Fever and illness management
Rapid neurological deterioration after an otherwise trivial fever, infection or illness is the commonest feature of the reported PEBEL1 individuals. This has triggered an irreversible clinical progression which has been lethal in the majority of clinical cases.
The rapid and severe clinical escalation of PEBEL1 limits opportunities for therapeutic interventions, therefore timely interventions are of utmost importance.
Since the rapid regression of individuals typically follows illness, infection or fever, careful management to reduce fever and avoid illness is recommended to potentially manage clinical relapses.
This approach is also recommended to possibly prevent acute decompensation in siblings with biallelic pathogenic NAXE variants who are not yet clinically affected.
Niacin treatment
There have been reports of several PEBEL1 individuals who did not succumb after illness which are thought to be potentially due to the introduction of niacin (also referred to as vitamin B3 or nicotinic acid or nicotinamide)-based therapies early in their clinical presentation. Specific examples include:
• A 4-year-old boy presented with early-onset progressive encephalopathy and was diagnosed with NAXE deficiency. After admission he was treated with coenzyme Q10, vitamin B1, vitamin B2, nicotinamide and other treatments. Some improvement in his condition was observed, he was weaned off ventilation and more than two years later remained alive, although with ataxia (Yu, Zhao et al. 2018).
• A female with NAXE deficiency that presented in early adulthood was treated with ubiquinol (150 mg coenzyme Q10) and niacin (40–80 mg/d), and showed improved clinical outcomes after treatment including dramatic improvements in severe spasticity, with ongoing motor and cognitive improvement (Trinh, Imhoff et al. 2019). This individual was surviving 7 years after diagnosis.
• A 20-month-old child presented with acute symptoms after a trivial infection. After genetic diagnosis with NAXE deficiency, they received vitamin B complex (thiamine 60 mg, riboflavin 3 mg, nicotinamide 30 mg and pyridoxine 3 mg per day) and coenzyme Q10, and this individual showed progressive neurological improvement, recovery of muscle power and at the time of the published report, remained alive at 5.5 years old (Chiu, Lin et al. 2021).
• A 2-year-old presented with ataxia, motor regression, encephalopathy and esotropia after an upper respiratory tract infection. After a genetic diagnosis of NAXE deficiency, he was treated with supplements including N-acetylcysteine (900 mg/day), niacin 50 mg/day (increased later to 200 mg/day), pyridoxine (25 mg/day), and riboflavin (25 mg/day). His clinical status improved and he had a near-return to baseline at a 6-month follow-up visit. After a second febrile illness 7 months post-initial presentation, there were no clinical or laboratory signs of decompensation (Manor, Calame et al. 2022).
• A boy first became symptomatic in infancy, with repeated neurological decompensations after infections, and cyclic recovery. At 2.5 years of age he was commenced on a mitochondrial cocktail of L-Carnitine 330 mg once daily, coenzyme q10 200 mg twice a day, B-100 complex once daily (100 mg of vitamins B1, B2, B3, B5 (pantothenic acid), and inositol, 10 mg of bioactive vitamin B6, 1,000 mcg of folic acid, 10 mg of choline, 500 mcg of bioactive vitamin B12, and 300 mcg of biotin in each tablet), and riboflavin 200 mg once daily, and had dramatic improvement in his neurological status. At the age of 19 years genetic testing identified NAXE deficiency and niacin (40mg twice daily) was added to his mitochondrial cocktail. At the age of 24 years, he remained neurologically stable (Almudhry, Prasad et al. 2024).
• There is one report of a patient with NAXE deficiency deteriorating to a fatal outcome despite being on high-dose niacin (Al-Amrani, Al-Thihli et al. 2024). The male child presented at 14 months with encephalopathy, ataxia and tremor, with a known pathogenic variant in NAXE, identified after two older sisters died. Niacin was introduced at a dose of 50 mg once daily and increased by 50 mg per day reaching 200 mg once daily (20 mg/kg/day) in addition to vitamin B complex, thiamine and pyridoxine. The patient initially responded well, regaining walking and improved cognition, although with a skin rash thought to be from high-dose niacin. Subsequently, he started to become lethargic and had loss of skills. The niacin dose was increased over the course of his regression, yet he continued to deteriorate. The decision was made to move toward palliation and the child died soon after.
The longest follow-up period following niacin treatment has been 7 years.
General management
PEBEL1 affects multiple systems so care of individuals should be carried out by a multidisciplinary team focussing on the clinical features of the affected individual. All affected individuals should have regular medical review to monitor progress of their condition. Since PEBEL1 can progress rapidly, prompt and aggressive management of febrile illnesses is strongly recommended in a genetically confirmed individual.
Genetic testing
PEBEL1 is associated with homozygous or compound heterozygous pathogenic or likely pathogenic variants in NAXE.
Genetic counselling is recommended for carriers, and prenatal testing options might be taken into consideration.
Testing for NAXE variants in individuals with neurological decline, skin lesions and/or leukoencephalopathy precipitated by a febrile illness or other childhood illnesses is warranted. Whole exome or genome sequencing alone or with RNAseq is recommended as a diagnostic tool in individuals with suspected NAXE variants.
NAXE