Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics

Abstract

Genetic (also known as familial) acute necrotizing encephalopathy (ANE1) is a rare disease presenting with encephalopathy often following preceding viral febrile illness in patients with a genetic predisposition resulting from a missense mutation in the gene encoding RAN Binding Protein 2 (RANBP2). The acute episode is characterized by deterioration in consciousness, often with focal neurologic deficits and seizures. Additionally, symmetric multifocal brain lesions are seen in the bilateral thalami as well as other characteristic regions, involving both gray and white matter. Prognosis is variable, with a high mortality rate and most surviving patients having persistent neurologic deficits. Early treatment with high dose steroids is associated with a more favorable outcome, however the diagnosis is often overlooked resulting in delayed treatment. The RANBP2 mutation associated with ANE1 causes an incompletely penetrant predisposition to encephalopathy in the setting of febrile illness through a mechanism that remains elusive. There are several non-mutually exclusive hypotheses suggesting possible etiologies for this phenotype based on the many functions of RANBP2 within the cell. These include dysfunctions in nucleocytoplasmic trafficking and intracellular metabolic regulation, as well as cytokine storm, and abnormal distribution of mitochondria. This narrative review explores these key concepts of the RANBP2 mutation and its clinical and therapeutic implications in pediatric populations.

Keywords: Acute necrotizing encephalopathy; Encephalopathy; Genetic; RANBP2; Thalami.

Figure 1

A) 12-year-old female with a diagnosis of ANE1. Axial FLAIR demonstrating bi-thalamic involvement and left temporal lobe edema. B) Same 12-year-old female with ANE1. Sagital T2 demonstrating thalamic and brainstem hypertintensities with sparing of the cortical structures

Figure 2

Dynamic changes of magnetic resonance imaging (MRI) of a patient with acute necrotizing encephalopathy (ANE). (a) was computerized tomography (CT) at onset; (b) and (c), (d) and (e), and (f) and (g) were, respectively, the T1-weighted image (T1WI), T2WI, and fluid attenuated inversion recovery (FLAIR) image at onset which showed lesions on bilateral thalamus and brain stem (blue arrow); (h) and (i), (g) and (k), and (l) were, respectively, the T1WI, T2WI, and FLAIR imaging of follow-up which revealed disappearance of the brain stem lesions and impressive regression of the thalamic lesions, just left hemosiderin deposition (red arrow). Displayed with permission from Wu et al., 2015.

Figure 3

Diffusion findings in acute-stage ANE in a 2-year-old girl. A, Diffusion-weighted MR images (b = 1000) show bilateral symmetric diffuse hyperintense lesions in the cerebellar-cerebral white matter, thalami, and pontine tegmenta. B, The ADC map shows three different patterns of the thalamus and cerebral white matter. The center of the lesions shows higher ADC values than those of normal parenchyma, the peripheral portion of central lesions shows very low ADC values, and outside the thalamus and cerebral white matter are high ADC values, findings compatible with vasogenic edema. Note that the splenium of corpus callosum, pontine tegmanta, optic radiatia, and cerebellar white matter have low ADC values in the central portion and high ADC values in the peripheral portion. C, Mean ADC values and pattern on the right thalamus (A, center of thalamic lesions; B, periphery of the central thalamic lesions; C, outside portions of the thalamic lesions). Displayed with permission from Albayram et al., 2004.

Figure 4

Roles of RANBP2 and effects of RANBP2 disruption