Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.
- MeSH
- dědičné senzorické a autonomní neuropatie * genetika MeSH
- kongenitální analgezie * genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
Acta orthopaedica. Supplementum, ISSN 1745-3690 ; vol. 77, no. 321, April 2006
32 s. : il., tab. ; 25 cm
- MeSH
- genetická predispozice k nemoci epidemiologie MeSH
- hodnocení rizik MeSH
- kongenitální analgezie epidemiologie genetika patofyziologie MeSH
- mutace MeSH
- neurotrofní faktory genetika MeSH
- prevalence MeSH
- regulace genové exprese MeSH
- rodokmen MeSH
- Geografické názvy
- Švédsko MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- vnitřní lékařství
- genetika, lékařská genetika
- neurologie
- NLK Publikační typ
- studie
- MeSH
- bolest etiologie genetika MeSH
- centrální nervový systém patofyziologie MeSH
- chemokiny genetika MeSH
- cytokiny genetika MeSH
- genetické asociační studie metody trendy využití MeSH
- genetický výzkum * MeSH
- hypohidróza etiologie genetika MeSH
- kongenitální analgezie * etiologie genetika MeSH
- lidé MeSH
- migréna s aurou * etiologie genetika MeSH
- multifaktoriální dědičnost fyziologie genetika MeSH
- neurony fyziologie MeSH
- polymorfismus genetický fyziologie genetika MeSH
- receptory N-methyl-D-aspartátu genetika MeSH
- synapse fyziologie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- dítě MeSH
- familiární dysautonomie MeSH
- glositida MeSH
- kojenec MeSH
- kongenitální analgezie genetika MeSH
- Leschův-Nyhanův syndrom MeSH
- lidé MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH