{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T21:26:03Z","timestamp":1776461163707,"version":"3.51.2"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"21","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Een Hart voor ALS\u201d, \u201cLaeversfonds voor ALS Onderzoek\u201d and \u201cthe Val\u00e9ry Perrier Race against ALS"},{"name":"Vlaamse Impulsfinanciering voor Netwerken voor Dementie Onderzoek","award":["IWT 135043"],"award-info":[{"award-number":["IWT 135043"]}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"crossref","award":["AARF-24-1300693"],"award-info":[{"award-number":["AARF-24-1300693"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003130","name":"FWO","doi-asserted-by":"publisher","award":["1225725N"],"award-info":[{"award-number":["1225725N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["A2022019F"],"award-info":[{"award-number":["A2022019F"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"name":"C1-internal funds from KU Leuven","award":["C14-17-107"],"award-info":[{"award-number":["C14-17-107"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Co-occurrence of double heterozygosity in TARDBP and C9ORF72 is exceedingly rare in amyotrophic lateral sclerosis. While TARDBP mutations and C9ORF72 hexanucleotide repeat expansions have each been independently implicated in disease pathogenesis, their combined effect on disease progression and neuropathology remains unclear. We present the first study documenting a patient harboring both a TARDBP mutation and a C9ORF72 expansion, with comprehensive postmortem data available, to elucidate any additive or synergistic effects on disease course and pathological burden. Detailed clinical assessments tracked the patient\u2019s progression, and neuropathological examination was performed postmortem. The presence and extent of TDP-43 pathology and other hallmark features were evaluated and compared to known patterns in carriers of isolated C9ORF72 mutations. The patient\u2019s clinical trajectory and pathological findings did not show evidence of a more aggressive disease course or heightened pathological burden attributable to the additional TARDBP mutation. Instead, the disease manifested in a manner consistent with other C9ORF72 carriers, suggesting that double heterozygosity do not necessarily exacerbate ALS pathology.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf147","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T14:35:21Z","timestamp":1758551721000},"page":"1829-1835","source":"Crossref","is-referenced-by-count":1,"title":["Tracing neuropathological signatures: <i>TARDBP<\/i> and <i>C9orf72<\/i> double mutations in a Sicilian family"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8247-1866","authenticated-orcid":false,"given":"Pegah","family":"Masrori","sequence":"first","affiliation":[{"name":"Department of Neurology, Neuromuscular Reference Centre, University Hospitals Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]},{"name":"Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven, University of Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5253-0730","authenticated-orcid":false,"given":"Sandra O","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI) KU Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lieselot","family":"Dedeene","sequence":"additional","affiliation":[{"name":"Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI) KU Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gauthier","family":"Remiche","sequence":"additional","affiliation":[{"name":"Universit\u00e9 libre de Bruxelles (ULB), H\u00f4pital Universitaire de Bruxelles (H.U.B), CUB H\u00f4pital Erasme, Service de Neurologie, Centre de R\u00e9f\u00e9rence Neuromusculaire ,","place":["Route de Lennik 808, 1070 Anderlecht (Brussels), Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilde","family":"Van Esch","sequence":"additional","affiliation":[{"name":"Center for Human Genetics, University Hospitals Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dietmar Rudolf","family":"Thal","sequence":"additional","affiliation":[{"name":"Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI) KU Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]},{"name":"Department of Pathology, University Hospitals Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Van Damme","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuromuscular Reference Centre, University Hospitals Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]},{"name":"Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven, University of Leuven , Herestraat 49, 3000 Leuven ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"2025101608313983000_ref1","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"key":"2025101608313983000_ref2","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"DeJesus-Hernandez","year":"2011","journal-title":"Neuron"},{"key":"2025101608313983000_ref3","article-title":"Stages of pTDP-43 pathology in amyotrophic lateral sclerosis","volume":"74","author":"Brettschneider","year":"2013","journal-title":"Ann Neurol"},{"key":"2025101608313983000_ref4","article-title":"Phases of a beta-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"2025101608313983000_ref5","article-title":"Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe consortium","volume":"18","author":"Alafuzoff","year":"2008","journal-title":"Brain Pathol"},{"key":"2025101608313983000_ref6","article-title":"TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis","volume":"7","author":"Van Deerlin","year":"2008","journal-title":"Lancet Neurol"},{"key":"2025101608313983000_ref7","article-title":"TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2025101608313983000_ref8","article-title":"Amyotrophic lateral sclerosis: dash-like accumulation of phosphorylated TDP-43 in somatodendritic and axonal compartments of somatomotor neurons of the lower brainstem and spinal cord","volume":"120","author":"Braak","year":"2010","journal-title":"Acta Neuropathol"},{"key":"2025101608313983000_ref9","article-title":"Dipeptide repeat protein and TDP-43 pathology along the hypothalamic-pituitary axis in C9orf72 and non-C9orf72 ALS and FTLD-TDP cases","volume":"140","author":"Dedeene","year":"2020","journal-title":"Acta Neuropathol"},{"key":"2025101608313983000_ref10","article-title":"Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers","volume":"130","author":"Mackenzie","year":"2015","journal-title":"Acta 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