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.

Cambridge Institute for Medical Research Keith Peters Building Cambridge Biomedical Campus Cambridge UK

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

Department of Clinical Chemistry University Hospital Zurich University of Zurich Zurich Switzerland

Department of Neurology Medical Faculty Uniklinik RWTH Aachen University Aachen Germany

Department of Orthopedics and Trauma Surgery Medical University of Vienna Vienna Austria

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

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

Friedrich Baur Institute Department of Neurology Ludwig Maximilians University Munich Germany

Institute of Human Genetics Medical Faculty Uniklinik RWTH Aachen University Aachen Germany

Institute of Human Genetics University Hospital Jena Jena Germany

Institute of Physiology Medical Faculty Uniklinik RWTH Aachen University Aachen Germany

Laboratory of Neuromuscular Pathology Institute Born Bunge Antwerp Belgium

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

Neuromuscular Reference Centre Department of Neurology Antwerp University Hospital Antwerp Belgium

Neuromuscular Unit Department of Neurology Istanbul Faculty of Medicine Istanbul University Istanbul Turkey

Nuffield Department of Clinical Neuroscience Oxford University Oxford UK

Peripheral Neuropathy Research Group Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Translational Neurosciences Faculty of Medicine and Health Sciences University of Antwerp Antwerp Belgium

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