{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T02:55:26Z","timestamp":1785207326976,"version":"3.55.0"},"reference-count":82,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T00:00:00Z","timestamp":1719705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union\u2019s Horizon 2020 research and innovation program","award":["721841"],"award-info":[{"award-number":["721841"]}]},{"name":"Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union\u2019s Horizon 2020 research and innovation program","award":["602273"],"award-info":[{"award-number":["602273"]}]},{"name":"Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union\u2019s Horizon 2020 research and innovation program","award":["RF-2011-02350347"],"award-info":[{"award-number":["RF-2011-02350347"]}]},{"name":"European Union seventh framework program for the PROPANE study","award":["721841"],"award-info":[{"award-number":["721841"]}]},{"name":"European Union seventh framework program for the PROPANE study","award":["602273"],"award-info":[{"award-number":["602273"]}]},{"name":"European Union seventh framework program for the PROPANE study","award":["RF-2011-02350347"],"award-info":[{"award-number":["RF-2011-02350347"]}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["721841"],"award-info":[{"award-number":["721841"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["602273"],"award-info":[{"award-number":["602273"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RF-2011-02350347"],"award-info":[{"award-number":["RF-2011-02350347"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Small-Fiber Neuropathy (SFN) is a disorder of the peripheral nervous system, characterised by neuropathic pain; approximately 11% of cases are linked to variants in Voltage-Gated Sodium Channels (VGSCs). This study aims to broaden the genetic knowledge on painful SFN by applying Whole-Exome Sequencing (WES) in Early-Onset (EO) cases. A total of 88 patients from Italy (n = 52) and the Netherlands (n = 36), with a disease onset at age \u2264 45 years old and a Pain Numerical Rating Score \u2265 4, were recruited. After variant filtering and classification, WES analysis identified 142 potentially causative variants in 93 genes; 8 are Pathogenic, 15 are Likely Pathogenic, and 119 are Variants of Uncertain Significance. Notably, an enrichment of variants in transient receptor potential genes was observed, suggesting their role in pain modulation alongside VGSCs. A pathway analysis performed by comparing EO cases with 40 Italian healthy controls found enriched mutated genes in the \u201cNicotinic acetylcholine receptor signaling pathway\u201d. Targeting this pathway with non-opioid drugs could offer novel therapeutic avenues for painful SFN. Additionally, with this study we demonstrated that employing a gene panel of reported mutated genes could serve as an initial screening tool for SFN in genetic studies, enhancing clinical diagnostics.<\/jats:p>","DOI":"10.3390\/ijms25137248","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:58:42Z","timestamp":1719925122000},"page":"7248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Broadening the Genetic Spectrum of Painful Small-Fiber Neuropathy through Whole-Exome Study in Early-Onset Cases"],"prefix":"10.3390","volume":"25","author":[{"given":"Kaalindi","family":"Misra","sequence":"first","affiliation":[{"name":"Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7419-523X","authenticated-orcid":false,"given":"Milena","family":"\u015al\u0119czkowska","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Department of Neurology, Mental Health and Neuroscience Research Intsitute, Maastricht University Medical Centre+, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Santoro","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9503-9404","authenticated-orcid":false,"given":"Monique M.","family":"Gerrits","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Centre+, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Mascia","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-8534","authenticated-orcid":false,"given":"Margherita","family":"Marchi","sequence":"additional","affiliation":[{"name":"Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Salvi","sequence":"additional","affiliation":[{"name":"Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert J. M.","family":"Smeets","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6940-0027","authenticated-orcid":false,"given":"Janneke G. J.","family":"Hoeijmakers","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mental Health and Neuroscience Research Intsitute, Maastricht University Medical Centre+, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-1368","authenticated-orcid":false,"given":"Filippo Giovanni","family":"Martinelli Boneschi","sequence":"additional","affiliation":[{"name":"Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milan, Italy"},{"name":"Clinical Neurology Unit, Azienda Socio-Sanitaria Territoriale Santi Paolo e Carlo and Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-0479","authenticated-orcid":false,"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Neurology and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy"},{"name":"Neurophysiology Service, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lauria Pinter","sequence":"additional","affiliation":[{"name":"Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"},{"name":"Department of Biomedical and Clinical Sciences \u201cLuigi Sacco\u201d, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2467-067X","authenticated-orcid":false,"given":"Catharina G.","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mental Health and Neuroscience Research Intsitute, Maastricht University Medical Centre+, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Esposito","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, 20132 Milan, Italy"},{"name":"Neurology and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/mus.27340","article-title":"Small Fiber Neuropathy: Swiss Cohort Characterization","volume":"64","author":"Bitzi","year":"2021","journal-title":"Muscle Nerve"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/ene.13508","article-title":"Associated Conditions in Small Fiber Neuropathy\u2014A Large Cohort Study and Review of the Literature","volume":"25","author":"Hoeijmakers","year":"2018","journal-title":"Eur. 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