Journal article
NAD(P)HX dehydratase (NAXD) deficiency: A novel neurodegenerative disorder exacerbated by febrile illnesses
NJ Van Bergen, Y Guo, J Rankin, N Paczia, J Becker-Kettern, LS Kremer, A Pyle, JF Conrotte, C Ellaway, P Procopis, K Prelog, T Homfray, J Baptista, E Baple, M Wakeling, S Massey, DP Kay, A Shukla, KM Girisha, LES Lewis Show all
Brain | OXFORD UNIV PRESS | Published : 2019
DOI: 10.1093/brain/awy310
Abstract
Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevat..
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Awarded by Fonds National de la Recherche Luxembourg
Funding Acknowledgements
We thank the Crane and Perkins families and the Lions International Club Esch-sur-Alzette for donations to this research. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. J.B.K. and N.P. were supported by an AFR-PhD grant (4044610) and a CORE junior grant (C16/BM/11339953), respectively, of the Fonds National de la Recherche Luxembourg. Sequencing, data analysis and Sanger validation of one sample (Case 1) were done in the Center for Applied Genomics at the Children's Hospital of Philadelphia through research funding from Aevi Genomic Medicine Inc. This study was partly supported by the German Bundesministerium fur Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET, 01GM1113 for H.P.) and through the E-Rare project GENOMIT (01GM1603 for H.P.). H.P. is supported by EU Horizon2020 Collaborative Research Project SOUND (633974). This work was supported by grants from Instituto de Salud Carlos III (PI17/00021); Departamento de Ciencia, Tecnologia y Universidad del Gobierno de Aragon (Grupos de Referencia B33_17R). R.W.T. is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease and Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. S.E. is a Wellcome Trust Senior Investigator.