Abstract
The objective is to report a patient with Gerstmann-Sträussler-Scheinker syndrome caused by a pathogenic PRNP P102L variant harboring an unexpected concomitant pathogenic GRN 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 TMEM106B as an important modifier of the protein TDP-43 neuropathology associated with the GRN 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 PRNP P102L variant and an unpenetrated GRN p.R110X variant; a protective TMEM106B 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.
Introduction
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare inherited human prion disorder caused mostly by the P102L variant in the prion protein-encoding gene (PRNP), with autosomal dominant transmission () and an estimated prevalence of 1–10 out of 100,000,000 worldwide (), although its prevalence may be even higher depending on endemic and familiar conditions (). GSS is often associated with severe spongiform vacuolation and loss of neurons (; ). Clinical symptoms mostly occur between the ages of 20 and 80, and survival ranges from a few months to 10 years ().
Four clinical subtypes of P102L GSS have been identified: typical GSS; GSS with areflexia and paresthesia; Creutzfeldt-Jakob-disease-like phenotype; and pure dementia GSS ().
Considerable clinical variability even within the same family can be observed (; ). Cerebrospinal fluid 14-3-3 positivity and high total tau protein levels are often not sensitive enough to detect GSS; nevertheless, even RT-QuIC can yield false negative results. MRI can show generalized atrophy of brain cortices or the cerebellum; however, early in the disease course can be normal (; ).
Progranulin (PGRN), a protein encoded by GRN gene, plays an important role in microglial function, neuroinflammatory regulation, and lysosomal homeostasis. GRN deficiency has been associated with impaired lysosomal function and altered protein degradation pathways, contributing to TDP-43 accumulation patology ().
Variants in the progranulin gene (GRN) are associated with a various spectrum of phenotypes of frontotemporal lobar degeneration (FTLD): behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), corticobasal syndrome, or posterior cortical atrophy (; ). In GRN carriers, atrophy predominantly involves the frontal, temporal, and parietal cortices but preserves the occipital regions at onset (). GRN variants are associated with TDP-43 neuronal inclusions (; ).
TMEM106B is considered an important genetic modifier in GRN-associated disorders through its influence on lysosomal morphology and function. Moreover, TMEM106B-mediated modulation of lysosomal pathways has been proposed as a potential mechanism influencing susceptibility to TDP-43 neuropathology (; ; ).
We report a patient with a unique co-occurrence of two rare pathogenic variants, the P102L variant in PRNP and the p.R110X variant in GRN and protective TMEM106B allele.
Case description
A 46-year-old woman with an unclear family history of a non-specified “neurological” disorder leading to death at the age of 50 years in her paternal grandmother presented with widespread paresthesia and dizziness of unremarkable onset, and cinnarizine and betahistine were administered. Early on, dysarthria and alexia with gait instability and lower limb ataxia ensued, and the patient was admitted to a regional hospital. Later, she experienced depressive symptoms.
Initial brain and cervical spine MRIs yielded no significant abnormalities, and only mild cerebellar atrophy and parietal atrophy were present (Figures 1a, b). Laboratory examinations ruled out secondary etiology; CSF analysis was normal. Neuropsychological profiling proved mild cognitive decline, particularly in working memory and attention, which initially seemed linked to the depressive syndrome treated with citalopram. Hereditary ataxia testing was negative.
Figure 1
Due to suspected atypical neurodegeneration, the patient was referred to a university hospital. Genetic analysis (whole exome sequencing) revealed the P102L variant in the PRNP gene and, surprisingly, a concomitant p.R110X variant in the GRN gene. The PRNP p.P102L variant represents a classic pathogenic alteration associated with Gerstmann-Sträussler-Scheinker syndrome (GSS). At the molecular level, it leads to conformational instability of the prion protein (PrP), promoting its misfolding and conversion to the pathological PrP∧Sc isoform. The subsequent accumulation of pathological PrP leads to the formation of amyloid deposits and progressive neurodegeneration. P102L is associated with significant phenotypic and neuropathological variability, which may be related to different conformations of prion strains and biochemical properties of PrP fragments. The clinical diagnosis was GSS (subtype of paresthesia with areflexia) (), which progressively worsened into a major cerebellar syndrome with severe ataxia.
The patient was consulted with a prion specialist to provide best supportive care. The clinical presentation further worsened toward severe dysarthria with saccadic speech, horizontal and vertical nystagmus, gaze apraxia with difficulties in gaze fixation to the target, limb ataxia with hypermetria and areflexia on the lower extremities. 2 years after disease onset, symptoms resulted in dependence on family members. Pregabalin was prescribed for widespread paresthesia. Amantadine was administered off-label to address gait impairment. All medications were administered in maximal doses with good tolerance and adherence, nevertheless without significant clinical impact. Supportive therapy included physiotherapy and speech therapy and palliative care. Neuropsychology testing concluded considerable impairment in visuospatial processing and language.
To a lesser degree, dysexecutive syndrome with disinhibition and emotional lability was present. EEG did not reveal periodic patterns. Brain MRI showed increased cerebellar (mainly of the vermis) and parietal atrophy and asymmetrical atrophy of the frontal operculum and insular cortex predominantly on the left side (Figures 1c, d).
The prognosis of the patient was poor due to a lethal diagnosis, and the patient died 4 years after disease onset from brain edema and intercurrent infection. Autopsy confirmed typical neuropathology of GSS in line with the previously detected PRNP gene sequence variant P102L (c.305C>T) (CCG>CTG) in heterozygous form overlapping with the known p.R110X variant in the GRN gene sequence. PRNP p.P102L: classified as a pathogenic variant, in accordance with the literature in Gerstmann-Sträussler-Scheinker syndrome (GSS). The GRN p.R110X variant has already been reported in public genetic databases (including NCBI/ClinVar) as a pathogenic or likely pathogenic loss-of-function variant associated with frontotemporal lobar degeneration (FTLD) (). Both variants were confirmed by Sanger sequencing. Severe generalized neuronal atrophy with prominent astrogliosis was observed in the cerebellum and subcortical gray matter; however, these changes combined with the pattern of typical spongiform encephalopathy were also observed in all cortical regions. Moreover, characteristic “kuru-like” prion protein plaques focally forming multicentric plaques were seen either in standard H&E staining or were clearly visualized by immunohistochemical reaction with antibodies raised against prion protein (clones 12F10 and 3F4). Surprisingly, neuropathology focused on pathological depositions of TDP-43 protein, a typical hallmark of the previously reported pathogenic GRN variant p.R110X, was negative in all investigated areas, including brain structures suspected of involvement from MRI scans. Only unspecific “dash-like” and “dot-like” intraneuronal depositions were observed in immunohistochemical investigation using antibodies against TDP-43 and its hyperphosphorylated form in the amygdala and hippocampal regions without pathognomonic diagnostic protein inclusions, typically observed in GRN mutations cases. Additionally, there were incidental findings of initial tauopathies, predominantly picture of primary age-related tauopathy (PART) and argyrophilic grain disease (AGD), although any pathogenic aberration was recorded in the MAPT gene.
The detailed course of the disease is summarized in Figure 2. The family pedigree is summarized in Figure 3. The patient's mother was genetically tested negative for both GRN and PRNP gene variants. The patient's father died from malignancy 10 years ago, and no tissue samples for DNA testing were available.
Figure 2
Figure 3
Discussion
We present a unique case with a concomitant presence of two distinct rare variants. The PRNP variant in our case is presumed to be of paternal origin. Retrospective family history revealed that the proband's paternal grandmother (I.4) had unspecified early-onset dementia, with death at the age of 50. Furthermore, archival records indicate that her sister (I.5) had neuropathologically confirmed GSS. However, due to a fire that destroyed the original samples, the exact sequence of the pathogenetic variant cannot be confirmed. The proband's father (II.4) died in mid-life from colorectal carcinoma, and another limitation is the inability to analyze his tissue samples, as they have been disposed from the archive. The mother (III.1) has negative genetic testing for PRNP and GRN variants and no personal or family history of dementia, which further supports the paternal origin of the variant. We negatively tested the proband's sister (III.1); nevertheless, the origin of the GRN variant remains unclear due to the absence of any biological material from other relatives.
A non-specific clinical presentation posed a significant diagnostic challenge. The clinical presentation of a very slow onset of paresthesia with cerebellar symptoms together with marked cerebellar and brainstem atrophy and the P102L variant in the PRNP gene was clearly compatible with GSS [subtype GSS with paresthesia and areflexia ()]. The cognitive profile was compatible with GSS as well; early manifestations included prodromal depression, disinhibition, and emotional lability. In later stages, significant deficits in working memory and attention developed, and impairments in visuospatial processing and language appeared to be associated with a prevalent dysexecutive syndrome.
The impact of the GRN variant on the phenotype is more questionable. Different clinical phenotypes have been linked with GRN variants, such as bvFTD (Baker et al., 2006), svPPA (), and rarely corticobasal syndrome or posterior cortical atrophy (; ). Moreover, autoptic investigation does not reveal typical morphological changes previously described in patients with GRN variants. A possible driving mechanism for this finding may be the modifier effect of TMEM106B in GRN-associated protein TDP-43 neuropathology through its influence on lysosomal morphology and function, which was proposed as a potential mechanism modulating susceptibility to TDP-43 protein inclusion-associated neuropathology (; ; ; ).
We thus hypothesize that in our case, the allele in the TMEM106B gene, rs3173615 (p.Thr185Ser), might have impacted on the absence of TDP-43 inclusions in the brain tissue expected as result of the GRN mutation. According to the literature, TMEM106B gene polymorphism is associated with reduced symptom severity and several clinical studies have since been published (); Nicholson and Rademakers stated that significant number of individuals with pathogenic GRN mutations and two protective TMEM106B alleles may remain without symptoms throughout life (). identified associations of TMEM106B in the GRN and C9orf72 genetic groups, in line with TMEM106B being identified as a important phenotypic modifier in those with TDP-43 pathology. Similar to our observation, in a recently published GRN family with a proband presenting with young-onset FTD whose parent is an asymptomatic carrier in the 1980s, the family may be protected from developing disease symptoms because of the modifying effect of TMEM106B ().
Variants in the TMEM106B gene have been proposed as modifiers of FTD disease risk, especially in GRN mutation carriers, due to their modifying effects on biomarkers, imaging, cognitive and clinical outcomes in genetic FTD and modifying the effect of autosomal dominant FTD mutations on the natural course of genetic FTD, particularly TDP-43 pathology (). Moreover, Feng et al. suggest that modulation of TMEM106B levels might affect disease progression of FTLD patients with GRN mutations in their review ().
We acknowledge that our study has several limitations. The hypothesized protective effect of the TMEM106B variants on other genes involved in neurodegeneration still needs more evidence. Another plausible explanation for the absence of TDP-43 neuropathology in brain tissue could be the relatively short disease course, with the possibility that the patient died before the neuropathological consequences associated with the GRN variant became fully manifest. An additional limitation is that, although GRN loss-of-function variants are generally associated with high age-dependent penetrance, nevertheless variant-specific penetrance data for p.R110X remain limited. A further limitation is the absence of relevant biological material to confirm the origin of both variants. Although we excluded maternal origin and the family history was positive in the paternal pedigree, we cannot confirm a direct transmission of both pathogenic variants. Moreover, there is lack of therapeutic recommendations; all therapeutic approaches remain supportive or off-label.
In conclusion, atypical neurodegenerative disorders may occur in unexpected comorbidity, and clinical manifestations may reach a broad spectrum of phenotypes according to the underlying neuropathology. Our case demonstrates an intriguing co-expression of three different genetic variants implied in neurodegeneration (PRNP, GRN, TMEM106B), largely predominated by the PRNP mutation resulting in fully developed GSS, clinically and neuropathologically, and, moreover, the surprising absence of TDP-43 protein inclusions in brain tissue expected from the pathogenic GRN mutation. Likely pathogenic and pathogenic variants as well as potential indirect genetic modifier may indirectly influence expression of pathogenic protein deposits, as in our case, with a possibly protective effect of a TMEM106B variant on a GRN mutation carrier. Nevertheless, further evidence is needed to support this hypothesis.
Statements
Data availability statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request. Due to privacy and ethical restrictions, the data are not publicly available.
Ethics statement
The studies involving humans were approved by Multicentric Ethics Committee of the Institute of Clinical and Experimental Medicine and Thomayer University Hospital in Prague, Czech Republic (approval no. G-25-58). The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants' legal guardians/next of kin because the reason why written informed consent was waived is the patient died. Written informed consent was obtained from the individuals' next of kin for the publication of any potentially identifiable images or data included in this article.
Author contributions
MS: Writing – review & editing, Conceptualization, Writing – original draft, Project administration, Visualization. BK: Writing – review & editing, Writing – original draft. EP: Data curation, Investigation, Writing – review & editing. JK: Writing – review & editing, Data curation. SO: Writing – review & editing. RR: Conceptualization, Writing – review & editing. RM: Conceptualization, Writing – original draft, Writing – review & editing, Supervision.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Ministry of Health of the Czech Republic (projects Conceptual Development of Research Organization: MH CZ-DRO-FTN 64190, MH CZ-DRO-VFN 64165 and MH CZ-DRO-NNH 23884, MH CZ-DRO-UHHK 00179906), the Agency for Health Research (AZV) of the Czech Republic (project NU23-04-00173), and the Program EXCELES (ID Project No. LX22NPO5107), which are funded by the European Union-Next Generation EU and by Charles University (projects Cooperatio Medical Diagnostics and Basic Medical Sciences and GAUK 362521). Supported by the national budget through MEYS, LRI CZECRIN (LM2023049).
Acknowledgments
The study protocol was approved by the Multicentric Ethics Committee of the Institute of Clinical and Experimental Medicine and Thomayer University Hospital in Prague, Czech Republic (approval no. G-25-58). The evaluation of off-label amantadine use is not an aim of this study, and the drug had been administered prior to its initiation. Its use outside approved indications, supported by a well-established safety profile, was carefully considered and conducted in accordance with institutional policies, following a thorough discussion and verbal consent from the patient. We gratefully acknowledge prof. Tomáš Honzík from General University Hospital in Prague for co-operation and genetic analysis data sharing. During the preparation of this manuscript, the authors used AJE's Rubriq AI service for language review. Following this process, the authors independently reviewed and revised the text as necessary and assume full responsibility for the content of the publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1
BakerM.MackenzieI. R.Pickering-BrownS. M.GassJ.RademakersR.LindholmC.et al. (2006). Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 442, 916–919. doi: 10.1038/nature05016
2
BaldwinK. J.CorrellC. M. (2019). Prion disease. Semin. Neurol.39, 428–439. doi: 10.1055/s-0039-1687841
3
BugianiO.GiacconeG.PiccardoP.MorbinM.TagliaviniF.GhettiB.et al. (2000). Neuropathology of Gerstmann-Sträussler-Scheinker disease. Microsc. Res. Tech.50, 10–15. doi: 10.1002/1097-0029(20000701)50:1<10::AID-JEMT3>3.0.CO;2-6
4
CaroppoP.BelinC.GrabliD.MailletD.De SeptenvilleA.MigliaccioR.et al. (2015). Posterior cortical atrophy as an extreme phenotype of GRN mutations. JAMA Neurol.72, 224–228. doi: 10.1001/jamaneurol.2014.3308
5
ChenC.DongX. P. (2016). Epidemiological characteristics of human prion diseases. Infect. Dis. Poverty. 5:47. doi: 10.1186/s40249-016-0143-8
6
ChenZ.KongY.ZhangJ.ZouW. Q.WuL. (2024). Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease. Neurobiol. Dis.195:106497. doi: 10.1016/j.nbd.2024.106497
7
Chen-PlotkinA. S.Martinez-LageM.SleimanP. M. A.CrutsM.EngelborghsS.De DeynP. P.et al. (2011). Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Arch. Neurol.68, 488–497. doi: 10.1001/archneurol.2011.53
8
FengT.LacrampeA.HuF. (2021). Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders. Acta Neuropathol.141, 327–339. doi: 10.1007/s00401-020-02246-3
9
GiuntaM.LibriI.PremiE.BrattiniC.PagheraB.ArchettiS.et al. (2021). Clinical and radiological features of posterior cortical atrophy in a GRN mutation carrier: a case report. Eur. J. Neurol.28, 344–348. doi: 10.1111/ene.14574
10
Le BerI.CamuzatA.HannequinD.PasquierF.GuedjE.GhanimM.et al. (2008). French research network on FTD/FTD-MND. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain. 131, 732–746. doi: 10.1093/brain/awn012
11
MirzaS. S.PasternakM.PatersonA. D.RogaevaE.TartagliaM. C.MitchellS. B.et al. (2025). Disease-modifying effects of TMEM106B in genetic frontotemporal dementia: a longitudinal GENFI study. Brain. 148, 2746–2762. doi: 10.1093/brain/awaf019
12
NeumannM.SampathuD. M.KwongL. K.TruaxA. C.MicsenyiM. C.ChouT. T.et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science.314, 130–133. doi: 10.1126/science.1134108
13
NicholsonA. M.RademakersR. (2016). What we know about TMEM106B in neurodegeneration. Acta Neuropathol.132, 639–651. doi: 10.1007/s00401-016-1610-9
14
PerneelJ.ManoochehriM.HueyE. D.CummingsJ. L.BrownJ.SpinaS.et al. (2023). Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family. Front. Neurol.14:1160248. doi: 10.3389/fneur.2023.1160248
15
PottierC.ZhouX.PerkersonR. B.BakerM.JenkinsG. D.SerieD. J.et al. (2018). Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol.17, 548–558. doi: 10.1016/S1474-4422(18)30126-1
16
SamraK.MacDougallA. M.BouziguesA.BocchettaM. Cash D. M GreavesC. V.et al. (2023). GENFI. Genetic forms of primary progressive aphasia within the GENFI cohort: comparison with sporadic primary progressive aphasia. Brain Commun.5:fcad036. doi: 10.1093/braincomms/fcad036
17
ShinM.KimD.HeoY. J.BaekJ. W.YunS.JeongH. W.et al. (2023). Gerstmann-Sträussler-Scheinker disease: a case report. J. Korean Soc. Radiol. 84, 745–749. doi: 10.3348/jksr.2022.0089
18
SungW.NohM. Y.NahmM.KimY. S.KiC. S.KimY. E.et al. (2024). Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia. J. Neuroinflammation. 21:47. doi: 10.1186/s12974-024-03039-1
19
TakahashiH.StrittmatterS. M. (2025). The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases. Mol. Neurodegener.20:86. doi: 10.1186/s13024-025-00873-6
20
TesarA.MatejR.KukalJ.JohanidesovaS.RektorovaI.VyhnalekM.et al. (2019). Clinical variability in P102L Gerstmann-Sträussler-Scheinker syndrome. Ann. Neurol.86, 643–652. doi: 10.1002/ana.25579
21
VandeberghM.RamosE. M.Corriveau-LecavalierN.RamananV. K.KornakJ.MesterC.et al. (2024). Gene-specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration. Neurology103:e209832. doi: 10.1212/WNL.000000000020983
22
WhitwellJ. L.WeigandS. D.BoeveB. F.SenjemM. L.GunterJ. L.DeJesus-HernandezM.et al. (2012). Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain. 135, 794–806. doi: 10.1093/brain/aws001
23
YoshimuraM.YuanJ. H.HigashiK.YoshimuraA.ArataH.OkuboR.et al. (2018). Correlation between clinical and radiologic features of patients with Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu). J. Neurol. Sci.391, 15–21. doi: 10.1016/j.jns.05.012
Summary
Keywords
case report, Gerstmann-Sträussler-Scheinker syndrome, prion, progranulin gene, TMEM106B, variant
Citation
Sykora M, Krenkova B, Parobkova E, Keller J, Ostry S, Rusina R and Matej R (2026) Gerstmann-Sträussler-Scheinker syndrome with unexpected concomitant GRN variant: case report. Front. Neurosci. 20:1857360. doi: 10.3389/fnins.2026.1857360
Received
16 April 2026
Revised
14 June 2026
Accepted
17 June 2026
Published
13 July 2026
Volume
20 - 2026
Edited by
Martine Tetreault, University of Montreal, Canada
Updates
Copyright
© 2026 Sykora, Krenkova, Parobkova, Keller, Ostry, Rusina and Matej.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Radoslav Matej, radoslav.matej@lf3.cuni.cz
† These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.