NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses

Brain. 2019 Jan 1;142(1):50-58. doi: 10.1093/brain/awy310.

Nicole J Van Bergen ¹ ², Yiran Guo ³, Julia Rankin ⁴ ⁵, Nicole Paczia ⁶, Julia Becker-Kettern ⁶, Laura S Kremer ⁷ ⁸, Angela Pyle ⁹, Jean-François Conrotte ⁶, Carolyn Ellaway ¹⁰ ¹¹ ¹², Peter Procopis ¹² ¹³, Kristina Prelog ¹⁴, Tessa Homfray ¹⁵, Júlia Baptista ⁴ ⁵, Emma Baple ⁴ ⁵, Matthew Wakeling ⁴, Sean Massey ¹, Daniel P Kay ⁶, Anju Shukla ¹⁶, Katta M Girisha ¹⁶, Leslie E S Lewis ¹⁷, Saikat Santra ¹⁸, Rachel Power ¹⁹, Piers Daubeney ¹⁹ ²⁰, Julio Montoya ²¹, Eduardo Ruiz-Pesini ²¹, Reka Kovacs-Nagy ⁷ ²², Martin Pritsch ²³, Uwe Ahting ⁷, David R Thorburn ¹ ² ²⁴, Holger Prokisch ⁷ ⁸, Robert W Taylor ⁹, John Christodoulou ¹ ² ¹⁰ ¹¹ ²⁴, Carole L Linster ⁶, Sian Ellard ⁴ ⁵, Hakon Hakonarson ³

Affiliations

1 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia.
2 Department of Paediatrics, University of Melbourne, Parkville, Melbourne, Australia.
3 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA USA.
4 University of Exeter Medical School, Exeter, UK.
5 Royal Devon Exeter NHS Foundation Trust, Exeter, UK.
6 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.
7 Institute of Human Genetics, Technische Universität München, Munich, Germany.
8 Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.
9 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
10 Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
11 Discipline of Genetic Medicine, University of Sydney, Sydney, Australia.
12 Neurology Department, Children's Hospital at Westmead, Sydney, Australia.
13 Discipline of Child and Adolescent Health, University of Sydney, Australia.
14 Medical Imaging Department, Children's Hospital at Westmead, Sydney, Australia.
15 Royal Brompton and St George's University Hospital, London, UK.
16 Department of Medical Genetics, Kasturba Medical College and Hospital, Manipal Academy of Higher Education, Manipal, India.
17 Department of Paediatrics, Kasturba Medical College and Hospital, Manipal Academy of Higher Education, Manipal, India.
18 Birmingham Children's Hospital, Birmingham, UK.
19 Royal Brompton Hospital, London, UK.
20 National Heart and Lung Institute, Imperial College, London, UK.
21 Departamento de Bioquimica y Biologia Molecular y Celular- CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón (IISAragon), Universidad Zaragoza, Zaragoza, Spain.
22 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
23 Department of Pediatric Neurology, DRK-Childrens-Hospital, Siegen, Germany.
24 Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia.

PMID: 30576410 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 elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial Reactive Oxygen Species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

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