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

Research output: Contribution to journalArticle

Viorica Chelban, Matthew P. Wilson, Jodi Warman Chardon, Jana Vandrovcova, M. Natalia Zanetti, Eleni Zamba-papanicolaou, Stephanie Efthymiou, Simon Pope, Maria R Conte, Giancarlo Abis, Yo-tsen Liu, Eloise Tribollet, Nourelhoda A. Haridy, Juan A Botía, Mina Ryten, Paschalis Nicolaou, Anna Minaidou, Kyproula Christodoulou, Kristin D. Kernohan, Alison Eaton & 18 more Matthew Osmond, Yoko Ito, Pierre Bourque, James E.C. Jepson, Oscar Bello, Fion Bremner, Carla Cordivari, Mary M. Reilly, Martha Foiani, Amanda Heslegrave, Henrik Zetterberg, Simon J.R. Heales, Nicholas W. Wood, James E. Rothman, Kym M Boycott, Philippa B. Mills, Peter T. Clayton, Henry Houlden

Original languageEnglish
Pages (from-to)225-240
Number of pages16
JournalAnnals of Neurology
Volume86
Issue number2
Early online date11 Jun 2019
DOIs
Publication statusPublished - 1 Aug 2019

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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 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 bi‐allelic mutations in PDXK in five individuals from two 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 one family, improvement in power, pain and fatigue contributing to patients regaining their ability to ambulate 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 aetiology characterised by reduced PLP levels.

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