Abstract
ObjectiveTo identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy.MethodsWe 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.ResultsWe 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.InterpretationWe 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
Highlights
IntroductionResearch Institute, Ottawa, Ontario, Canada; 6Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; 7Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom; 8Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 9Cyprus School of Molecular Medicine, Nicosia, Cyprus; 10Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 11Randall Centre of Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London, London, United Kingdom; 12Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; 13National Yang-Ming University School of Medicine, Taipei, Taiwan; 14Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 15Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Asyut, Egypt; 16Reta Lila Weston Research Laboratories, University College London Queen Square Institute of Neurology, London, United Kingdom; 17Department of Information and Communications Engineering, University of Murcia, Murcia, Spain; 18Department of Medical & Molecular Genetics, King’s College London, Guy’s Hospital, London, United Kingdom; 19Newborn Screening Ontario, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 20Neuro-ophthalmology Department, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 21Clinical Neurophysiology Department, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 22Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, United Kingdom; 23UK Dementia Research Institute at University College London, London, United Kingdom; 24Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; 25Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; 26Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom; and 27Department of Cell Biology, Yale School of Medicine, New Haven, CT
We show that biallelic mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low pyridoxal 50phosphate (PLP)
We show that the biochemical profile in affected individuals can be rescued with PLP supplementation and that this is associated with improvement in clinical scales
Summary
Research Institute, Ottawa, Ontario, Canada; 6Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; 7Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom; 8Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 9Cyprus School of Molecular Medicine, Nicosia, Cyprus; 10Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 11Randall Centre of Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London, London, United Kingdom; 12Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; 13National Yang-Ming University School of Medicine, Taipei, Taiwan; 14Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 15Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Asyut, Egypt; 16Reta Lila Weston Research Laboratories, University College London Queen Square Institute of Neurology, London, United Kingdom; 17Department of Information and Communications Engineering, University of Murcia, Murcia, Spain; 18Department of Medical & Molecular Genetics, King’s College London, Guy’s Hospital, London, United Kingdom; 19Newborn Screening Ontario, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 20Neuro-ophthalmology Department, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 21Clinical Neurophysiology Department, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 22Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, United Kingdom; 23UK Dementia Research Institute at University College London, London, United Kingdom; 24Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; 25Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; 26Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, London, United Kingdom; and 27Department of Cell Biology, Yale School of Medicine, New Haven, CT
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