RANBP2 susceptibility to infection-induced encephalopathy: Clinicoradiologic and molecular description in a Malaysian family

Abstract

Pathogenic variants in RANBP2 cause autosomal dominant familial and recurrent Acute Necrotizing Encephalopathy of Childhood (ANEC). Affected children typically experience a 3-stage disease: a 3 to 5 days prodrome of non-specific febrile illness, acute encephalopathy, and recovery with or without neurological sequelae or death. Neuroradiological finding of bilateral symmetrical thalamic lesions raise the suspicion of this diagnosis. A devastating disease, reported mortality approaches 1/3 of those affected and only approximately 10% of patients recover completely without sequelae. We report a Malaysian family with RANBP2 pathogenic variant c.1754C>T (p.Thr585Met). The clinical presentation and course over a maximum of 7 years, as well as neuroradiological features of the 3 affected children are described. In contrast to the reported high mortality and morbidity, our patients have recovered with minor sequelae. We would like to highlight the absence of pathogenic variants in both parents' blood, raising the possibility of germline mosaicism in one of the parents as the underlying genetic mechanism of inheritance. To our knowledge, this is the first report of germline mosaicism in RANBP2 Susceptibility to Infection-induced Encephalopathy.

Keywords: ANEC; Bilateral symmetrical thalamic hyperintensities; RANBP2.

Fig. 1

Family pedigree.

Fig. 2

Brain MRI findings in the three siblings. T2-weighted images obtained during the acute encephalopathy (top row – Sibling 1, middle – Sibling 2, bottom – Sibling 3). Abnormal signals were visible in the brainstem [pons & midbrain] (blue arrow), lateral geniculate nuclei (yellow arrow), temporal lobes (green arrow), thalami (red arrow), external capsules (purple arrow) and insular cortices (orange arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)