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NAXD Deficiency: Heterogeneous Phenotypes and Positive Response to Niacin Treatment
Najmesadat Seyedkatouli1, Liana N Semcesen2, Lucia Gallucci1
1Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Journal of Inherited Metabolic Disease
|July 13, 2026
Summary
Progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is a rare neurometabolic disorder. Niacin (vitamin B3) shows promise in managing PEBEL2, improving outcomes in patients experiencing febrile episodes.
Area of Science:
- Neurology
- Metabolic Disorders
- Genetics
Background:
- Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is a rare autosomal recessive neurometabolic disorder.
- Pathogenic variants in the NAXD gene cause PEBEL2, often triggered by febrile illness or infection leading to rapid clinical decline.
Purpose of the Study:
- To expand the understanding of the clinical and molecular spectrum of PEBEL2.
- To investigate the functional impact of NAXD variants and explore potential therapeutic interventions.
Main Methods:
- Described nine new PEBEL2 cases with diverse clinical presentations.
- Performed functional analysis of missense variants and comparative proteomic analysis.
- Assessed the efficacy of high-dose niacin (vitamin B3) therapy.
Main Results:
- Identified typical neurological, atypical cardiac, and prenatal neurodegeneration presentations.
- Demonstrated impaired NAXD protein function (solubility, activity, thermostability) and cofactor accumulation in patient fibroblasts.
- Observed improved outcomes in four patients treated with niacin during febrile episodes.
Conclusions:
- PEBEL2 presents a broader clinical spectrum than previously recognized, including cardiac and prenatal forms.
- Niacin therapy may be a promising treatment to improve outcomes across the PEBEL2 clinical spectrum.
- Early recognition and intervention are crucial for managing this rare neurometabolic disorder.
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