A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder

Abstract

<b><i>Introduction:</i></b> Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are required redox equivalents for essential biochemical reactions. Their hydrated forms, NADHX and NAD(P)HX, are inhibitors for several dehydrogenases and cause harmful byproducts. NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) together form the nicotinamide repair system. <b><i>Case Presentation:</i></b> A 7-month-old boy was admitted due to myoclonic seizures, impaired consciousness, and rapid loss of head control. One of his siblings regressed after a febrile seizure and died at 7 months. He had lethargy and axial hypotonia but skin lesions and organomegaly were not noted. Basal metabolic tests were within normal limits except serum and cerebrospinal fluid lactate levels, which were mildly elevated. Mitochondrial cocktail was added to the antiepileptic treatment with suspicion of mitochondrial disease. Whole-exome sequencing showed a novel homozygous mutation (c.247G>A) in the <i>NAXD</i> gene. His seizures stopped within a few weeks. However, he died at the age of 18 months. <b><i>Discussion:</i></b> Prominent features of NAXD deficiency are progressive neurological deterioration after fever, cardiomyopathy, skin lesions, and premature death. Unlike the cases reported in the literature, our patient had neither preceding fever nor skin lesion during follow-up. It appears that cases show phenotypic diversity.

Transient response to high‐dose niacin therapy in a patient with NAXE deficiency

“…A total of 19 articles were found concerning PEBEL-1 and PEBEL-2 describing a total of 45 patients. 2,[11][12][13][14][15][16][17][18][19] 32 patients were found to have PEBEL-1 and 13 patients were found to have PEBEL-2. Eight patients were treated…”

Progressive encephalopathy after routine 4‐month immunizations in a patient with NAXD genetic variant

“…Clinical presentation of these disorders typically occurs secondary to an acute stressor—such as a fever, infection, or physical stress—as these stressors result in the generation of toxic products. If there is an error in metabolite repair, then toxic products accumulate and can result in metabolic decompensation (Lucas et al, 2021; Oz Tuncer et al, 2022; Malik et al, 2020; Van Bergen et al, 2018; Zhou et al, 2019).…”

“…Clinical findings have included skin lesions, myopathy, seizures, hypotonia, ataxia, diarrhea, vomiting, cardiac manifestations, respiratory failure, anemia, pancytopenia, elevated creatinine kinase, and/or elevated lactate. Ultimately, this disease frequently results in neurologic deterioration and death in the first few years of life (Lucas et al, 2021; Majethia et al, 2021; Oz Tuncer et al, 2022; Malik et al, 2020; Van Bergen et al, 2018; Van Bergen et al, 2022; Zhou et al, 2019). Neuroimaging abnormalities include edema and signal abnormalities in the cortical and subcortical regions (Van Bergen et al, 2018; Zhou et al, 2019).…”