Fever and illness management
Rapid neurological deterioration after an otherwise trivial fever, infection or illness is the commonest feature of the reported PEBEL2 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 PEBEL2 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 NAXD variants who are not yet clinically affected.
Niacin treatment
There have been reports of a handful of PEBEL2 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. High-dose vitamin B3 (100 - 500 mg/d) was reported to alleviate the skin manifestations and stabilise neurological symptoms ranging from 11 months to over at least a 3-year period.
Variants in the partner enzyme to NAXD, called NAXE, cause a similar neurological and dermatological picture. In a handful of NAXE cases, niacin therapy has also been tested.
An individual with NAXE deficiency was treated with 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. Another individual with NAXE deficiency 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.
The longest follow-up period for NAXE deficiency following niacin treatment has been 7 years. There is one report of a patient with NAXE deficiency deteriorating to a fatal outcome despite being on high-dose niacin.
General management
PEBEL2 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 PEBEL2 can progress rapidly, prompt and aggressive management of febrile illnesses is strongly recommended in a genetically confirmed individual.
Genetic testing
PEBEL2 is associated with homozygous or compound heterozygous pathogenic or likely pathogenic variants in NAXD.
Genetic counselling is recommended for carriers, and prenatal testing options might be taken into consideration.
Testing for NAXD variants in individuals with neurological decline, skin lesions and/or cardiac presentations precipitated by a febrile illness or head trauma is warranted. Whole exome or genome sequencing alone or with RNAseq is recommended as a diagnostic tool in individuals with suspected NAXD variants.
NAXD