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

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.

• Authors: Nicole J Van Bergen, Yiran Guo, Julia Rankin, Nicole Paczia, Julia Becker-Kettern, Laura S Kremer, Angela Pyle, Jean-François Conrotte, Carolyn Ellaway, Peter Procopis, Kristina Prelog, Tessa Homfray, Júlia Baptista, Emma Baple, Matthew Wakeling, Sean Massey, Daniel P Kay, Anju Shukla, Katta M Girisha, Leslie E S Lewis, Saikat Santra, Rachel Power, Piers Daubeney, Julio Montoya, Eduardo Ruiz-Pesini, Reka Kovacs-Nagy, Martin Pritsch, Uwe Ahting, David R Thorburn, Holger Prokisch, Robert W Taylor, John Christodoulou, Carole L Linster, Sian Ellard, Hakon Hakonarson
• Journal: Brain : a journal of neurology (Brain) Vol. 142 Issue 1 Pg. 50-58 (01 01 2019) ISSN: 1460-2156 [Electronic] England
• PMID: 30576410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NAD
• 6-hydroxy-1,4,5,6-tetrahydronicotinamide adenine dinucleotide
• Hydro-Lyases
• NAXD protein, human

Topics

• Child, Preschool
• Computer Simulation
• Female
• Fever (complications, metabolism)
• Fibroblasts (metabolism)
• Genetic Vectors
• Humans
• Hydro-Lyases (deficiency, genetics)
• Infant
• Kinetics
• Lentivirus
• Male
• Mitochondria (metabolism)
• Mutation
• NAD (analogs & derivatives, metabolism)
• Neurodegenerative Diseases (complications, genetics, metabolism)
• Primary Cell Culture
• Whole Genome Sequencing