Adult-Onset Neurodegeneration in Nucleotide Excision Repair Disorders (NERDND ): Time to Move Beyond the Skin

August 01, 2022

Isabell Cordts 1, Demet Önder 2 3, Andreas Traschütz 4 5, Xenia Kobeleva 2 3, Ivan Karin 6, Martina Minnerop 7 8 9, Peter Koertvelyessy 10, Saskia Biskup 11, Stephan Forchhammer 12, Johannes Binder 13, Andreas Tzschach 14, Frank Meiss 15, Axel Schmidt 16, Martina Kreiß 16, Kirsten Cremer 16, Martin A Mensah 17 18, Joohyun Park 19, Maren Rautenberg 19, Natalie Deininger 19, Marc Sturm 19, Paul Lingor 1, Thomas Klopstock 6 20 21, Markus Weiler 22, Franz Marxreiter 23 24, Matthis Synofzik 4 5, Christian Posch 25 26, Judith Sirokay 27, Thomas Klockgether 2 3, Tobias B Haack 19 28, Marcus Deschauer 1

Abstract

Background: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations.

Objective: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs.

Methods: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments.

Results: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage.

Conclusions: We introduce NERDND as adult-onset neurodegeneration (ND ) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: NER; UV sensitivity; ataxia; dementia; xeroderma pigmentosum.

  1. Department of Neurology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
  2. Department of Neurology, University Hospital Bonn, Bonn, Germany.
  3. German Center for Neurodegenerative Diseases, Bonn, Germany.
  4. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  5. German Center for Neurodegenerative Diseases, Tübingen, Germany.
  6. Friedrich-Baur-Institute, Department of Neurology, University Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  7. Institute of Neuroscience and Medicine, Research Centre Jülich, Jülich, Germany.
  8. Department of Neurology, Center for Movement Disorders and Neuromodulation, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
  9. Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
  10. Department of Neurology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  11. CeGaT GmbH und Praxis für Humangenetik Tübingen, Tübingen, Germany.
  12. Division of Dermatooncology, Department of Dermatology, University of Tübingen, Tübingen, Germany.
  13. Zentrum für Nervenheilkunde, Herbolzheim, Germany.
  14. Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  15. Department of Dermatology and Venereology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  16. Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
  17. Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  18. BIH Biomedical Innovation Academy, Digital Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany.
  19. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  20. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  21. German Center for Neurodegenerative Diseases, Munich, Germany.
  22. Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
  23. Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  24. Center for Rare Diseases (ZSEER), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  25. Department of Dermatology and Allergy, School of Medicine, German Cancer Consortium, Technical University of Munich, Munich, Germany.
  26. Faculty of Medicine, Sigmund Freud University Vienna, Vienna, Austria.
  27. Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany.
  28. Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.