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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation
Annals of Neurology, Volume 86, No. 2, Year 2019
Notification
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Description
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. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC6772106/bin/ANA-86-225-s001.docx
https://efashare.b-cdn.net/share/pmc/articles/PMC6772106/bin/ANA-86-225-s002.mp4
Authors & Co-Authors
Chelban, Viorica
United Kingdom, London
Ucl Queen Square Institute of Neurology
Moldova, Chisinau
Institute of Emergency Medicine
Wilson, Matthew P.
United Kingdom, London
University College London
Warman-Chardon, Jodi P.
Canada, Ottawa
University of Ottawa
Canada, Ottawa
Ottawa Hospital Research Institute
Vandrovcova, J.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Zanetti, María Natalia
United Kingdom, London
Ucl Queen Square Institute of Neurology
Zamba-Papanicolaou, Eleni
Cyprus, Nicosia
Cyprus Institute of Neurology and Genetics
Efthymiou, Stephanie
United Kingdom, London
Ucl Queen Square Institute of Neurology
Pope, Simon A.S.
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Conte, Maria R.
United Kingdom, London
Faculty of Life Sciences & Medicine
Abis, Giancarlo
United Kingdom, London
Faculty of Life Sciences & Medicine
Liu, Yotsen
Taiwan, Taipei
Taipei Veterans General Hospital
Taiwan, Taipei
National Yang-ming University Taiwan
Tribollet, Eloise
United Kingdom, London
Ucl Queen Square Institute of Neurology
Haridy, Nourelhoda A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Egypt, Asyut
Assiut University
Botia, Juan A.
United Kingdom, London
Reta Lila Weston Institute of Neurological Studies
Spain, Murcia
Universidad de Murcia
Ryten, Mina
United Kingdom, London
Reta Lila Weston Institute of Neurological Studies
United Kingdom, London
King's College London
Nicolaou, Paschalis
Cyprus, Nicosia
Cyprus Institute of Neurology and Genetics
Minaidou, Anna
Cyprus, Nicosia
Cyprus Institute of Neurology and Genetics
Christodoulou, Kyproula
Cyprus, Nicosia
Cyprus Institute of Neurology and Genetics
Kernohan, Kristin D.
Canada, Ottawa
University of Ottawa
Canada, Ottawa
Children's Hospital of Eastern Ontario, Ottawa
Eaton, Alison J.
Canada, Ottawa
University of Ottawa
Osmond, Matthew
Canada, Ottawa
University of Ottawa
Ito, Yoko A.
Canada, Ottawa
University of Ottawa
Bourque, Pierre Raymond J.
Canada, Ottawa
University of Ottawa
Canada, Ottawa
Ottawa Hospital Research Institute
Jepson, James E.C.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Bello, Oscar
United Kingdom, London
Ucl Queen Square Institute of Neurology
Bremner, Fion D.
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Cordivari, Carla
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Reilly, Mary M.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Foiani, Martha S.
United Kingdom, London
National Hospital for Neurology and Neurosurgery
United Kingdom, London
Ucl Queen Square Institute of Neurology
Heslegrave, Amanda J.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
University College London
Zetterberg, Henrik H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
University College London
Sweden, Gothenburg
Sahlgrenska Universitetssjukhuset
Sweden, Gothenburg
Göteborgs Universitet
Heales, Simon J.R.
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Wood, Nick William
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Rothman, James E.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United States, New Haven
Yale School of Medicine
Boycott, Kym M.
Canada, Ottawa
University of Ottawa
Mills, Philippa B.
United Kingdom, London
University College London
Clayton, Peter T.
United Kingdom, London
University College London
Houlden, Henry H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
National Hospital for Neurology and Neurosurgery
Kriouile, Y.
Unknown Affiliation
El-Khorassani, Mohammed
Unknown Affiliation
Aguennouz, M’Hammed H.
Unknown Affiliation
Groppa, Stanislav A.
Unknown Affiliation
Marinova Karashova, Blagovesta
Unknown Affiliation
Van-Maldergem, Lionel
Unknown Affiliation
Nachbauer, Wolfgang
Unknown Affiliation
Boesch, Sylvia M.
Unknown Affiliation
Arning, Larissa
Unknown Affiliation
Timmann, Dagmar
Unknown Affiliation
Cormand, Bru
Unknown Affiliation
Pérez-Dueñas, Belén
Unknown Affiliation
Di Rosa, Gabriella
Unknown Affiliation
Goraya, Jatinder Singh
Unknown Affiliation
Sultan, Tipu
Unknown Affiliation
Mine, Jyun
Unknown Affiliation
Avdjieva - Tzavella, Daniela Mircheva
Unknown Affiliation
Kathom, Hadil Mohamed
Unknown Affiliation
Tincheva, Radka Stefanova
Unknown Affiliation
Banu, Selina H.
Unknown Affiliation
Pineda-Marfà, Mercedes
Unknown Affiliation
Veggiotti, Pierangelo
Unknown Affiliation
Ferrari, Michel Dominique
Unknown Affiliation
van den Maagdenberg, Arn Mjm
Unknown Affiliation
Verrottï, Alberto
Unknown Affiliation
Marseglia, Gian Luigi
Unknown Affiliation
Savasta, Salvatore M.
Unknown Affiliation
García-Silva, Mayte
Unknown Affiliation
Ruiz, Alfons Macaya
Unknown Affiliation
Garavaglia, Barbara M.
Unknown Affiliation
Borgione, Eugenia
Unknown Affiliation
Portaro, Simona
Unknown Affiliation
Sanchez, Benigno Monteagudo
Unknown Affiliation
Boles, Richard G.
Unknown Affiliation
Papacostas, Savvas S.
Unknown Affiliation
Vikelis, Michail
Unknown Affiliation
Giunti, Paola
Unknown Affiliation
Salpietro, Vincenzo Damiano
Unknown Affiliation
O’Connor, Emer
Unknown Affiliation
Kullmann, Dimitri M.
Unknown Affiliation
Kaiyrzhanov, Rauan
Unknown Affiliation
Sullivan, Roisin
Unknown Affiliation
Khan, Alaa Matooq
Unknown Affiliation
Yau, Wai Yan
Unknown Affiliation
Charlotte Hostettler, Isabel
Unknown Affiliation
Papanicolaou, Eleni Zamba
Unknown Affiliation
Dardiotis, Efthymios
Unknown Affiliation
Maqbool, Shazia
Unknown Affiliation
Ibrahim, Shahnaz Hamid
Unknown Affiliation
Kirmani, Salman
Unknown Affiliation
Rana, Nuzhat Noureen
Unknown Affiliation
Atawneh, Osama M.
Unknown Affiliation
Lim, Shenyang
Unknown Affiliation
Shaikh, Mohd Farooq
Unknown Affiliation
Koutsis, Georgios
Unknown Affiliation
Breza, Marianthi
Unknown Affiliation
Mangano, Salvatore
Unknown Affiliation
Scuderi, Carmela
Unknown Affiliation
Morello, Giovanna
Unknown Affiliation
Stojkovic, Tanya
Unknown Affiliation
Torti, Erin E.
Unknown Affiliation
ZOLLO, M.
Unknown Affiliation
Heimer, Gali
Unknown Affiliation
Dauvilliers, Yves A.
Unknown Affiliation
Striano, Pasquale
Unknown Affiliation
Al-Khawaja, Issam
Unknown Affiliation
Al-Mutairi, Fuad
Unknown Affiliation
Alkuraya., Fowzan S.
Unknown Affiliation
Hamed, Sherifa Ahmed
Unknown Affiliation
Rizig, Mie A.
Unknown Affiliation
Okubadejo, Njideka U.
Unknown Affiliation
Ojo, Oluwadamilola Omolara
Unknown Affiliation
Wahab, Kolawole Wasiu
Unknown Affiliation
Bello, Abiodun Hamzat
Unknown Affiliation
Obiabo, Yahaya Olugbo
Unknown Affiliation
Nwazor, Ernest Okwundu
Unknown Affiliation
Ekenze, Oluchi S.
Unknown Affiliation
Williams, Uduak Effiong
Unknown Affiliation
Iyagba, Alagoma M.
Unknown Affiliation
Komolafe, Morenikeji Adeyoyin
Unknown Affiliation
Oguntunde, Olapeju Funke
Unknown Affiliation
Senkevich, Konstantin
Unknown Affiliation
Shashkin, Chingiz
Unknown Affiliation
Zharkinbekova, N. A.
Unknown Affiliation
Koneyev, Kairgali
Unknown Affiliation
Manizha, Ganieva
Unknown Affiliation
Isrofilov, Maksud
Unknown Affiliation
Guliyeva, Ulviyya
Unknown Affiliation
Salayev, Kamran A.
Unknown Affiliation
Khachatryan, Samson G.
Unknown Affiliation
Silvestri, Gabriella
Unknown Affiliation
Bourinaris, Thomas
Unknown Affiliation
Xiromerisiou, Georgia
Unknown Affiliation
Fidani, Liana
Unknown Affiliation
Spanaki, Cleanthe
Unknown Affiliation
Tucci, Arianna
Unknown Affiliation
Statistics
Citations: 61
Authors: 134
Affiliations: 18
Identifiers
Doi:
10.1002/ana.25524
ISSN:
03645134
Research Areas
Disability
Genetics And Genomics
Health System And Policy