PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation. Issue 2 (1st July 2019)

• Record Type: Journal Article
• Authors: 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;
• Other Names: Kriouile Yamna investigator.; Khorassani Mohamed El investigator.; Aguennouz Mhammed investigator.; Groppa Stanislav investigator.; Marinova Karashova Blagovesta investigator.; Van Maldergem Lionel investigator.; Nachbauer Wolfgang investigator.; Boesch Sylvia investigator.; Arning Larissa investigator.; Timmann Dagmar investigator.; Cormand Bru investigator.; Pérez‐Dueñas Belen investigator.; Di Rosa Gabriella investigator.; Goraya Jatinder S. investigator.; Sultan Tipu investigator.; Mine Jun investigator.; Avdjieva Daniela investigator.; Kathom Hadil investigator.; Tincheva Radka investigator.; Banu Selina investigator.; Pineda‐Marfa Mercedes investigator.; Veggiotti Pierangelo investigator.; Ferrari Michel D. investigator.; van den Maagdenberg Arn M J M investigator.; Verrotti Alberto investigator.; Marseglia Giangluigi investigator.; Savasta Salvatore investigator.; García‐Silva Mayte investigator.; Ruiz Alfons Macaya investigator.; Garavaglia Barbara investigator.; Borgione Eugenia investigator.; Portaro Simona investigator.; Sanchez Benigno Monteagudo investigator.; Boles Richard investigator.; Papacostas Savvas investigator.; Vikelis Michail investigator.; Rothman James investigator.; Giunti Paola investigator.; Houlden Henry investigator.; Chelban Viorica investigator.; Salpietro Vincenzo investigator.; Oconnor Emer investigator.; Efthymiou Stephanie investigator.; Kullmann Dimitri investigator.; Kaiyrzhanov Rauan investigator.; Sullivan Roisin investigator.; Khan Alaa Matooq investigator.; Yau Wai Yan investigator.; Hostettler Isabel investigator.; Papanicolaou Eleni Zamba investigator.; Dardiotis Efthymios investigator.; Maqbool Shazia investigator.; Ibrahim Shahnaz investigator.; Kirmani Salman investigator.; Rana Nuzhat Noureen investigator.; Atawneh Osama investigator.; Lim Shen‐Yang investigator.; Shaikh Farooq investigator.; Koutsis George investigator.; Breza Marianthi investigator.; Mangano Salvatore investigator.; Scuderi Carmela investigator.; Borgione Eugenia investigator.; Morello Giovanna investigator.; Stojkovic Tanya investigator.; Torti Erin investigator.; Zollo Massimi investigator.; Heimer Gali investigator.; Dauvilliers Yves A. investigator.; Striano Pasquale investigator.; Al‐Khawaja Issam investigator.; Al‐Mutairi Fuad investigator.; Alkuraya Fowzan S investigator.; Sherifa Hamed investigator.; Rizig Mie investigator.; Okubadejo Njideka U. investigator.; Ojo Oluwadamilola O. investigator.; Oshinaike Olajumoke O. investigator.; Wahab Kolawole investigator.; Bello Abiodun H. investigator.; Abubakar Sanni investigator.; Obiabo Yahaya investigator.; Nwazor Ernest investigator.; Ekenze Oluchi investigator.; Williams Uduak investigator.; Iyagba Alagoma investigator.; Taiwo Lolade investigator.; Komolafe Morenikeji investigator.; Oguntunde Olapeju investigator.; Pchelina Sofya investigator.; Senkevich Konstantin investigator.; Haridy Nourelhoda investigator.; Shashkin Chingiz investigator.; Zharkynbekova Nazira investigator.; Koneyev Kairgali investigator.; Manizha Ganieva investigator.; Isrofilov Maksud investigator.; Guliyeva Ulviyya investigator.; Salayev Kamran investigator.; Khachatryan Samson investigator.; Rossi Salvatore investigator.; Silvestri Gabriella investigator.; Bourinaris Thomas investigator.; Xiromerisiou Georgia investigator.; Fidani Liana investigator.; Spanaki Cleanthe investigator.; Tucci Arianna investigator.;
• Is Part Of: Annals of neurology. Volume 86:Issue 2(2019)
• Page Start: 225
• Page End: 240
• Publication Date: 2019-07-01
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.25524
• Languages: English
• ISSNs: 0364-5134

Abstract

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 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