberg, Germany

    Nenad Blau

  2. Laboratory Genetic Metabolic Diseases, University of Amsterdam Academic Medical Centre, Amsterdam, The Netherlands

    Marinus Duran

  3. Section of Clinical Pharmacology, Washington State University, Spokane, Washington, USA

    K Michael Gibson

  4. Division of Metabolism, Department of Pediatric Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy

    Carlo Dionisi Vici

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Plecko, B., Struys, E.A., Jakobs, C. (2014). Vitamin B6-Dependent and Responsive Disorders. In: Blau, N., Duran, M., Gibson, K., Dionisi Vici, C. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40337-8_11

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  • DOI: https://doi.org/10.1007/978-3-642-40337-8_11

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-40336-1

  • Online ISBN: 978-3-642-40337-8

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