Genet Med. 2023 May 13:100897. doi: 10.1016/j.gim.2023.100897. Online ahead of print.
PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN Binding Protein 2 (RANBP2) associated Acute Necrotizing Encephalopathy sub-type 1 (ANE1). We provide clinical, genetic and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.
METHODS: Evaluation of clinical data, neuroradiological studies, genomic sequencing and protein immunoblotting results in eight children from four families who experienced acute febrile encephalopathy.
RESULTS: All eight healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death, to severe neurological deficits, to normal outcomes. The neuroradiological findings overlapped with ANE, but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1; a subset studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in one family.
CONCLUSIONS: Biallelic variants in RNH1 confer susceptibility to a sub-type of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies such as RNH1 and improve outcomes in the probands and at-risk siblings.
PMID:37191094 | DOI:10.1016/j.gim.2023.100897