NAXD Deficiency: Heterogeneous Phenotypes and Positive Response to Niacin Treatment

This is the authors' abstract. We don't add key points for this paper.

Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in NAXD, in which febrile illness or infection triggers rapid clinical deterioration. We describe nine new cases that expand the clinical and molecular spectrum. Four children showed the typical presentation of severe neurological decline following fever or illness and carried variants affecting the enzyme domain. Four cases presented with illness-triggered cardiac dysfunction associated with variants in the mitochondrial targeting sequence. One case showed severe prenatal neurodegeneration resulting in stillbirth. In two patients, disease onset followed COVID-19 infection. Functional analysis of five missense variants demonstrated impaired NAXD protein solubility, reduced NADHX dehydratase activity and/or decreased thermostability. Patient fibroblasts confirmed accumulation of damaged cofactors (S-, R- and cyclic NADHX) and reduced NAXD protein levels. Comparative proteomic analysis revealed distinct molecular profiles in atypical cardiac and prenatal cases compared with typical neurological presentations. Four patients received high-dose niacin (vitamin B3) and survived repeated febrile episodes. These findings support early recognition and suggest that niacin therapy may improve outcomes across the clinical spectrum of PEBEL2.