Niacin therapy improves outcome and normalizes metabolic abnormalities in an NAXD-deficient patient
Joshua Manor, Daniel G. Calame, Charul Gijavanekar, Alyssa A. Tran, Jawid M. Fatih, Seema R. Lalani, Elizabeth Mizerik, Mered Parnes, Vidya Mehta, Adekunle M. Adesina, James R. Lupski, Fernando Scaglia, Sarah H. Elsea
Abstract
Spontaneous chemical reactions and substrate promiscuity of metabolic enzymes can result in the generation of cytotoxic byproducts which are processed by several dedicated, highly conserved enzymatic repair systems. 1 Such is the case with the cofactor nicotinamide adenine dinucleotide (phosphate), which either in its oxidized [NAD(P) + ] or reduced form [NAD(P)H], plays an important role in many redox reactions. Under stress conditions (e.g. thermal stress), NAD(P) + /NAD(P)H can be converted into a toxic metabolite, NAD(P)HX [hydrated NAD(P)H]. NAD(P)HX epimerase, NAXE and a hydratase, NAXD, comprise a two-step repair system which converts NAD(P)HX back into NAD(P)H, 2 a ubiquitous repair mechanism conserved across all taxa and present in the cytosol, mitochondria and endoplasmic reticulum. Van Bergen et al. 4 recently described a cohort of six patients with NAXD deficiency resulting in a fatal infantile encephalopathy triggered by febrile illness and accompanied by pellagra-like cutaneous lesions (MIM #618321). 6] Additionally, 40-80 mg/day of niacin was trialled in a patient with NAXE deficiency, along with coenzyme Q 10 , which resulted in