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Genetic pain loss disorders

Nature Reviews Disease Primers volume 8, Article number: 41 (2022) Cite this article

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Abstract

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.

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Fig. 1: Pain processing pathway.
Fig. 2: Overview on cellular mechanisms in CIP and HSAN.
Fig. 3: HSAN and ER-phagy.
Fig. 4: Clinical images of patients with CIP or HSAN.
Fig. 5: Human iPSC models in CIP/HSAN research.

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Acknowledgements

The authors thank the patients and their relatives who have supported their research activity for years. The authors express their gratitude to the family who was available for the experience report during the writing of the article. The European Network on Inherited Sensory Neuropathies and Insensitivity to Pain (ENISNIP) is supported by the Deutsche Forschungsgemeinschaft (DFG) (I.K. and J.S.; KU 1587/6-1, SE 1839/2-1), the Ministry of Education, Youth and Sports (MEYS), Czech Republic (P.L.), the Austrian Science Fund (FWF) (M.A.-G.), the Swiss National Science Foundation (SNSF) (T.H.), the Scientific and Technological Research Council of Turkey (TUBITAK) (A.Ç. and Y.P.), under the frame of the European Joint Programme on Rare Diseases (EJP RD). In addition, the ENISNIP project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the EJP RD COFUND-EJP no. 825575. The study was supported by a grant from the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (A.La. and A.Li. and I.K.; IZKF TN1-1/IA 532001, IZKF TN1-2/IA 532002). A.La. has a research contract with Hoffmann-La Roche and Grünenthal and receives consulting fees from Grünenthal, which do not affect the work presented here. J.J.C. is supported by the Medical Research Council (MR/R011737/1) and the Wellcome Trust (200183/Z/15/Z). J.N.W. is supported by the Wellcome trust (200183/Z/15/Z) and Versus Arthritis (21950). The research of C.G.W. is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by the Association Belge contre les Maladies Neuromusculaires (ABMM). J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund – Flanders (FWO) under grant agreement number 1805021N. J.V.L. is supported by a DOC-PR04 PhD fellowship from the University of Antwerp. Several authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD) and of the European Reference Network for Rare Neurological Diseases (ERN-RND). V.T. and J.B. are partners in the Solve-RD EU project (Horizon 2020 under grant agreement no. 779257). J.B., V.T. and J.V.L. are members of the µNEURO Research Centre of Excellence of the University of Antwerp. The authors thank A. Clark, Nuffield Department of Clinical Neurosciences, Oxford, UK, for providing Fig. 5d and A. Neureiter, Institute of Physiology, Uniklinik RWTH Aachen, Germany, for providing Fig. 5a and Fig. 5b.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany

    Annette Lischka, Miriam Elbracht, Katja Eggermann & Ingo Kurth

  2. Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic

    Petra Lassuthova

  3. Neuromuscular Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Arman Çakar & Yesim Parman

  4. Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK

    Christopher J. Record & Mary M. Reilly

  5. Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Jonas Van Lent & Vincent Timmerman

  6. Laboratory of Neuromuscular Pathology, Institute Born Bunge, Antwerp, Belgium

    Jonas Van Lent, Jonathan Baets & Vincent Timmerman

  7. Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    Jonathan Baets

  8. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium

    Jonathan Baets

  9. Department of Neurology, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany

    Maike F. Dohrn

  10. Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA

    Maike F. Dohrn

  11. Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany

    Jan Senderek

  12. Institute of Physiology, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany

    Angelika Lampert

  13. Nuffield Department of Clinical Neuroscience, Oxford University, Oxford, UK

    David L. Bennett

  14. Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK

    John N. Wood & James J. Cox

  15. Department of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Thorsten Hornemann

  16. Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria

    Michaela Auer-Grumbach

  17. Institute of Human Genetics, University Hospital Jena, Jena, Germany

    Christian A. Hübner

  18. Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK

    C. Geoffrey Woods

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Contributions

Introduction (I.K., A.Li., M.E., M.M.R., V.T., J.J.C., C.G.W. and D.L.B.); Epidemiology (I.K., A.Ç. and M.M.R.); Mechanisms/pathophysiology (I.K., A.Li., A.Ç., K.E., M.E., T.H., J.S., V.T., J.J.C., C.G.W., C.A.H., J.V.L., J.B., J.N.W., A.La., D.L.B. and M.F.D.); Diagnosis, screening and prevention (I.K., P.L., A.Ç., K.E., Y.P., M.M.R., J.J.C., C.G.W., C.J.R., J.B. and M.F.D.); Management (I.K., M.A.-G., M.E., Y.P., M.M.R. and C.J.R.); Quality of life (I.K., M.M.R. and C.G.W.); Outlook (I.K., P.L., T.H., J.S., C.G.W., J.V.L., A.Li. and D.L.B.); Overview of Primer (I.K.).

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Correspondence to Ingo Kurth.

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Nature Reviews Disease Primers thanks Angelo Schenone and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Lischka, A., Lassuthova, P., Çakar, A. et al. Genetic pain loss disorders. Nat Rev Dis Primers 8, 41 (2022). https://doi.org/10.1038/s41572-022-00365-7

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