Acute Necrotizing Encephalopathy: 2 Case Reports on RANBP2 Mutation

Introduction

Infection-induced acute encephalopathy 3 (IIAE3, MIM # 608033) is an autosomal dominant disease with reduced penetrance resulting from a pathogenic variant in the RANBP2 gene. IIAE3 results in the susceptibility to the recurrence of acute necrotizing encephalopathy (ANE1) which presents as bilateral symmetric thalamic, midbrain and/or hindbrain lesions that typically develops within 1-4 days post-acute viral infection, commonly occurring before age 6. ^{1 –6} Most cases progress through a characteristic prodromal, acute and recovery stage. ⁶ The prodromal stage often presents with a nonspecific febrile viral-like illness lasting up to 5 days. ⁷ An acute phase follows where the inciting infection progresses into deteriorating consciousness, seizure, focal neurological deficits and coma. ^5,8 The final recovery stage is variable and can result in a full resolution of brain lesions, atrophy, the deposition of hemosiderin or the development of white matter cysts. ⁹ This case series is a presentation of 2 patients from our institution, one with a pathogenic RANBP2 gene variant and one with a variant of unknown significance in the RANBP2 gene highlighting similarities and differences in the patient presentations and disease course.

Case Presentation

Case 1

A 9-month-old previously healthy female presented with a seizure and a 4-day history of fever. Her family history was significant for an aunt who passed away of infection leading to encephalitis at age 30. She had no additional seizures, but developed weakness and spasticity in her left side, and developmental regression. An infectious study was positive for Human herpesvirus 6 (HHV-6). Her CSF results showed glucose of 66 mg/dL (reference range: 60-80 mg/dL) and protein of 43 mg/dL (reference range: 15-45 mg/dL), concerning for meningoencephalitis. EEG was consistent with encephalopathy. Brain MRI from an outside hospital reported extensive signal abnormalities and associated diffusion restriction and hemorrhage in the bilateral thalami, external capsules, medial temporal lobes, cerebral peduncles, pons, hypothalamus and mammillary bodies suggestive of possible acute viral encephalitis. Infectious and metabolic work up were negative. An epilepsy panel showed heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) associated with susceptibility to recurrent acute necrotizing encephalopathy (ANE1). Parental testing was recommended, but not completed due to the family’s socioeconomic situation. Patient was treated with high dose steroids and intravenous immunoglobulin (IVIG). She was discharged from the hospital with deficits including developmental delay, weakness, spasticity (left>right), and dysphagia and since then has been receiving IVIG every 2 months. She had recurrence of seizures 2 year later. Repeat MRI brain at our facility showed cystic encephalomalacia in above regions which is an expected change in RANBP2 induced ANE1 (Figure 1).

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Figure 1.

First patient’s follow-up MRI showing cystic encephalomalacia in bilateral medial thalamus (A) and pons (B). Second patient’s DWI MRI showing subtle increased signal in bilateral hippocampus (C) and thalamus (D), and T2 coronal (E) and FLAIR axial showing increased signal in bilateral thalamus (F).

Discussion

RAN Binding Protein 2 (RANBP2) gene on chromosome 2q13 encodes for a nuclear pore protein that is expressed in all tissues and plays a role in regulation of proteostasis, chemokine signaling, intracellular metabolism, and mitochondrial distribution. Several varied hypotheses propose a number of explanations for phenotypic presentation based on RANBP2’s wide range of intracellular functions. The proposed cellular dysfunctions include problems with transport between the nucleus and the cytoplasm, error with intracellular metabolic regulation, abnormalities in mitochondrial distribution and erroneous elicitation of a cytokine storm. ⁶

The pathophysiology of familial acute necrotizing encephalopathy (ANE1) is poorly understood due to the complexity and rarity of the disease. The leading hypothesis is that a trigger in genetically susceptible individuals with RANBP2 mutations leads to abnormal nuclear signaling resulting in a cytokine storm that allows cytokines into the central nervous system, disrupting the blood brain barrier and causing encephalopathy. ¹⁰ The triggering event is most commonly viral, such as influenza A and B, HHV6, HHV7, parainfluenza, varicella, enterovirus, rotavirus, herpes simplex virus, rubella, coxsackievirus A9, and measles. ¹¹

A RANBP2 c.1754C>T; p.Thr585Met missense mutation is most often associated with ANE1. Other mutations that have been identified in the literature include p.Thr653Ile, p.Ile656Val and p.Trp681Cys. ⁶ Four criterion have been proposed for RANBP2 testing including the presence of encephalopathy and polyfocal neurological deficits, supportive features, elevated CSF protein of greater than 0.45 g/L if no CSF pleocytosis is present and MRI findings of symmetric or asymmetric polyfocal lesions in the external capsule or brainstem. ¹ The case 2 highlights clinical course of acute encephalopathy following a febrile illness, deterioration of consciousness, the supportive feature of seizures, brain imaging demonstrating symmetric bilateral thalamic lesions, CSF findings of increased protein and no pleocytosis as well as the exclusion of other infectious, toxic or autoimmune etiologies. Leucine at 450 position is located at the Leucine rich domain and is highly conserved through species. In silico algorithms suggest that this variant is probably deleterious (SIFT, Polyphen-2 (0.808), mutationtaster (Table 1). ^{12 –15} The patient presentation meets the 4 clinical criteria and provides evidence that p.Leu450Phe is likely a clinically significant variant of ANE1.

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Table 1.

RANBP2 Gene Showing Conservation Across Species: Sequences Were Aligned Using COBALT (10) Using the RefSeqs of Homo Sapiens (NP_006258.3), Pan Troglodytes (XP_024210382.1), Macaca fascicularis (XP_005575292.1), Mus Musculus (NP_035370.2), Cricetulus Griseus (XP_027244142.1).^a

H. Sapiens	440	LGLQWNSLPALPGIRKWLKQ	459
P. Troglodytes	439	LGLQWNSLPALPGIRKWLKQ	458
M. Fascicularis	440	LGLQWNSLPALPAIRKWLKQ	459
M. musculus	440	LGLQWNSLSTLPAIRKWLKQ	459
C. Griseus	440	LGLQWNSLPTLPAIRKWLKQ	459

^a In red, we have highlighted the leucine of interest.

Prior studies indicate there is no predilection to the gender and both males and females were approximately equally affected by ANE. Ages of impacted individuals ranged from 5 months to 36 years. Commonly presenting clinical features include encephalopathy, seizures and febrile illness. ^{1 –5} Less than 10% of individuals fully recover from the acute phase without deficits. Outcomes can include permanent neurologic deficit and death with a mortality rate of 30%. ⁵ Poorer outcomes are associated with an onset of symptoms before the age of 1, delirium, hemorrhage or tissue loss on brain MRI and high levels of aminotransferase and CSF protein, while improved outcomes are associated with early treatment with high dose steroids and the lack of brainstem lesions. ⁹

Conclusion

Above discussed cases highlights variability in presentation and genetic heterogeneity of ANE1 that resulted in very different outcomes. Patient 1 was treated with high dose steroids and IVIG and was discharged with significant neurological deficits, while patient 2 was treated with high dose steroids, IVIG, an interleukin-1 inhibitor and plasmapheresis and ultimately had minimal residual deficits. Broader recognition of the clinical presentation of ANE1 and the clinically significant mutations of RANBP2 has the potential to improve long term outcomes with a more rapid and effective treatment course.