The phenotypic spectrum of PCDH12 associated disorders - Five new cases and review of the literature

  • Author Footnotes
    1 These are the shared first authors.
    Walid Fazeli
    Correspondence
    Corresponding author. Department of Neuropediatrics, University Children's Hospital Bonn, Bonn, Germany Venusberg-Campus 1, 53127, Bonn, Germany
    Footnotes
    1 These are the shared first authors.
    Affiliations
    Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Institute for Molecular and Behavioral Neuroscience, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany
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  • Author Footnotes
    1 These are the shared first authors.
    Daniel Bamborschke
    Footnotes
    1 These are the shared first authors.
    Affiliations
    Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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  • Abubakar Moawia
    Affiliations
    Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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  • Somayeh Bakhtiari
    Affiliations
    Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA

    Departments of Child Health, Cellular & Molecular Medicine, and Neurology and Program in Genetics, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA
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  • Abbas Tafakhori
    Affiliations
    Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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  • Matthias Giersdorf
    Affiliations
    Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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  • Andreas Hahn
    Affiliations
    Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, Germany
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  • Anja Weik
    Affiliations
    CeGAT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
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  • Kirsten Kolzter
    Affiliations
    Children's Hospital Amsterdamer Straße, Kliniken der Stadt Köln, Cologne, Germany
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  • Sajad Shafiee
    Affiliations
    Neurological Surgery Department, Mazandaran University of Medical Sciences, Sari, Iran
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  • Sheng Chih Jin
    Affiliations
    Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
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  • Friederike Körber
    Affiliations
    Department of Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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  • Min Ae Lee-Kirsch
    Affiliations
    Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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  • Hossein Darvish
    Affiliations
    Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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  • Sebahattin Cirak
    Affiliations
    Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

    Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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  • Michael C. Kruer
    Affiliations
    Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA

    Departments of Child Health, Cellular & Molecular Medicine, and Neurology and Program in Genetics, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA
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  • Anne Koy
    Affiliations
    Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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  • Author Footnotes
    1 These are the shared first authors.
Published:October 30, 2021DOI:https://doi.org/10.1016/j.ejpn.2021.10.011

      Highlights

      • PCDH12 mutations associated with spectrum of epilepsy-dyskinesia disorders.
      • Five new cases, three novel PCDH12 mutations and review of the literature.
      • Novel observation: malformations of medulla oblongata in PCDH12 patients.
      • Novel observation: clinical overlap with interferonopathies and.
      • Increased interferon signature as potential hint to underlying disease mechanism.

      Abstract

      PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion.
      To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications.
      Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients.
      This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability.

      Keywords

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