Acute Necrotising Encephalopathy(ANE) is a rare familial(ANE1) or sporadic disorder not previously reported in South Africa. Acute encephalopathy occurs abruptly 1-3 days after onset of a febrile illness. Bilateral thalamic oedema is characteristic, with brainstem, cerebellar, temporal lobe, external and internal capsules and spinal cord abnormalities reported.

We report 4 South African children from an extended family. Onset was at 11, 16, 20 months, and 8 years 10 months. Two were siblings and two first cousins (3 M:1F). Three had acute decline in consciousness, one had vomiting and weakness. Seizures occurred in two. Two required respiratory support.  All had elevated serum inflammatory markers and influenza virus detected on nasopharyngeal aspirate, and one had elevated CSF protein. Five days of 30milligrams/kg/day methylprednisolone was given. All survived, but with developmental delay and dyskinetic disorders.

A c.1754C>T, p.(Thr585Met) heterozygous mutation in RANBP2 was present in all cases. Four parents, the maternal grandmother and an asymptomatic 12y F were heterozygous for the same mutation. One parent had a meningitic illness in childhood.  These are the first genetically confirmed cases of RANBP2 in sub-Saharan Africa.

The family live remote from tertiary facilities. Education of local medical support was important as time to initiation of steroids may determine outcome. Negative genetic testing in a grandchild with febrile seizures avoided unnecessary imaging and anxiety.

Factors beyond genetic carrier state are implicated in view of the much worse outcome of the youngest generation. There may be epigenetic phenomena which influence disease course.