Acute necrotizing encephalopathy (ANE) is a host-mediated phenomenon with viral triggers typically including influenza and parainfluenza viruses [1]. It presents with a spectrum of symptoms from vomiting to seizures and coma with a potential to cause long-standing neurocognitive impairment [2]. Sporadic (ANE) and recurrent/familial (ANE1) forms are now recognised in the literature with the latter being described after the discovery of mutations in the RANBP2 gene [1]. The diagnosis requires exclusion of other causes of encephalopathy, a high index of suspicion from the history (i.e. of recurrent attacks) and diagnostic clues from prompt MRI imaging.

Although the association of the H1N1 strain of influenza as a trigger for isolated ANE has been previously described, this is the first case of the H1N1 strain being isolated in the recurrent/familial form, ANE1, with a confirmed missense mutation in RANBP2. This is only the second report of the T653i mutation in RANBP2 giving rise to a clinical phenotype of ANE1. In the previous reported case, the pathogenic significance of this specific mutation was not clearly established. Our familial cohort proves beyond doubt that that the T653i is a pathogenic mutation.