{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:10:26Z","timestamp":1783923026314,"version":"3.55.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>\n                    The objective is to report a patient with Gerstmann-Str\u00e4ussler-Scheinker syndrome caused by a pathogenic\n                    <jats:italic>PRNP<\/jats:italic>\n                    P102L variant harboring an unexpected concomitant pathogenic\n                    <jats:italic>GRN<\/jats:italic>\n                    variant p.R110X and to discuss the potential contribution of combined genetic pathology to the clinical and neuroimaging phenotype confirmed by autopsy. Moreover, we discuss the potential role of\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    as an important modifier of the protein TDP-43 neuropathology associated with the\n                    <jats:italic>GRN<\/jats:italic>\n                    mutation in this case. The patient underwent detailed clinical assessment, serial neuropsychological evaluation, brain MRI, cerebrospinal fluid analysis, whole-exome sequencing, and next generation sequencing. A postmortem neuropathologic examination was performed to confirm the diagnosis. The patient presented slowly progressive paresthesia, cerebellar ataxia, dysarthria, and later cognitive and behavioral changes. Genetic testing revealed a heterozygous\n                    <jats:italic>PRNP<\/jats:italic>\n                    P102L variant and an unpenetrated\n                    <jats:italic>GRN<\/jats:italic>\n                    p.R110X variant; a protective\n                    <jats:italic>TMEM106B<\/jats:italic>\n                    polymorphism associated with TDP-43 pathology was also identified. Neuroimaging demonstrated progressive cerebellar and parietal atrophy with asymmetric left frontal opercular and insular involvement. The clinical course was dominated by a cerebellar GSS phenotype. The patient died 4 years after symptom onset. Neuropathology confirmed GSS, nevertheless without detectable TDP-43-associated neuropathology. This case highlights the diagnostic complexity of rare neurodegenerative disorders and illustrates that pathogenic variants may not influence phenotypic expression. Comprehensive genetic testing should be considered in atypical cases, as certain genetic variants may contribute to phenotypic variability and represent potential modifiers of phenotypic expression.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2026.1857360","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:34:09Z","timestamp":1783920849000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gerstmann-Str\u00e4ussler-Scheinker syndrome with unexpected concomitant GRN variant: case report"],"prefix":"10.3389","volume":"20","author":[{"given":"Matyas","family":"Sykora","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]},{"name":"Department of Neurology, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]},{"name":"BrainBank, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibiana","family":"Krenkova","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Ceske Budejovice","place":["Ceske Budejovice, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Parobkova","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]},{"name":"BrainBank, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u0159\u00ed","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Radiology, University Hospital Motol and Homolka","place":["Prague, Czechia"]},{"name":"Department of Neurology, Third Faculty of Medicine, Charles University","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svatopluk","family":"Ostry","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Ceske Budejovice","place":["Ceske Budejovice, Czechia"]},{"name":"Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University in Prague and Military University Hospital","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Rusina","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Hradec Kralove, Faculty of Medicine Hradec Kralove, Charles University","place":["Hradec Kralove, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radoslav","family":"Matej","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]},{"name":"BrainBank, Third Faculty of Medicine, Charles University and Thomayer University Hospital","place":["Prague, Czechia"]},{"name":"Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital","place":["Prague, Czechia"]},{"name":"Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/nature05016","article-title":"Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17","volume":"442","author":"Baker","year":"2006","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1055\/s-0039-1687841","article-title":"Prion disease","volume":"39","author":"Baldwin","year":"2019","journal-title":"Semin. 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