{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:35:01Z","timestamp":1771335301808,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Mutations in the gene encoding for optineurin (<jats:italic>OPTN<\/jats:italic>) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in <jats:italic>OPTN<\/jats:italic> mutation carriers have revealed transactive response DNA\u2010binding protein 43\u2009kDa (TDP\u201043) pathology, in addition to accumulations of tau and alpha\u2010synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the <jats:italic>OPTN<\/jats:italic> gene and different clinical presentations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole\u2010exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS\u2010FTLD pattern associated with prominent neuronal and oligodendroglial TDP\u201043 pathology, and an atypical limbic 4\u2010repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5\u2009years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the <jats:italic>OPTN<\/jats:italic> gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p><jats:italic>OPTN<\/jats:italic> mutations can be associated with extensive TDP\u201043 pathology and limbic\u2010predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS\u2010FTD spectrum within the same family.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52075","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T05:39:51Z","timestamp":1714541991000},"page":"1579-1589","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clinical heterogeneity within the <scp>ALS\u2010FTD<\/scp> spectrum in a family with a homozygous optineurin mutation"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6989-7539","authenticated-orcid":false,"given":"Tandis","family":"Parvizi","sequence":"first","affiliation":[{"name":"Department of Neurology Medical University of Vienna  Vienna Austria"},{"name":"Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigrid","family":"Klotz","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna  Vienna Austria"},{"name":"Division of Neuropathology and Neurochemistry, Department of Neurology Medical University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Keritam","sequence":"additional","affiliation":[{"name":"Department of Neurology Medical University of Vienna  Vienna 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Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1668-5177","authenticated-orcid":false,"given":"Alexander","family":"Zimprich","sequence":"additional","affiliation":[{"name":"Department of Neurology Medical University of Vienna  Vienna Austria"},{"name":"Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6581-4572","authenticated-orcid":false,"given":"Jakob","family":"Rath","sequence":"additional","affiliation":[{"name":"Department of Neurology Medical University of Vienna  Vienna Austria"},{"name":"Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"St\u00f6gmann","sequence":"additional","affiliation":[{"name":"Department of Neurology 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