Review

. 2022 Jun 16;8(1):41.

doi: 10.1038/s41572-022-00365-7.

Genetic pain loss disorders

Annette Lischka¹, Petra Lassuthova², Arman Çakar³, Christopher J Record⁴, Jonas Van Lent^{5

6}, Jonathan Baets^{6

7

8}, Maike F Dohrn^{9

10}, Jan Senderek¹¹, Angelika Lampert¹², David L Bennett¹³, John N Wood¹⁴, Vincent Timmerman^{5

6}, Thorsten Hornemann¹⁵, Michaela Auer-Grumbach¹⁶, Yesim Parman³, Christian A Hübner¹⁷, Miriam Elbracht¹, Katja Eggermann¹, C Geoffrey Woods¹⁸, James J Cox¹⁴, Mary M Reilly⁴, Ingo Kurth¹⁹

Affiliations

¹ Institute of Human Genetics, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
² Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
³ Neuromuscular Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁴ Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁵ Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁶ Laboratory of Neuromuscular Pathology, Institute Born Bunge, Antwerp, Belgium.
⁷ Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
⁸ Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
⁹ Department of Neurology, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
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.
¹¹ Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
¹² Institute of Physiology, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
¹³ Nuffield Department of Clinical Neuroscience, Oxford University, Oxford, UK.
¹⁴ Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK.
¹⁵ Department of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁶ Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.
¹⁷ Institute of Human Genetics, University Hospital Jena, Jena, Germany.
¹⁸ Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK.
¹⁹ Institute of Human Genetics, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany. ikurth@ukaachen.de.

PMID: 35710757
DOI: 10.1038/s41572-022-00365-7

Review

Genetic pain loss disorders

Annette Lischka et al. Nat Rev Dis Primers. 2022.

. 2022 Jun 16;8(1):41.

doi: 10.1038/s41572-022-00365-7.

Authors

Affiliations

¹ Institute of Human Genetics, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
² Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
³ Neuromuscular Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁴ Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁵ Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁶ Laboratory of Neuromuscular Pathology, Institute Born Bunge, Antwerp, Belgium.
⁷ Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
⁸ Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
⁹ Department of Neurology, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
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.
¹¹ Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
¹² Institute of Physiology, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
¹³ Nuffield Department of Clinical Neuroscience, Oxford University, Oxford, UK.
¹⁴ Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK.
¹⁵ Department of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁶ Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.
¹⁷ Institute of Human Genetics, University Hospital Jena, Jena, Germany.
¹⁸ Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK.
¹⁹ Institute of Human Genetics, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany. ikurth@ukaachen.de.

PMID: 35710757
DOI: 10.1038/s41572-022-00365-7

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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References

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1. Rotthier, A. et al. Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. Brain 132, 2699–2711 (2009). - PubMed - PMC
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