Skip to main content
SpringerLink
Log in

Disorders of Thiamine and Pyridoxine Metabolism

  • Chapter
Inborn Metabolic Diseases

  • 3368 Accesses

Zusammenfassung

Thiamine (Vitamin B1) is a water-soluble vitamin transported across cell membranes by two closely related transporters, THTR1 and THTR2. The active cofactor of thiamine, thiamine pyrophosphate (TPP), is formed in the cytoplasm by the enzyme thiamine pyrophosphokinase. TPP enters mitochondria with a specific TPP transporter. Pyridoxine (Vitamin B6) is a water-soluble vitamin with broad availability from various food sources, including dairy products, meat, cereals and vegetables. The three vitamers, pyridoxal, pyridoxamine and pyridoxine and their phosphorylated esters are absorbed in the small intestine. Within the cells vitamers are rephosphorylated by kinases and further oxidised to the active cofactor pyridoxal 5´-phosphate (PLP) by pyridox(am)ine 5´-phosphate oxidase (PNPO).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kitamura K, Yamaguchi T, Tanaka H et al. (1996) TPN-induced fulminant beriberi: a report on our experience and a review of the literature. Surg Today 26:769–776

    Google Scholar 

  2. Thauvin-Robinet C, Faivre L, Barbier ML et al. (2004) Severe lactic acidosis and acute thiamin deficiency: a report of 11 neonates with unsupplemented total parenteral nutrition. J Inherit Metab Dis 27:700–704

    Google Scholar 

  3. Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP (2001) Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Blood Cells Mol Dis 27:135–138

    Google Scholar 

  4. Ricketts CJ, Minton JA, Samuel J et al. (2006) Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families. Acta Paediatr 95:99–104

    Google Scholar 

  5. Lorber A, Gazit AZ, Khoury A, Schwartz Y, Mandel H (2003) Cardiac manifestations in thiamine-responsive megaloblastic anemia syndrome. Pediatr Cardiol 24:476–481

    Google Scholar 

  6. Scharfe C, Hauschild M, Klopstock T et al. (2000) A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. J Med Genet 37:669–673

    Google Scholar 

  7. Alfadhel M, Almuntashri M, Jadah RH et al. (2013) Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis 8:83

    Google Scholar 

  8. Yamada K, Miura K, Hara K et al. (2010) A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations. BMC Med Genet 11:171

    Google Scholar 

  9. Perez-Duenas B, Serrano M, Rebollo M et al. (2013) Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency. Pediatrics 131:e1670–1675

    Google Scholar 

  10. Fassone E, Wedatilake Y, DeVile CJ et al. (2013) Treatable Leigh-like encephalopathy presenting in adolescence. BMJ Case Report doi:10.1136/bcr-2013-200838

    Google Scholar 

  11. Kono S, Miyajima H, Yoshida K et al. (2009) Mutations in a thiamine-transporter gene and Wernicke’s-like encephalopathy. N Engl J Med 360:1792–1794

    Google Scholar 

  12. Debs R, Depienne C, Rastetter A et al. (2010) Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations. Arch Neurol 67:126–130

    Google Scholar 

  13. Gerards M, Kamps R, van Oevelen J et al. (2013) Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain 136:882–890

    Google Scholar 

  14. Kevelam SH, Bugiani M, Salomons GS et al. (2013) Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. Brain 136:1534–1543

    Google Scholar 

  15. Zeng WQ, Al-Yamani E, Acierno JS Jr et al. (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77:16–26

    Google Scholar 

  16. Tabarki B, Alfadhel M, AlShahwan S et al. (2015) Treatment of biotin-responsive basal ganglia disease: Open comparative study between the combination of biotin plus thiamine versus thiamine alone. Eur J Paediatr Neurol 19:547–552

    Google Scholar 

  17. Vlasova TI, Stratton SL, Wells AM, Mock NI, Mock DM (2005) Biotin deficiency reduces expression of SLC19A3, a potential biotin transporter, in leukocytes from human blood. J Nutr 135:42–47

    Google Scholar 

  18. Banka S, de Goede C, Yue WW et al. (2014) Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations. Mol Genet Metab 113:301–306

    Google Scholar 

  19. Fraser JL, Vanderver A, Yang S et al. (2014) Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies. Mol Genet Metab Rep 1:66–70

    Google Scholar 

  20. Mayr JA, Freisinger P, Schlachter K et al. (2011) Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet 89:806–812

    Google Scholar 

  21. Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Morton DH (2002) Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. Am J Med Genet 112:318–326

    Google Scholar 

  22. Spiegel R, Shaag A, Edvardson S et al. (2009) SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann Neurol 66:419–424

    Google Scholar 

  23. Rosenberg MJ, Agarwala R, Bouffard G et al. (2002) Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet 32:175–179

    Google Scholar 

  24. Brown G (2014) Defects of thiamine transport and metabolism. J Inherit Metab Dis 37:577–585

    Google Scholar 

  25. Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U (2006) Variant maple syrup urine disease (MSUD) – the entire spectrum. J Inherit Metab Dis 29:716–724

    Google Scholar 

  26. Chuang DT, Chuang JL, Wynn RM (2006) Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr 136:243S–249S

    Google Scholar 

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

    Google Scholar 

  28. Stockler S, Plecko B, Gospe SM Jr et al. (2011) Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Gen Metab 104:48–60

    Google Scholar 

  29. Gospe SM Jr, Hecht ST (1998) Longitudinal MRI findings in pyridoxine-dependent seizures. Neurology 51:74–78

    Google Scholar 

  30. Mills PB, Struys E, Jakobs C et al. 2006) Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 12:307–309

    Google Scholar 

  31. Struys EA, Bok LA, Emal D et al. (2012) The measurement of urinary Delta(1)-piperideine-6-carboxylate, the alter ego of alpha-aminoadipic semialdehyde, in Antiquitin deficiency. J Inherit Metab Dis 35:909–916

    Google Scholar 

  32. Mercimek-Mahmutoglu S, Donner EJ, Siriwardena K (2013) Normal plasma pipecolic acid level in pyridoxine dependent epilepsy due to ALDH7A1 mutations. Mol Genet Metab 110:197

    Google Scholar 

  33. Plecko B, Paul K, Paschke E et al. (2007) Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat 28:19–26

    Google Scholar 

  34. Mefford HC, Zemel M, Geraghty E et al. (2015) Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology 85:756–762

    Google Scholar 

  35. Gallagher RC, Van Hove JL, Scharer G et al. (2009) Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol 65:550–556

    Google Scholar 

  36. Mills PB, Footitt EJ, Mills KA et al. (2010) Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain J Neurol 133:2148–2159

    Google Scholar 

  37. Coughlin CR, 2nd, van Karnebeek CD, Al-Hertani W et al. (2015) Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome. Mol Genet Metabol 116:35–43

    Google Scholar 

  38. Bok LA, Been JV, Struys EA et al. (2010) Antenatal treatment in two Dutch families with pyridoxine-dependent seizures. Eur J Pediatrics 169:297–303

    Google Scholar 

  39. 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

    Google Scholar 

  40. Flynn MP, Martin MC, Moore PT et al. (1989) Type II hyperprolinaemia in a pedigree of Irish travellers (nomads). Arch Dis Childhood 64:1699–1707

    Google Scholar 

  41. 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

    Google Scholar 

  42. Levtova A, Camuzeaux S, Laberge AM et al. (2015) Normal Cerebrospinal Fluid Pyridoxal 5’-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy. JIMD Rep 22:67–75

    Google Scholar 

  43. Kuo MF, Wang HS (2002) Pyridoxal phosphate-responsive epilepsy with resistance to pyridoxine. Pediatr Neurol 26:146–147

    Google Scholar 

  44. Brautigam C, Hyland K, Wevers R et al. (2002) Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33:113–117

    Google Scholar 

  45. Mills PB, Surtees RA, 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 14:1077–1186

    Google Scholar 

  46. Musayev FN, Di Salvo ML, Saavedra MA et al. (2009) Molecular basis of reduced pyridoxine 5’-phosphate oxidase catalytic activity in neonatal epileptic encephalopathy disorder. J Biol Chem 284:30949–30956

    Google Scholar 

  47. Mills PB, Camuzeaux SS, Footitt EJ et al. (2014) Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain J Neurol 137:1350–1360

    Google Scholar 

  48. Plecko B, Paul K, Mills P et al. (2014) Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 82:1425–1433

    Google Scholar 

  49. Sudarsanam A, Singh H, Wilcken B et al. (2014) Cirrhosis associated with pyridoxal 5’-phosphate treatment of pyridoxamine 5’-phosphate oxidase deficiency. JIMD Rep 17:67–70

    Google Scholar 

  50. Balasubramaniam S, Bowling F, Carpenter K et al. (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:S25–33

    Google Scholar 

  51. Bianchi ML (2015) Hypophosphatasia: an overview of the disease and its treatment. Osteoporosis 26:2743–2757

    Google Scholar 

  52. Horn D, Wieczorek D, Metcalfe K et al. (2014) Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome. Eur J Hum Genet 22:762–767

    Google Scholar 

  53. Cellini B, Montioli R, Oppici E, Astegno A, Voltattorni CB (2014) The chaperone role of the pyridoxal 5’-phosphate and its implications for rare diseases involving B6-dependent enzymes. Clin Biochem 47:158–165

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oxford Medical Genetics Laboratories, The Churchill Hospital, South Parks Road, OX3 7LE, Oxford, UK

    Garry Brown

  2. Division of Child Neurology, University Children’s Hospital, Steinwiesstrasse 75, 8032, Zürich, Switzerland

    Barbara Plecko

Authors
  1. Garry Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Plecko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Garry Brown or Barbara Plecko .

Editor information

Editors and Affiliations

  1. Department of Neurology, Neurometabolic Unit, Hôpital Pitié Salpêtrière, Paris, France

    Jean-Marie Saudubray

  2. Division of Metabolism, University Children’s Hospital, Zurich, Switzerland

    Matthias R. Baumgartner

  3. Willink Biochemical Genetics Unit Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK

    John Walter

  4. Central Manchester University Hospitals NHS Foundation Trust, St Mary‘s Hospital, Manchester, UK

    John Walter

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Brown, G., Plecko, B. (2016). Disorders of Thiamine and Pyridoxine Metabolism. In: Saudubray, JM., Baumgartner, M., Walter, J. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-49771-5_28

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-49771-5_28

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-49769-2

  • Online ISBN: 978-3-662-49771-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation