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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\u2010triggered 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\u201019 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\u2010, R\u2010 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\u2010dose 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.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70217","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:45:14Z","timestamp":1783925114000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>NAXD<\/scp>\n                    Deficiency: Heterogeneous Phenotypes and Positive Response to Niacin Treatment"],"prefix":"10.1002","volume":"49","author":[{"given":"Najmesadat","family":"Seyedkatouli","sequence":"first","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg  Esch\u2010sur\u2010Alzette Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana N.","family":"Semcesen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Gallucci","sequence":"additional","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg  Esch\u2010sur\u2010Alzette Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Sikora","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute, Royal Children's Hospital  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Fran\u00e7ois","family":"Conrotte","sequence":"additional","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg  Esch\u2010sur\u2010Alzette Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei R. 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