Naxd-KO Mouse

Naxd, also known as NAD(P)HX dehydratase, is a highly conserved enzyme essential for the intracellular repair of damaged nicotinamide nucleotide cofactors [NAD(P)HX], which are formed when the central cofactors NAD(P)H are damaged by hydration [2,6]. This repair process is crucial as the accumulation of damaged metabolites can have devastating effects on tissues such as the brain and heart. The gene has two isoforms, with exon 1 containing a mitochondrial propeptide and an alternative start codon in exon 2 initiating a cytosolic isoform [2].

Pathogenic variants in Naxd are associated with a rare metabolite repair disorder. In affected individuals, febrile illnesses can trigger progressive encephalopathy, often accompanied by skin eruptions, leading to high mortality rates [4]. Patients with variants affecting both cytosolic and mitochondrial isoforms present with neurological defects, seizures, and skin lesions, while those with variants only affecting the mitochondrial isoform have myopathy, moderate neuropathy, and cardiac issues without the characteristic skin lesions, seizures, or neurological degeneration [2]. Naxd-deficient patients also show elevated serum or cerebrospinal fluid lactate levels and brain neuroimaging abnormalities [3]. Niacin-based therapies have shown promise in improving outcomes and normalizing metabolic abnormalities in Naxd-deficient patients [1]. A case of an adult succumbing to Naxd-related neurometabolic crisis at 32 years of age, likely triggered by mild head trauma, was reported, extending the understanding of Naxd deficiency [5].

In conclusion, Naxd plays a vital role in the repair of damaged NAD(P)HX, and its deficiency leads to severe neurometabolic disorders. Understanding the function of Naxd through the study of its deficiency in patients helps in identifying early diagnostic markers and developing effective treatment strategies, such as niacin-based therapies, for these life-threatening conditions [1,2,3,4,5,6].