Fatal infantile encephalopathy due to NAXE variant: Navigating the Metabolic-Mitochondrial overlap in NAXE gene

Abstract

Abstract Background Progressive Encephalopathy with Brain Edema and/or Leukoencephalopathy-1 (PEBEL-1) is a rare, rapidly progressive, and often fatal infantile neurometabolic disorder caused by pathogenic variants in the NAXE gene. Loss of NAXE impairs the NAD(P)HX repair pathway, leading to toxic accumulation of damaged nicotinamide nucleotide metabolites. The clinical course typically shows recurrent, fever-triggered neurological decompensation, mimicking combined metabolic and mitochondrial dysfunction. The condition progresses quickly to severe neuroregression and death. This report describes an early-onset, lethal case of NAXE -related encephalopathy exhibiting the classical fluctuating course and rapid decline. Case presentation A 5-month-old male infant, born to consanguineous parents with a history of multiple unexplained infant deaths, presented with fever, acute encephalopathy, and seizures. Initial metabolic evaluation suggested a neurometabolic disorder. Whole-exome sequencing identified a homozygous NAXE variant (c.401_402del, p.Phe134TrpfsTer13) consistent with PEBEL-1. Despite intensive management, including a mitochondrial cocktail, corticosteroids, and intravenous immunoglobulin, the child experienced progressive neuroregression, choreoathetosis, hypotonia, and intractable seizures. His condition continued to deteriorate, culminating in death secondary to aspiration. The clinical course illustrates the characteristic severity and high lethality of NAXE deficiency. Conclusion This case highlights the diagnostic complexity of NAXE -related infantile encephalopathy, a disorder with overlapping metabolic and mitochondrial features and a rapidly progressive, treatment-refractory course. The underlying defect in NAD(P)HX repair renders conventional metabolic and immunomodulatory therapies largely ineffective. Early genetic testing is crucial, especially in consanguineous families with recurrent neonatal or infant deaths. Although emerging therapies such as NAD⁺ precursors (e.g., niacin) or pyridoxine supplementation are under investigation, their clinical efficacy remains uncertain. NAXE variant should be considered in infants presenting with episodic encephalopathy, movement disorder, and unexplained neuroregression.