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15.09 Inherited peripheral neuropathies: analysis of PDXK gene identifies a new treatable disorder
  1. Viorica Chelban1,2,
  2. Matthew P Wilson3#,
  3. Jodi Warman Chardon4,5,6#,
  4. Jana Vandrovcova1#,
  5. M Natalia Zanetti7,
  6. Eleni Zamba-Papanicolaou8,9,
  7. Stephanie Efthymiou1,
  8. Simon Pope10,
  9. Maria R Conte11,
  10. Giancarlo Abis11,
  11. Yo-Tsen Liu12,13,14,
  12. Eloise Tribollet1,
  13. Nourelhoda A Haridy1,15,
  14. Juan A Botía16,17,
  15. Mina Ryten16,18,
  16. Paschalis Nicolaou8,9,
  17. Anna Minaidou8,9,
  18. Kyproula Christodoulou8,9,
  19. Kristin D Kernohan6,19,
  20. Alison Eaton6,
  21. Matthew Osmond6,
  22. Yoko Ito6,
  23. Pierre Bourque4,5,
  24. James EC Jepson7,
  25. Oscar Bello7,
  26. Fion Bremner20,
  27. Carla Cordivari21,
  28. Mary M Reilly1,
  29. Martha Foiani21,22,
  30. Amanda Heslegrave22,23,
  31. Henrik Zetterberg22,23,24,25,
  32. Simon JR Heales10,
  33. Nicholas W Wood1,26,
  34. James E Rothman7,27,
  35. Kym M Boycott6,
  36. Philippa B Mills3#,
  37. Peter T Clayton3#,
  38. Henry Houlden1,26#
  1. 1Department of Neuromuscular Diseases
  2. 2Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Toma Ciorbă 1, 2052 Chisinau, Republic of Moldova
  3. 3Genetics and Genomic Medicine, GOS Institute of Child Health, University College London, London WC1N 1EH
  4. 4Department of Medicine (Neurology), University of Ottawa
  5. 5Ottawa Hospital Research Institute
  6. 6Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, K1H 8L1, Canada Ontario, Canada
  7. 7Department of Clinical and Experimental Epilepsy
  8. 8The Cyprus Institute of Neurology and Genetics
  9. 9Cyprus School of Molecular Medicine Nicosia, Cyprus
  10. 10Neurometabolic Unit
  11. 11Randall Centre of Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London, London SE1 1UL, UK
  12. 12Department of Neurology, Neurological Institute, Taipei Veterans General Hospital
  13. 13National Yang-Ming University School of Medicine
  14. 14Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
  15. 15Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt
  16. 16Reta Lila Weston Research Laboratories
  17. 17Department of Information and Communications Engineering, University of Murcia, Campus Espinardo, 30100 Murcia, Spain
  18. 18Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, SE1 9RT, London, UK
  19. 19Newborn Screening Ontario, Children’s Hospital of Eastern Ontario, Ottawa, Canada
  20. 20Neuro-ophthalmology Department
  21. 21Clinical Neurophysiology Department
  22. 22Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
  23. 23UK Dementia Research Institute at UCL, London WC1N 3BG, UK
  24. 24Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden
  25. 25Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden
  26. 26Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
  27. 27Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520-8002, USA
  28. #These authors contributed equally to the work

Abstract

Polyneuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people. However, 40% of patients with primary polyneuropathies have no disease-causing mutation identified.

We investigated patients with gene-negative primary polyneuropathies using a combination of whole genome sequencing, homozygosity mapping and segregation analysis. Pathogenicity was confirmed via enzymatic assays and mass spectroscopy on recombinant protein and patient-derived fibroblasts, plasma and erythrocytes. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the ATP binding.

We report that biallelic mutations in human PDXK are associated with primary axonal polyneuropathy and optic atrophy. Pyridoxal kinase (PDXK) is involved in converting vitamin B6 to its active form, pyridoxal 5’-phosphate (PLP). We show that PDXK mutations lead to disease via decreased plasma PLP concentrations. Our functional studies revealed conformational rearrangement in the mutant enzyme around the kinase ATP-binding pocket with impaired PDXK ability to bind ATP and leading to reduced erythrocyte PDXK activity. We show that both the human clinical picture and biochemical profile in PDXK mutations are rescued by PLP supplementation. Patients regained their ability to walk independently. Furthermore, treatment-led normalisation of plasma PLP levels, correlated with reduction of neurofilament light chain concentrations, a biomarker of axonal breakdown.

In conclusion, biallelic mutations in human PDXK are associated with a novel disorder leading to treatable primary axonal polyneuropathy and optic atrophy and identifies PLP as therapeutic target.

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