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Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.
Shashi, Vandana; Schoch, Kelly; Ganetzky, Rebecca; Kranz, Peter G; Sondheimer, Neal; Markert, M Louise; Cope, Heidi; Sadeghpour, Azita; Roehrs, Philip; Arbogast, Thomas; Muraresku, Colleen; Tyndall, Amanda V; Esser, Michael J; Woodward, Kristine E; Ping-Yee Au, Billie; Parboosingh, Jillian S; Lamont, Ryan E; Bernier, Francois P; Wright, Nicola A M; Benseler, Susa M; Parsons, Simon J; El-Dairi, Mays; Smith, Edward C; Valdez, Purnima; Tennison, Michael; Innes, A Micheil; Davis, Erica E.
Afiliación
  • Shashi V; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC. Electronic address: vandana.shashi@duke.edu.
  • Schoch K; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC.
  • Ganetzky R; Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
  • Kranz PG; Division of Neuroradiology, Department of Radiology, Duke University Medical Center, Durham, NC.
  • Sondheimer N; Synlogic Therapeutics, Boston, MA.
  • Markert ML; Department of Pediatrics, Duke University School of Medicine, Durham, NC; Department of Immunology, Duke University Medical Center, Durham, NC.
  • Cope H; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC.
  • Sadeghpour A; Center for Human Disease Modeling, Duke University Medical Center, Durham, NC; Duke Precision Medicine Program, Department of Medicine, Division of General Internal Medicine, Duke University Medical Center, Durham, NC.
  • Roehrs P; Pediatric Stem Cell Transplant and Cellular Therapy, Department of Pediatrics, University of Virginia, Charlottesville, VA.
  • Arbogast T; Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • Muraresku C; Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Tyndall AV; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Esser MJ; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Woodward KE; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Ping-Yee Au B; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Parboosingh JS; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Lamont RE; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Bernier FP; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Wright NAM; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Benseler SM; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • Parsons SJ; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
  • El-Dairi M; Department of Ophthalmology, Duke University Medical Center, Durham, NC.
  • Smith EC; Division of Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC.
  • Valdez P; Department of Pediatrics, Duke University School of Medicine, Durham, NC.
  • Tennison M; Department of Neurology, University of North Carolina at Chapel Hill, NC.
  • Innes AM; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. Electronic address: Micheil.innes@ahs.ca.
  • Davis EE; Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL. Electronic address: eridavis@luriechildrens.org.
Genet Med ; 25(9): 100897, 2023 09.
Article en En | MEDLINE | ID: mdl-37191094
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 subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 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 neurologic 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 that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encefalopatías / Leucoencefalitis Hemorrágica Aguda / Encefalopatía Aguda Febril Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Child / Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encefalopatías / Leucoencefalitis Hemorrágica Aguda / Encefalopatía Aguda Febril Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Child / Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos