NAXE, also known as APOA1BP, encodes NAD(P)HX epimerase. This enzyme is a key component of the NAD(P)HX repair system, which is responsible for restoring NADH and NADPH after their inactivation by hydration. The NAD(P)HX repair pathway is crucial for maintaining normal cellular redox balance and energy metabolism, as NAD(P)H is essential for numerous cellular processes, including the mitochondrial respiratory chain [1,2].

Pathogenic variants in NAXE are associated with a fatal neurometabolic disorder [1,2]. Patients typically present with rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, often precipitated by inflammatory stress such as fever or infection [1]. Some patients also exhibit skin manifestations like well-demarcated erythematous and erosive plaques on flexural surfaces [5]. The disease mechanism involves the non-enzymatic conversion of NAD(P)H to NAD(P)HX during stress, which accumulates in the absence of NAXE-mediated repair, leading to NAD(P)H depletion, biochemical signs of mitochondrial dysfunction, and acute depletion of NAD+ [1]. Niacin-based therapies show promise in reversing primary metabolomic abnormalities and improving clinical status [1,4]. In one case, a biallelic GGGCC repeat expansion in the NAXE promoter region led to transcriptional suppression, reduced RNA and protein levels, and NAXE-related mitochondrial encephalopathy [3].

In conclusion, NAXE is essential for the NAD(P)HX repair system, maintaining cellular redox and energy metabolism. Deficiency in NAXE, as revealed through patient-based studies, leads to a severe neurometabolic disorder. Understanding NAXE's function is crucial for developing targeted treatments for this life-threatening condition, and niacin-based therapies could be a potential treatment strategy [1,4].

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. Ozaki, Kokoro, Yatsuka, Yukiko, Oyazato, Yoshinobu, Murayama, Kei, Okazaki, Yasushi. 2024. Biallelic GGGCC repeat expansion leading to NAXE-related mitochondrial encephalopathy. In NPJ genomic medicine, 9, 48. doi:10.1038/s41525-024-00429-5. https://pubmed.ncbi.nlm.nih.gov/39455596/

4. 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/

5. 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/