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272 Inherited peripheral neuropathies: analysis of PDXK gene identifies a new treatable disorder
  1. Viorica Chelban1,
  2. Matthew Wilson2,
  3. Natalia Zanetti3,
  4. Eleni Zamba-Papanicolaou4,
  5. Maria Conte5,
  6. Carla Cordivari6,
  7. Philippa Mills2,
  8. Nicholas Wood1,
  9. Peter Clayton2,
  10. Henry Houlden1
  1. 1Department of Neuromuscular Diseases, UCL Institute of Neurology
  2. 2Genetics and Genomic Medicine, GOS Institute of Child Health, UCL
  3. 3Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology
  4. 4The Cyprus Institute of Neurology and Genetics
  5. 5Randall Centre of Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College
  6. 6Clinical Neurophysiology Department National Hospital for Neurology and Neurosurgery


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, homozigosity 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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