From ran(bp2) dom to Recurrent: A Case of Familial Acute Necrotizing Encephalopathy

ABSTRACT

Introduction: Acute necrotizing encephalopathy (ANE) is a rare condition often triggered by infection and characterized by febrile prodromal illness, seizures, altered mental status and bilateral brain lesions. While many cases are isolated, a recurrent familial pattern has been linked to missense mutation of the gene encoding RAN binding protein 2 (RANBP2). Early administration of high dose steroids has been associated with improved outcomes, while IVIG and tocilizumab have also shown benefit. Case Description A two-year-old male presented with vomiting, somnolence and seizure-like activity. Evaluation revealed positive SARS-CoV2, adenovirus and rhinovirus/enterovirus PCR by nasopharyngeal swab, and Mycoplasma pneumoniae IgM. MRI showed numerous foci of restricted diffusion and microhemorrhage as well as necrotic change in the internal capsules. He was diagnosed with ANE. He recovered to neurologic baseline following treatment with IVIG and corticosteroids. After six months, the patient presented with similar symptoms. SARS-CoV2 IgG was positive, but no new infectious pathogens were identified. Cerebrospinal fluid (CSF) analysis showed elevated IL-6 and IL-8 levels, suggestive of inflammatory breakdown of the blood-brain barrier. Brain MRI demonstrated worsened bilateral T2/fluid attenuated inversion reduction signal abnormalities and necrosis within the midbrain and pons bilaterally, concerning for recurrent ANE. Following multidisciplinary consultation, the patient was treated with corticosteroids and IVIG. Tocilizumab was later added due to elevated CSF IL-6. Worsening MRI findings (Figure 1) coupled with decrease in strength and spontaneous movement prompted plasma exchange (PLEX) therapy. While his exam improved after PLEX, treatment was discontinued due to development of a pericardial effusion. The patient steadily improved neurologically and was transitioned to inpatient rehabilitation with an ongoing steroid taper, monthly IVIG, and tocilizumab therapy. Given recurrence of ANE, an epilepsy genetic sequencing panel was ordered and revealed heterozygous mutation in RANBP2 (c.1966A>G p.Ile656Val). Discussion: During the patient's initial presentation, it was reasonable to conclude an infectious trigger for ANE given the presence of several potential inciting pathogens. Upon recurrence, investigation of underlying genetic predisposition was warranted. This patient exhibited the classic clinical and radiographic findings of recurrent ANE and was found to have RANBP2 mutation. Available literature suggests pathogenicity of the same mutation identified in this case due to its location in a highly conserved genetic region and its presence in affected members of a family with ANE. To our knowledge, this is the second report of this specific RANBP2 mutation in association with ANE. Conclusion: While ANE may present as a singular event following infection, recurrence is rare and should prompt evaluation of underlying genetic predisposition. Consideration of familial ANE with testing for RANBP2 mutation may lead to early genetic counseling. Our case also provides additional support for the pathogenicity of the RANBP2 (p.Ile656Val) mutation. (Figure Presented).