NAXD, or nicotinamide adenine dinucleotide phosphate hydrate dehydratase, is a highly conserved enzyme crucial for intracellular repair of damaged redox-inactive derivatives NAD(P)HX, which are formed from NAD(P)H due to hydration. This repair process is vital for maintaining the normal function of central cofactors NAD(P)H, thus being involved in various metabolic pathways [2,5].

In humans, pathogenic variants in NAXD are associated with a metabolite repair disorder. Patients with NAXD deficiency often experience progressive neurological deterioration, frequently triggered by febrile illness, and may also present with skin lesions, elevated lactate levels, and brain neuroimaging abnormalities. Different variants affecting sub-cellular compartments lead to distinct clinical phenotypes. For example, variants affecting both cytosolic and mitochondrial isoforms result in neurological defects, seizures, and skin lesions, while those affecting only the mitochondrial isoform cause myopathy, moderate neuropathy, and cardiac issues without the characteristic skin lesions or neurological degeneration [2,3]. Niacin-based therapies seem promising in improving outcomes and normalizing metabolic abnormalities in NAXD-deficient patients [1]. A case of an adult patient succumbing to NAXD-related neurometabolic crisis at 32 years old, likely triggered by mild head trauma, was reported, expanding the understanding of the clinical and genetic spectrum of NAXD deficiency [4].

In conclusion, NAXD is essential for the repair of damaged NAD(P)HX, and its deficiency leads to severe health issues, mainly in the neurological, cardiac, and muscular systems. Although there are no mentions of KO/CKO mouse models in the given references, the human-based studies have clearly demonstrated the importance of NAXD in maintaining normal physiological functions, especially in preventing the accumulation of damaged metabolites that can cause devastating effects in tissues like the brain and heart [2,3,4,5].

References:

1. Manor, Joshua, Calame, Daniel G, Gijavanekar, Charul, Scaglia, Fernando, Elsea, Sarah H. . Niacin therapy improves outcome and normalizes metabolic abnormalities in an NAXD-deficient patient. In Brain : a journal of neurology, 145, e36-e40. doi:10.1093/brain/awac065. https://pubmed.ncbi.nlm.nih.gov/35231119/

2. Van Bergen, Nicole J, Walvekar, Adhish S, Patraskaki, Myrto, Linster, Carole L, Christodoulou, John. 2022. Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency. In Journal of inherited metabolic disease, 45, 1028-1038. doi:10.1002/jimd.12541. https://pubmed.ncbi.nlm.nih.gov/35866541/

3. Majethia, Purvi, Mishra, Shivani, Rao, Lakshmi Priya, Rao, Raghavendra, Shukla, Anju. 2021. NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature. In European journal of medical genetics, 64, 104266. doi:10.1016/j.ejmg.2021.104266. https://pubmed.ncbi.nlm.nih.gov/34161859/

4. Van Bergen, Nicole J, Gunanayagam, Karen, Bournazos, Adam M, Cooper, Sandra T, Christodoulou, John. 2023. Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma. In International journal of molecular sciences, 24, . doi:10.3390/ijms24043582. https://pubmed.ncbi.nlm.nih.gov/36834994/

5. Van Bergen, Nicole J, Guo, Yiran, Rankin, Julia, Ellard, Sian, Hakonarson, Hakon. . NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. In Brain : a journal of neurology, 142, 50-58. doi:10.1093/brain/awy310. https://pubmed.ncbi.nlm.nih.gov/30576410/