Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Without Borders
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Without Borders
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

December 2020; 6 (6) Clinical/Scientific NotesOpen Access

Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation

Timo Hautala, Jie Chen, Laura Tervonen, Terhi Partanen, Satu Winqvist, Johanna Lehtonen, Janna Saarela, Minna Kraatari, Outi Kuismin, Tytti Vuorinen, Virpi Glumoff, Pirjo Åström, Usko Huuskonen, Lazaro Lorenzo, Jean-Laurent Casanova, Shen-Ying Zhang, Mikko R.J. Seppänen
First published November 25, 2020, DOI: https://doi.org/10.1212/NXG.0000000000000532
Timo Hautala
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jie Chen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura Tervonen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terhi Partanen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Satu Winqvist
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johanna Lehtonen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Janna Saarela
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Minna Kraatari
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Outi Kuismin
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tytti Vuorinen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Virpi Glumoff
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pirjo Åström
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Usko Huuskonen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lazaro Lorenzo
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean-Laurent Casanova
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shen-Ying Zhang
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mikko R.J. Seppänen
From the Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation
Timo Hautala, Jie Chen, Laura Tervonen, Terhi Partanen, Satu Winqvist, Johanna Lehtonen, Janna Saarela, Minna Kraatari, Outi Kuismin, Tytti Vuorinen, Virpi Glumoff, Pirjo Åström, Usko Huuskonen, Lazaro Lorenzo, Jean-Laurent Casanova, Shen-Ying Zhang, Mikko R.J. Seppänen
Neurol Genet Dec 2020, 6 (6) e532; DOI: 10.1212/NXG.0000000000000532

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
111

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Susceptibility to herpes simplex virus type 1 (HSV-1) encephalitis (HSE-1) in otherwise healthy individuals, in the course of primary infection, can be caused by single-gene inborn errors of Toll-like receptor 3 (TLR3) dependent, interferon (IFN)-α/β-mediated immunity,1,2 or by single-gene inborn errors of snoRNA31.3 These variations underlie infections of the forebrain, whereas mutations of DBR1 underlie infections of the brainstem.3 HSV-2 encephalitis (HSE-2) is typically observed in neonates, albeit also rarely in older children and adults.4 Its manifestations include altered level of consciousness, cranial neuropathies or more extensive brainstem encephalitis, hemiparesis, hemisensory loss, and permanent neurologic deficit.4 MRI in HSE-2 may show normal findings, nonspecific white matter, orbitofrontal, mesial temporal lobe, or brainstem lesions. Inborn errors of immunity underlying HSE-2 have not been described.

A 40-year-old previously healthy woman had suffered from headache and fever of up to 38°C for 6 days when she suddenly developed aphasia. At hospital admission, her body temperature was 37.1°C, blood pressure was 138/90 mm Hg, and vital signs were normal. She was fully conscious and co-operative but aphasic. Her blood hemoglobin level was low (107 g/L, normal range 117–155 g/L), with normal C-reactive protein level, blood white cell and thrombocyte counts, and negative blood and urine cultures. Acute phase brain CT, CT angiography and contrast enhanced MRI were unremarkable. CSF showed elevated mononuclear (98%) white cell count (166 × 106/L; normal <3 × 106/L) and high protein concentration (1,192 mg/L; normal range 150–500 mg/L). CSF was positive for HSV-2 and negative for HSV-1 nucleic acid by automated and accredited real-time PCR (artus HSV-1/2 PCR Kits; QIAsymphony SP, Rotor-Gene Q, Qiagen, Hilden, Germany). EEG showed left focal frontotemporobasal 2 Hz slow wave activity consistent with viral encephalitis (figure). She received IV acyclovir for 21 days with improvement in aphasia. Neuropsychological assessment 1 month later revealed poor word fluency, problems with memory interference, and delayed word list memory. The patient continued to suffer from lassitude and mild depression at least for over 12 months after the acute episode. Her presentation was consistent with International the Encephalitis Consortium diagnostic criteria for encephalitis.5 After the acute episode, she developed frequently recurrent eczema herpeticum of lower back tested positive for HSV-2 nucleic acid, suggesting recent primary HSV-2 infection. She did not suffer from genital herpes. This was controlled with peroral prophylactic valacyclovir 500 mg twice daily.

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure EEG shows focal left frontotemporobasal 2 Hz slow wave activity consistent with encephalitis diagnosis

Normal background activity and the patient is awake.

The patient was remitted for immunologic evaluation. Family history was unremarkable; she had no history of general infection susceptibility, autoimmunity, or secondary immunodeficiency. Blood white cell and lymphocyte (CD19+ B, CD4+ and CD8+ T, CD16+CD56+ NK) counts and percentages of T and B lymphocyte subclasses were normal, suggesting normal maturation. She was positive for anti-HSV2 immunoglobulin G (IgG) and negative for anti-HSV1 IgG. Whole exome sequencing showed a heterozygous rs147431766 TLR3 (chr4:187005064C>T, ENSG00000164342:ENST00000296795:exon4:c.C2224T:p.L742F) variant, enriched over 23-fold in the Finnish compared with non-Finnish Europeans (allele frequency 0.01621 vs 0.0006819, Genome Aggregation Database; gnomad.broadinstitute.org/). TLR3 p.L742F variant is in vitro severely hypomorphic based on experiments on TLR3-deficient P2.1 fibrosarcoma cell line, and the production of IFN-λ and interleukin-6 in response to TLR3 activation by poly(I:C) stimulation was impaired in previously tested SV40 immortalized human skin fibroblasts heterozygous for this variation.6 She was also found to be positive for TRF1-interacting nuclear factor 2 (TINF2) variant p.Y312* (rs201677741) previously associated with Ewing sarcoma. Pathogenic TINF variants are associated with autosomal dominant dyskeratosis congenita and pathologic telomere lengths (OMIM 604319). However, her telomere length was within the normal interval compared with healthy controls of similar age. Patient's father had died of aggressive cholangiocarcinoma, and her mother has had one episode of varicella zoster skin infection. TLR3 p.L742F and TINF2 p.Y312* variants were inherited from the mother. Patient's sister had suffered from recurrent laboratory confirmed cutaneous HSV2 infections. Her targeted testing did not reveal TLR3 p.L742F or TINF2 p.Y312* variants.

Previous evidence shows that inborn errors in TLR3-mediated immune response may explain HSE-1 in a subset of patients.1,–,3 Our patient suffered an HSE-2 episode associated with impaired TLR3-mediated antiviral response. To our knowledge, this is the first report of a genetic mechanism potentially explaining HSE-2 in immunocompetent patients. The TLR3 p.L742F variant found in our patient is enriched in Finnish population; we can only speculate that this property may associate with HSV-2 CNS infections in Finland.7 We emphasize that our report does not prove causality between TLR3 deficiency and HSE-2 but suggests that TLR3 signaling defects may need to be contemplated in otherwise healthy HSE-2 patients.

Study funding

No targeted funding reported.

Disclosure

The authors report no disclosures. Go to Neurology.org/NG for full disclosures.

Appendix Authors

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Received August 13, 2020.
  • Accepted in final form September 22, 2020.
  • Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Zhang SY,
    2. Jouanguy E,
    3. Ugolini S, et al
    . TLR3 deficiency in patients with herpes simplex encephalitis. Science 2007;317:1522–1527.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Lim HK,
    2. Seppänen M,
    3. Hautala T, et al
    . TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology 2014;83:1888–1897.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Zhang SY
    . Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity. Hum Genet 2020;139:911–918.
    OpenUrl
  4. 4.↵
    1. Berger JR,
    2. Houff S
    . Neurological complications of herpes simplex virus type 2 infection. Arch Neurol 2008;65:596–600.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Venkatesan A,
    2. Tunkel AR,
    3. Bloch KC, et al
    . Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013;57:1114–1128.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Partanen T,
    2. Chen J,
    3. Lehtonen J, et al
    . Heterozygous TLR3 mutation in patients with hantavirus encephalitis. J Clin Immunol 2020;40:1156–1162.
    OpenUrl
  7. 7.↵
    1. Kupila L,
    2. Vuorinen T,
    3. Vainionpää R,
    4. Hukkanen V,
    5. Marttila RJ,
    6. Kotilainen P
    . Etiology of aseptic meningitis and encephalitis in an adult population. Neurology 2006;66:75–80.
    OpenUrlCrossRefPubMed
View Abstract

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

NOTE: All contributors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.ng.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

  • Stay timely. Submit only on articles published within the last 8 weeks.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • 200 words maximum.
  • 5 references maximum. Reference 1 must be the article on which you are commenting.
  • 5 authors maximum. Exception: replies can include all original authors of the article.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Letters

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Letters Submission Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Study funding
    • Disclosure
    • Appendix Authors
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures

Related Articles

  • No related articles found.

Topics Discussed

  • All Immunology
  • All Genetics
  • Encephalitis
  • Viral infections

Alert Me

  • Alert me when eletters are published
Advertisement
Neurology Genetics: 7 (2)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2021 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise