NAXE, also known as APOA1BP, encodes NAD(P)HX epimerase, an enzyme crucial for the NAD(P)HX repair system. This system restores NADH and NADPH after their inactivation by hydration, playing a vital role in maintaining normal cellular redox balance and energy metabolism, especially in the context of the mitochondrial respiratory chain [1,2].

NAXE deficiency, caused by pathogenic variants in the NAXE gene, leads to a fatal neurometabolic disorder. Clinical features include rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, often precipitated by inflammatory stress. Biochemically, it shows acute depletion of NAD+, signs of mitochondrial dysfunction, and altered lipidomics. Niacin supplementation has been shown to reverse primary metabolomic abnormalities and improve the clinical status in some cases [1]. Different phenotypes have been observed based on the nature of the NAXE mutations, with some patients showing milder symptoms starting in early adulthood [3]. Some patients also present with skin manifestations, such as well-demarcated erythematous and erosive plaques, which can progress to blistering and necrosis, mainly affecting flexural surfaces [4].

In conclusion, NAXE is essential for the proper functioning of the NAD(P)HX repair system, maintaining normal cellular metabolism. Research on NAXE-related disorders, though not specifically from KO/CKO mouse models in the provided references, has revealed its significant role in neurometabolic diseases. Understanding NAXE's function is crucial for developing effective treatments for these rare and often fatal disorders.

References:

1. Manor, Joshua, Calame, Daniel, Gijavanekar, Charul, Scaglia, Fernando, Elsea, Sarah H. 2022. NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction. In Molecular genetics and metabolism, 136, 101-110. doi:10.1016/j.ymgme.2022.04.003. https://pubmed.ncbi.nlm.nih.gov/35637064/

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. Trinh, Joanne, Imhoff, Sophie, Dulovic-Mahlow, Marija, Lohmann, Katja, Brüggemann, Norbert. 2019. Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment. In Journal of neurology, 267, 770-782. doi:10.1007/s00415-019-09640-2. https://pubmed.ncbi.nlm.nih.gov/31745726/

4. Abdulkarim, Boraan, Mittal, Setu, Vahidnezhad, Hassan, Camilleri, Michael J, Mohandesi, Nessa Aghazadeh. 2025. Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist. In Pediatric dermatology, 42, 233-239. doi:10.1111/pde.15868. https://pubmed.ncbi.nlm.nih.gov/39887790/