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 V max and increase in K M 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.

NAXD Deficiency Associated with Perinatal Autoinflammation, Pancytopenia, Dermatitis, Colitis, and Cystic Encephalomalacia

“…Here, we report the fulminant course of NAXD deficiency in a neonate presenting with severe clinical signs of autoinflammation, necrotizing dermatitis, ulcerative colitis, pancytope-nia, and cystic encephalomalacia. Unlike previously described cases with NAXD deficiency, who presented with first symptoms between 3 months and 3 years of age, 10,11 the patient developed disease already in the third week of life. NAD(P)HX dehydratase encoded by the NAXD gene is an ubiquitously expressed integral component of the mitochondrial matrix involved in an essential metabolite repair system that removes toxic NAD(P)HX side products.…”

Unexpected NADPH Hydratase Activity in the Nitrile Reductase QueF from Escherichia coli

“…Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) catalyzes the conversion of NADH to NADHX, but no analogous enzymatic transformation of NADPH has yet been reported. Discovery of an enzymatic equivalent of the acid‐catalyzed degradation of NADPH might have biological significance . Knowing the enzymes other than GAPDH that could play a role in the formation of NAD(P)HX is therefore important.…”

Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle

“…Bacteria, yeast, and plants show subtle phenotypes and can survive without functional NAD(P)HX repair systems [18,105,106]. In humans, NAXD or NAXE inactivating mutations cause severe encephalopathy and early childhood death [17,107,108].…”

“…Enzymatic activities involved in metabolite repair or metabolite damage preemption can collectively be referred to as metabolite damage control systems. The physiological importance of metabolite damage and its repair or preemption has been revealed over the past ~ 15 years as a handful of metabolic diseases in humans were discovered to be caused by disruption of metabolite damage control systems [15‐17]. Further, many metabolite damage control systems are highly conserved across the three domains of life [18,19], indicating that they arose early in life’s history and were invariably maintained in diverse species.…”