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.

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

“…Previous reports elucidated to a correlation between neuroradiologic lesions and outcome. Poor prognostic factors suggested by evidence at case series level are the presence of hemorrhage and cavitation, involvement of brainstem, bilateral as oppose to unilateral thalami and cerebral or cerebellar white matter [ 5 , 16 ]. It is worthwhile to mention that Sibling 3 who has all of these features recovered well without neurological sequelae.…”

“…A loss of function of RANBP2 results in disruption of cell processes, leading to cytokine dysregulation, breakdown of blood brain barrier and disordered oxidative phosphorylation and energy metabolism in neuronal cells. These translate clinically as increased risk of stress-induced neurotoxicity in the affected individual [ 5 , 7 , 11 ]. This disease is synonymously known as RANBP2 Susceptibility to Infection-induced Encephalopathy, Infection-induced Acute Encephalopathy 3 (OMIM 608033 ) and ANE1.…”

“…Implicated organisms include influenza, parainfluenza, herpes, enteroviruses, coxsackie, rotavirus and mycoplasma among others [ [8] , [9] , [10] ]. Distinctive pathologic lesions on magnetic resonance imaging (MRI) are bilateral symmetrical signal abnormalities in thalami, brainstem, temporal lobe, limbic system, external capsule and occasionally basal ganglia; these lesions may undergo hemorrhagic conversion [ [2] , [3] , 5 , 6 , 8 , 10 , [13] , [14] , 15 ]. ANE1 follows an autosomal dominant Mendelian inheritance pattern but with incomplete penetrance [ [10] , [11] , [12] ], which could contribute to underdiagnosis.…”

“…ANE1 follows an autosomal dominant Mendelian inheritance pattern but with incomplete penetrance [ [10] , [11] , [12] ], which could contribute to underdiagnosis. Its prevalence and incidence are unknown; to date 85 cases have been reported worldwide [ 5 ].…”

Acute necrotizing encephalopathy of childhood: a single-center experience

“…Acute necrotizing encephalitis (ANE) is a rare but severe disease with neurological complications triggered by possible viral or bacterial infections, with multifocal brain lesions, especially in the bilateral thalamus. Mizuguchi et al first described the form seen in childhood (acute necrotizing encephalitis of childhood; ANEC) in 1995 [1,2]. Although it has been reported with high rates from Japan so far, as a result of studies conducted worldwide, ANE has been observed to be not specific to a particular race [1][2][3][4].…”