Phenotypic diversity in NAXE mutations

NAD(P)HX epimerase (NAXE) gene mutations have been associated with early onset progressive encephalopathy. We present three patients with NAXE gene mutations and different initial manifestations.

Patient(P)1 was a 30 month-old boy whose neurological regression started after an infection and progressed, ultimately leading to death one year later. His brain magnetic resonance imaging (MRI) findings were suggesting metabolic stroke. P2, nine year-old sister of P1, had mild developmental delay since birth, seizures after age 5 years and pellagra-like skin lesions. P3 was a 15 year old female presenting multifocal neurological signs progressing over months and leading to respiratory insufficiency. Her initial MRI was normal but inflammatory lesions appeared three months after the onset of symptoms. Laboratory investigations including biochemical, serological and metabolic tests, and brain biopsy were unrevealing. Clinical presentation of P1 and P3 initially suggested autoimmune neurological disease, but no response to immunotherapy was obtained. Two different types of variants c.641T > G; p.Ile214Ser and c.128 C > A, p.Ser43* were detected in NAXE in these patients' two unrelated families. All patients were given mitochondrial cocktail including niacin.

NAXE plays an important role in the electron donors for the mitochondrial respiratory chain. Mutations result in accumulation of toxic metabolites, disruption of energy production, and possibly cell death. P1-3 displayed different ages of onset, different clinical courses and MRI findings unreported previously, suggesting immune-mediated encephalitis and metabolic stroke in P1, and an inflammatory process in P3. NAXE mutations should be considered in progressive central nervous system symptoms.