NAXD Encephalopathy Mimicking Neuroinflammatory Disease

ABSTRACT Neurometabolic diseases are a group of genetic disorders caused by defects in metabolic networks. To characterize the clinical, radiological, and molecular phenotype of three patients with variants in the NAXD gene, together with a review of the literature. A retrospective review of medical records was conducted. Three patients with chronic, progressive, recurrent encephalopathy triggered by fever were identified, with two clinically relevant variants in compound heterozygosity in the NAXD (NM_001242882.2) gene. Individuals 1 and 2: c.794_798dup and c.922C>T. Individual 3: c.269G>T and c.922C>T. We report three patients with neurometabolic disease characterized by recurrent progressive encephalopathy, developmental regression, and movement disorders, associated with systemic involvement and inflammatory‐appearing central nervous system lesions due to NAXD enzymatic deficiency. The condition follows a febrile episode, often resulting in early mortality. Other cases showed recurrent episodes triggered by febrile events, characterized by encephalopathy, abnormal movements, ataxia, and seizures. The most frequent systemic manifestations included hematological, mucocutaneous, and cardiac involvement. These three patients broaden the clinical and molecular spectrum of NAXD ‐associated encephalopathy. Given its potential therapeutic implications, this condition should be considered in the differential diagnosis of neuroinflammatory diseases with poor outcomes, especially in cases with multisystem manifestations.