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dc.contributor.authorVan Bergen, NJ
dc.contributor.authorGuo, Y
dc.contributor.authorRankin, J
dc.contributor.authorPaczia, N
dc.contributor.authorBecker-Kettern, J
dc.contributor.authorKremer, LS
dc.contributor.authorPyle, A
dc.contributor.authorConrotte, J
dc.contributor.authorEllaway, CJ
dc.contributor.authorProcopis, P
dc.contributor.authorPrelog, K
dc.contributor.authorHomfray, T
dc.contributor.authorBaptista, J
dc.contributor.authorBaple, E
dc.contributor.authorWakeling, M
dc.contributor.authorMassey, S
dc.contributor.authorKay, DP
dc.contributor.authorShukla, A
dc.contributor.authorGirisha, KM
dc.contributor.authorLewis, LES
dc.contributor.authorSantra, SD
dc.contributor.authorPower, R
dc.contributor.authorDaubeney, P
dc.contributor.authorMontoya, J
dc.contributor.authorRuiz-Pesini, E
dc.contributor.authorKovacs-Nagy, R
dc.contributor.authorPritsch, M
dc.contributor.authorAhting, U
dc.contributor.authorThorburn, DR
dc.contributor.authorProkisch, H
dc.contributor.authorTaylor, R
dc.contributor.authorChristodoulou, J
dc.contributor.authorLinster, C
dc.contributor.authorEllard, S
dc.contributor.authorHakonarson, H

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 SNADHX, 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.

dc.titleNAXDmutations cause a novel neurodegenerative disorder exacerbated by febrile illnesses
dc.typeMeeting Abstract
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.rights.embargoperiodNot known
rioxxterms.typeConference Paper/Proceeding/Abstract

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