Susceptibility to Infection-Induced Acute Encephalopathy 3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

Excerpt

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: Infection-induced acute encephalopathy 3 (IIAE3) is the susceptibility to recurrent acute necrotizing encephalopathy (ANE) caused by a heterozygous pathogenic variant in RANBP2. ANE refers to the specific neurologic presentation in which bilateral symmetric thalamic, midbrain, and/or hindbrain lesions occur within days following the onset of an acute viral illness caused by influenza A, influenza B, parainfluenza II, human herpes virus 6, coxsackie virus, or an enterovirus. Although most IIAE3 occurs before age six years, first episodes have been observed in teenagers and adults. ANE begins within 12 hours to three or four days of the first awareness of viral symptoms (fever, cough, rhinorrhea, vomiting, diarrhea, and malaise). The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%). One third of affected individuals die during the acute phase of the encephalopathy; of the survivors, one half have permanent neurologic damage and the remainder have no discernible residual symptoms. Fifty per cent of persons with IIAE3 will have at least one repeat episode and some will have multiple repeat episodes

Diagnosis/testing: IIAE3 is suspected in individuals with typical clinical and MRI findings, and is confirmed in those with a heterozygous pathogenic variant in RANBP2.

Management: Treatment of manifestations: Treatments for IIAE3 remain anecdotal and it should be noted that patients have recovered without specific intervention. Treatment is aimed at reducing the inflammatory state by administration of corticosteroids during an acute episode of encephalopathy (not supported by data from IIAE-3-specific studies) as well as IVIg, plasmapheresis, and TNFα antagonists with varied, but overall limited, therapeutic effects.

Prevention of primary manifestations: Routine vaccinations and yearly influenza vaccinations are recommended, although there are theoretic concerns for live influenza and cellular pertussis preparations. No studies have suggested that vaccinations cause acute necrotizing encephalopathy (ANE) in an individual heterozygous for an RANBP2 pathogenic variant.

Surveillance: No standard tests allow prediction of the triggering of an ANE event or progression of an event once one occurs.

Agents/circumstances to avoid: Avoid individuals who are ill with an infectious disease and adhere to strict precautions regarding hand washing. Based on a single case report of ANE in one individual (not known to have a RANBP2 pathogenic variant), avoidance of cellular pertussis in DTaP immunization is recommended.

Evaluation of relatives at risk: In a family with IIAE3, molecular genetic testing of at-risk first-degree relatives, especially children, is warranted so that those who have inherited the RANBP2 pathogenic variant can benefit from prompt intervention in the early stages of ANE.

Genetic counseling: Susceptibility to IIAE3 is inherited in an autosomal dominant manner. To date the majority of individuals diagnosed with IIAE3 have a parent who is heterozygous for a RANBP2 pathogenic variant; however, due to reduced penetrance, the parent may not have manifested the disease state. Also, a proband with susceptibility to IIAE3 may have the disorder as the result of a de novo pathogenic variant. Each child of an individual with susceptibility to IIAE3 has a 50% chance of inheriting the pathogenic variant. When the RANBP2 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible.