000086438 001__ 86438
000086438 005__ 20200716101453.0
000086438 0247_ $$2doi$$a10.1093/brain/awy310
000086438 0248_ $$2sideral$$a109754
000086438 037__ $$aART-2019-109754
000086438 041__ $$aeng
000086438 100__ $$aVan Bergen, N.J.
000086438 245__ $$aNAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses
000086438 260__ $$c2019
000086438 5060_ $$aAccess copy available to the general public$$fUnrestricted
000086438 5203_ $$aPhysical 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.
000086438 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B33-17R$$9info:eu-repo/grantAgreement/ES/ISCIII/PI17-00021
000086438 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000086438 590__ $$a11.337$$b2019
000086438 591__ $$aNEUROSCIENCES$$b13 / 271 = 0.048$$c2019$$dQ1$$eT1
000086438 591__ $$aCLINICAL NEUROLOGY$$b6 / 204 = 0.029$$c2019$$dQ1$$eT1
000086438 592__ $$a5.408$$b2019
000086438 593__ $$aNeurology (clinical)$$c2019$$dQ1
000086438 593__ $$aMedicine (miscellaneous)$$c2019$$dQ1
000086438 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000086438 700__ $$aGuo, Y.
000086438 700__ $$aRankin, J.
000086438 700__ $$aPaczia, N.
000086438 700__ $$aBecker-Kettern, J.
000086438 700__ $$aKremer, L.S.
000086438 700__ $$aPyle, A.
000086438 700__ $$aConrotte, J.F.
000086438 700__ $$aEllaway, C.
000086438 700__ $$aProcopis, P.
000086438 700__ $$aPrelog, K.
000086438 700__ $$aHomfray, T.
000086438 700__ $$aBaptista, J.
000086438 700__ $$aBaple, E.
000086438 700__ $$aWakeling, M.
000086438 700__ $$aMassey, S.
000086438 700__ $$aKay, D.P.
000086438 700__ $$aShukla, A.
000086438 700__ $$aGirisha, K.M.
000086438 700__ $$aLewis, L.E.S.
000086438 700__ $$aSantra, S.
000086438 700__ $$aPower, R.
000086438 700__ $$aDaubeney, P.
000086438 700__ $$0(orcid)0000-0003-1770-6299$$aMontoya, J.$$uUniversidad de Zaragoza
000086438 700__ $$0(orcid)0000-0002-0269-7337$$aRuiz-Pesini, E.$$uUniversidad de Zaragoza
000086438 700__ $$aKovacs-Nagy, R.
000086438 700__ $$aPritsch, M.
000086438 700__ $$aAhting, U.
000086438 700__ $$aThorburn, D.R.
000086438 700__ $$aProkisch, H.
000086438 700__ $$aTaylor, R.W.
000086438 700__ $$aChristodoulou, J.
000086438 700__ $$aLinster, C.L.
000086438 700__ $$aEllard, S.
000086438 700__ $$aHakonarson, H.
000086438 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000086438 773__ $$g142, 1 (2019), 50-58$$pBrain$$tBrain$$x0006-8950
000086438 8564_ $$s372289$$uhttps://zaguan.unizar.es/record/86438/files/texto_completo.pdf$$yPostprint
000086438 8564_ $$s113907$$uhttps://zaguan.unizar.es/record/86438/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000086438 909CO $$ooai:zaguan.unizar.es:86438$$particulos$$pdriver
000086438 951__ $$a2020-07-16-09:07:51
000086438 980__ $$aARTICLE