PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.
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Chelban Viorica, Wilson Matthew P, Warman Chardon Jodi, Vandrovcova Jana, Zanetti M Natalia, Zamba-Papanicolaou Eleni, Efthymiou Stephanie, Pope Simon, Conte Maria R, Abis Giancarlo, Liu Yo-Tsen, Tribollet Eloise, Haridy Nourelhoda A, Botía Juan A, Ryten Mina, Nicolaou Paschalis, Minaidou Anna, Christodoulou Kyproula, Kernohan Kristin D, Eaton Alison, Osmond Matthew, Ito Yoko, Bourque Pierre, Jepson James E C, Bello Oscar, Bremner Fion, Cordivari Carla, Reilly Mary M, Foiani Martha, Heslegrave Amanda, Zetterberg Henrik, Heales Simon J R, Wood Nicholas W, Rothman James E, Boycott Kym M, Mills Philippa B, Clayton Peter T, Houlden Henry, Care4Rare Canada Consortium and the SYNaPS Study Group
Аннотация
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.