NAXD Deficiency Associated with Perinatal Autoinflammation, Pancytopenia, Dermatitis, Colitis, and Cystic Encephalomalacia

Abstract

NAD(P)HX dehydratase (NAXD) catalyzes the recovery of toxic derivatives of nicotinamide adenine dinucleotides which play an essential role in mitochondrial metabolism. Mutations in NAXD were recently shown to cause early-onset neurodegeneration exacerbated by febrile illness. Here, we report a novel homozygous stop-gain variant in NAXD in an infant who presented with a fulminant course of autoinflammation, dermatitis, colitis, and cystic encephalomalacia beginning at 3 weeks of age. Our findings support the central role of NAXD-mediated metabolite repair for normal tissue function and implicate innate immune processes in the pathogenesis of NAXD deficiency.

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

“…The skin involvement comprising lesions evolving from erythematous to violaceous patches and plaques of the flexural surfaces with rapid progression to full skin necrosis, as seen in our patient, is consistent with previous reports of NAXD variants (Lucas et al, 2021; Majethia et al, 2021; Malik et al, 2020; Van Bergen et al, 2018; Zhou et al, 2019). Differential diagnoses of the skin changes included nutritional deficiencies (particularly pellagra [niacin deficiency] and zinc deficiency), hartnup disease, and staphylococcal scalded skin syndrome.…”

“…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).…”