2. Academic Validation
  3. PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation

  • Ann Neurol. 2019 Aug;86(2):225-240. doi: 10.1002/ana.25524.
Viorica Chelban 1 2,  Matthew P Wilson 3,  Jodi Warman Chardon 4 5 6,  Jana Vandrovcova 1,  M Natalia Zanetti 7,  Eleni Zamba-Papanicolaou 8 9,  Stephanie Efthymiou 1,  Simon Pope 10,  Maria R Conte 11,  Giancarlo Abis 11,  Yo-Tsen Liu 12 13 14,  Eloise Tribollet 1,  Nourelhoda A Haridy 1 15,  Juan A Botía 16 17,  Mina Ryten 16 18,  Paschalis Nicolaou 8 9,  Anna Minaidou 8 9,  Kyproula Christodoulou 8 9,  Kristin D Kernohan 6 19,  Alison Eaton 6,  Matthew Osmond 6,  Yoko Ito 6,  Pierre Bourque 4 5,  James E C Jepson 7,  Oscar Bello 7,  Fion Bremner 20,  Carla Cordivari 21,  Mary M Reilly 1,  Martha Foiani 21 22,  Amanda Heslegrave 22 23,  Henrik Zetterberg 22 23 24 25,  Simon J R Heales 10,  Nicholas W Wood 1 26,  James E Rothman 7 27,  Kym M Boycott 6,  Philippa B Mills 3,  Peter T Clayton 3,  Henry Houlden 1 26,  Care4Rare Canada Consortium and the SYNaPS Study Group 6
Affiliations

Affiliations

  • 1 Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, United Kingdom.
  • 2 Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Chisinau, Moldova.
  • 3 Genetics and Genomic Medicine, University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
  • 4 Department of Medicine (Neurology), University of Ottawa, Ottawa, Ontario, Canada.
  • 5 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • 6 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
  • 7 Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom.
  • 8 Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
  • 9 Cyprus School of Molecular Medicine, Nicosia, Cyprus.
  • 10 Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
  • 11 Randall Centre of Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London, United Kingdom.
  • 12 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 13 National Yang-Ming University School of Medicine, Taipei, Taiwan.
  • 14 Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
  • 15 Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Asyut, Egypt.
  • 16 Reta Lila Weston Research Laboratories, University College London Queen Square Institute of Neurology, London, United Kingdom.
  • 17 Department of Information and Communications Engineering, University of Murcia, Murcia, Spain.
  • 18 Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom.
  • 19 Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • 20 Neuro-ophthalmology Department, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
  • 21 Clinical Neurophysiology Department, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
  • 22 Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, United Kingdom.
  • 23 UK Dementia Research Institute at University College London, London, United Kingdom.
  • 24 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  • 25 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
  • 26 Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
  • 27 Department of Cell Biology, Yale School of Medicine, New Haven, CT.
PMID: 31187503 DOI: 10.1002/ana.25524
Abstract

Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.

Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification.

Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant Enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization.

Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240.

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