NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction

Mol Genet Metab. 2022 Jun;136(2):101-110. doi: 10.1016/j.ymgme.2022.04.003. Epub 2022 Apr 18.


The NAD(P)HX repair system is a metabolite damage repair mechanism responsible for restoration of NADH and NADPH after their inactivation by hydration. Deficiency in either of its two enzymes, NAD(P)HX dehydratase (NAXD) or NAD(P)HX epimerase (NAXE), causes a fatal neurometabolic disorder characterized by decompensations precipitated by inflammatory stress. Clinical findings include rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, while neuroimaging abnormalities are subtle or nonspecific, making a clinical diagnosis challenging. During stress, nonenzymatic conversion of NAD(P)H to NAD(P)HX increases, and in the absence of repair, NAD(P)H is depleted, and NAD(P)HX accumulates, leading to decompensation; however, the contribution of each to the metabolic derangement is not established. Herein, we summarize the clinical knowledge of NAXE deficiency from 30 cases and lessons learned about disease pathogenesis from cell cultures and model organisms and describe a metabolomics signature obtained by untargeted metabolomics analysis in one case at the time of crisis and after initiation of treatment. Overall, biochemical findings support a model of acute depletion of NAD+, signs of mitochondrial dysfunction, and altered lipidomics. These findings are further substantiated by untargeted metabolomics six months post-crisis showing that niacin supplementation reverses primary metabolomic abnormalities concurrent with improved clinical status.

Keywords: Fever induced encephalopathy; Mitochondrial dysfunction; NAD(+); NAD(P)HX epimerase; NAXE; Neurometabolic disorders; PEBEL1; Pellagra.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Metabolic Diseases* / metabolism
  • Metabolic Diseases* / pathology
  • NAD* / isolation & purification
  • NADP* / metabolism
  • Racemases and Epimerases* / deficiency
  • Racemases and Epimerases* / metabolism


  • NAD
  • NADP
  • Racemases and Epimerases