[en] 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Enzymology & Metabolism (Linster Group)
Disciplines :
Neurology
Author, co-author :
Van Bergen, Nicole ✱; Murdoch Children’s Research Institute, Royal Children’s Hospital ; University of Melbourne > Department of Paediatrics
Guo, Yiran ✱
Rankin, Julia ✱
PACZIA, Nicole ✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
BECKER-KETTERN, Julia ✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Kremer, Laura
Pyle, Angela
CONROTTE, Jean-François ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Ellaway, Carolyn
Procopis, Peter
Prelog, Kristina
Homfray, Tessa
Baptista, Júlia
Baple, Emma
Wakeling, Matthew
Massey, Sean
KAY, Daniel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Shukla, Anju
Girisha, Katta
Lewis, Leslie
Santra, Saikat
Power, Rachel
Daubeney, Piers
Montoya, Julio
Ruiz-Pesini
Kovacs-Nagy, Reka
Pritsch, Martin
Ahting, Uwe
Thorburn, David
Prokisch, Holger
Taylor, Robert
Christodoulou, John; Murdoch Children's Research Institutem Royal Children's Hospital ; University of Melbourne > Department of Paediatrics
LINSTER, Carole ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)