Portal de Periódicos da CAPES

Tournaments

2019; Wiley; Volume: 26; Issue: S1 Linguagem: Inglês

10.1111/ene.14023

1468-1331

Viorica Chelban, Michael L. Wilson, Jana Vandrovcová, Nadia Zanetti, Eleni Zamba‐Papanicolaou, Stéphanie Efthymiou, S Pope, Marisa Conte, Kyproula Christodoulou, Paschalis Nicolaou, Anna Minaidou, Marco Foiani, Henrik Zetterberg, Nicholas Wood, James E. Rothman, Philippa B. Mills, Peter T. Clayton, Henry Houlden, Raffaele Dubbioso, Stefano Tozza, Sirio Cocozza, Daniele Severi, Maria Nolano, Giuseppe Pontillo, Lucio Santoro, Fiore Manganelli, Erik Ellwardt, Dirk Luchtman, Frauke Zipp, Stefan Bittner, Heather Wilson, George Dervenoulas, Gennaro Pagano, Robin J. Tyacke, J. M. Myers, Roger N. Gunn, Eugenii A. Rabiner, David Nutt, Marios Politis, Ermelinda De Meo, Lucia Moiola, Maria Pia Amato, Angelo Ghezzi, Pierangelo Veggiotti, Ruggero Capra, Massimo Filippi, Maria A. Rocca, M Moseby Knappe, Erik Westhall, Steven B. Backman, Irina Dragancea, Hans Friberg, Niklas Nielsen, Janneke Horn, Jesper Kjærgaard, Tobias Cronberg,

Sports Analytics and Performance

Background and aims: Peripheral neuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people.No diseasemodifying treatment has been established in these conditions where 40% of patients with primary peripheral neuropathies have no disease-causing mutation identified.Methods: 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 patientderived fibroblasts, plasma and erythrocytes.We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the ATP binding.Results: We report that biallelic mutations in human PDXK are associated with primary axonal polyneuropathy and optic atrophy, characterised by blindness and severe muscle weakness leading to patients becoming wheelchair-bound.Pyridoxal kinase (PDXK) is converting vitamin B6to 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 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 to normalisation of plasma PLP levels, correlated with reduction of neurofilament light chain concentrations, an axonal breakdown biomarker. Conclusion: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.