AbstractNAD(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.