Gerstmann-Sträussler-Scheinker Disease Research Articles

Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease

ObjectivesTo elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. MethodsThe genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. ResultsA total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27–30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. ConclusionThis study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.

[Clinical characteristics and diagnostics of human spongiform encephalopathies: an update].

Human spongiform encephalopathies are rare transmissible neurodegenerative diseases of the brain and the nervous system that are caused by misfolding of the physiological prion protein into apathological form and its deposition in the central nervous system (CNS). Prion diseases include Creutzfeldt-Jakob disease (CJD, sporadic or familial), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Prion diseases can be differentiated into three etiological categories: spontaneous (sporadic CJD), inherited (familial CJD, FFI, and GSS) and acquired (variant CJD and iatrogenic CJD). Most cases occur sporadically. Prion diseases can lead to avariety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play acrucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. Acausal treatment or specific therapeutic agents are not yet available. In general, apalliative therapeutic concept is indicated.

A Theoretical Framework on the Biology of Prion Diseases.

Prion diseases or TSE diseases are a group of neurodegenerative disorders that manifest in several forms in humans, such as Kuru disease, Creutzfeldt‒Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia. In this study, we propose a multimodular hypothesis of prion diseases. According to this hypothesis, a prion disease manifests because of the interaction of two genetic modules, such as the PRNP gene module and that of the gene or genes responsible for one or more chaperones, with one or some chemical module on whose structure the products of the genes or genetic modules interact. This study presents the perspective that modular thinking can allow us to overcome conceptual obstacles in the understanding and interpretation of prion diseases. The structure of the chemical module or modules is directly responsible for the folding or misfolding of the PrPC protein. The etiology of acquired prion diseases is explained based on this hypothesis. Hence, it has been proposed that (g) CJD involves the PRNP gene mutant and one or more mutant genes for one or more chaperone genes. In contrast, sCJD has one or more mutant chaperone genes. When does iCJD occur? Healthy individuals manifest acquired prion disease through contamination when infected with one or more mutant chaperones. The mutant chaperones interact with the prion protein, and PrPC is converted to its isoform PrPSc. In a recent study, there was a case of an individual with CJD after COVID-19 infection. This case emphasizes the link between neuroinflammation and protein misfolding and provides proof that chemical module formation is a necessary condition for the manifestation of prion diseases.

Pearls & Oy-sters: Deep Phenotyping of Abnormal Eye Movements Advances the Detection of Gerstmann-Sträussler-Scheinker Syndrome.

A 58-year-old previously healthy woman presents with 3 years of rapidly progressive ataxia, parkinsonism, dysautonomia, peripheral neuropathy, leg weakness, spasticity, hyperreflexia, and mild vertical-gaze palsy. She has a matrilineal family history of neurodegenerative diseases. She was initially postulated to have spinocerebellar ataxia or atypical parkinsonism with cerebellar features. However, on closer inspection, her abnormal extraocular eye movements suggested rare mimicking disorders such as prion disease as part of the differential diagnosis, requiring further evaluation. This case highlights how deep phenotyping can open new diagnostic considerations, inform additional workup, and yield the precise diagnosis of Gerstmann-Sträussler-Scheinker syndrome (GSS).

Calabria as a Genetic Isolate: A Model for the Study of Neurodegenerative Diseases.

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology—ranging from clinical activity to the genealogical reconstruction of families/populations across the centuries, the creation of databases, and molecular/genetic research—was modelled on the characteristics of the Calabrian population for more than three decades. This methodology allowed the identification of several novel genetic mutations or variants associated with neurodegenerative diseases. In addition, a higher prevalence of several hereditary neurodegenerative diseases has been reported in this population, such as Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Niemann–Pick type C disease, spinocerebellar ataxia, Creutzfeldt–Jakob disease, and Gerstmann–Straussler–Scheinker disease. Here, we summarize and discuss the results of research data supporting the view that Calabria could be considered as a genetic isolate and could represent a model, a sort of outdoor laboratory—similar to very few places in the world—useful for the advancement of knowledge on neurodegenerative diseases.

Methionine homozygosity for PRNP polymorphism and susceptibility to human prion diseases

BackgroundNo studies have assessed the independent association of methionine homozygosity at codon 129 with the susceptibility to prion diseases, controlling for the effects of the codon 219 polymorphisms and other...

Research Progress of Prion Characteristics and Pathogenesis

Prions are infectious proteins that cause disease in variable species of animals, including human being. The normal, cellular protein PrP (PrPC) is converted into PrPSc through a post translational process during which it acquires a high β-sheet content which made the protein resistant to degradation by proteinase K due to its PrP 27-30 domain that increase its half-life to &gt;48 hours as compared to that of the normal 3-6 hours, its stay leads to self-propagation and toxicity. The disease pathology is associated with many disturbances mainly in central nervous system which resulted from increased oxidative stress and mitochondrial dysfunction, disturbance of iron metabolism, alteration of calcium metabolism, increases of inflammatory cytokines, chemokine’s and nuclear factor-kappa β activity. The entire process creates a spongy hole inside the nervous system which leads to condition called encephalopathy. The agent cause scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease), transmissible mink encephalopathy (TME) in mink, chronic wasting disease (CWD) in white tailed deer, elk, mule deer and moose, feline spongiform encephalopathy in cats, exotic ungulate encephalopathy (EUE) in Nyala and Oryx. In humans it causes Creutzfeldt-Jakob disease (CJD) and its varieties, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (sFI) and Kuru. Prion diseases have zoonotic and interspecies transmission. Banning Meat bone meal and culling infected animals are recommended.

Novel Experimental Therapies for Transmissible Spongiform Encephalopathies, Future Beyond Supportive Treatment

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a group of rare, transmissible, and progressive neurodegenerative conditions that have been described in several mammalian species . In humans, TSEs encompass Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia and kuru disease. TSEs share a common pathogenic pathway that consists in protein misfolding and accumulation of prion protein (PrP). At a clinical level, neurodegeneration explains main clinical findings such as rapidly progressive dementia, focal neurologic deficits, cognitive impairment, among others.

A rare challenge in general surgery: double surgical procedure for large and small bowel obstruction in a patient with Gerstmann- Sträussler-Scheinker syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare, infectious syndrome related to a mutation in the prion protein gene. Described here are the challenges posed by surgery for a patient with GSS. A 61-yr-old woman with GSS was admitted to this department and underwent surgery twice for large and small bowel obstruction. This is the first report of two major surgical procedures in a patient with GSS. Experiences with this case and precautions when using a disposable device during endotracheal intubation and a surgical procedure to manage a patient with GSS are described.

Structural Features of Heparin and Its Interactions With Cellular Prion Protein Measured by Surface Plasmon Resonance.

Self-propagating form of the prion protein (PrPSc) causes many neurodegenerative diseases, such as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS). Heparin is a highly sulfated linear glycosaminoglycan (GAG) and is composed of alternating D-glucosamine and L-iduronic acid or D-glucuronic acid sugar residues. The interactions of heparin with various proteins in a domain-specific or charged-dependent manner provide key roles on many physiological and pathological processes. While GAG-PrP interactions had been previously reported, the specific glycan structures that facilitate interactions with different regions of PrP and their binding kinetics have not been systematically investigated. In this study, we performed direct binding surface plasmon resonance (SPR) assay to characterize the kinetics of heparin binding to four recombinant murine PrP constructs including full length (M23–230), a deletion mutant lacking the four histidine-containing octapeptide repeats (M23–230 Δ59–90), the isolated N-terminal domain (M23–109), and the isolated C-terminal domain (M90–230). Additionally, we found the specific structural determinants required for GAG binding to the four PrP constructs with chemically defined derivatives of heparin and other GAGs by an SPR competition assay. Our findings may be instrumental in developing designer GAGs for specific targets within the PrP to fine-tune biological and pathophysiological activities of PrP.

A novel PRNP-G131R variant associated with familial prion disease.

Roughly 40 autosomal dominant mutations of the prion protein gene ( PRNP ) cosegregate with familial Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, or Gerstmann-Sträussler-Scheinker disease (GSS).1,2 Genetic prion disease in African Americans is rarely reported. We sequenced the PRNP coding segment of a 43-year-old African American woman with rapidly progressive dementia and a positive family history of early onset dementia not previously recognized as genetic prion disease.

Gerstmann-Sträussler-Scheinker disease (PRNP p.D202N) presenting with atypical parkinsonism.

The p.D202N mutation in PRNP is a rare variant associated with Gerstmann-Straussler-Scheinker disease (GSS), a genetic form of prion cerebral amyloidosis. To date, there have been only 4 reports of this mutation worldwide and only one detailed clinical study (table e-1, [links.lww.com/NXG/A223][1]).1–4 Here, we describe the clinical phenotype and the results of neuroradiologic and laboratory investigations in an Italian patient carrying this genetic variant. [1]: http://links.lww.com/NXG/A223

Editors' note: Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings.

In the article “Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings,” Kang et al. presented the case of a 49-year-old man with progressive ataxia, dysarthria, and cognitive impairment who was found to have a heterozygous mutation in the prion protein (PRNP) gene, suspected to be de novo, resulting in a diagnosis of Gerstmann-Sträussler-Scheinker disease (GSS). In the accompanying discussion, they also presented a review of the clinical manifestations, diagnostic test results, and presence of family history of GSS in 86 patients (including theirs). In response, Dr. Paucar notes that the polymorphic PRNP codon 129M has disease-modifying effect on GSS and that real-time quaking-induced conversion (RT-QuIC) can be helpful in patients with suspected prion disease, especially with ambiguous family history, and that a discussion of transmissibility of GSS-associated PRNP mutations would have been helpful. Responding to these comments, Park et al. report the results of PRNP codon 129M polymorphisms in their review and that they found the methionine/valine heterozygote to have slightly earlier disease onset. They note that they could not evaluate the role of RT-QuIC but report that 87.7% of the patients with the P102L mutation (found in their patient) had a positive family history, whereas 8 other single-case mutations had a negative family history. In the article “Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings,” Kang et al. presented the case of a 49-year-old man with progressive ataxia, dysarthria, and cognitive impairment who was found to have a heterozygous mutation in the prion protein (PRNP) gene, suspected to be de novo, resulting in a diagnosis of Gerstmann-Sträussler-Scheinker disease (GSS). In the accompanying discussion, they also presented a review of the clinical manifestations, diagnostic test results, and presence of family history of GSS in 86 patients (including theirs). In response, Dr. Paucar notes that the polymorphic PRNP codon 129M has disease-modifying effect on GSS and that real-time quaking-induced conversion (RT-QuIC) can be helpful in patients with suspected prion disease, especially with ambiguous family history, and that a discussion of transmissibility of GSS-associated PRNP mutations would have been helpful. Responding to these comments, Park et al. report the results of PRNP codon 129M polymorphisms in their review and that they found the methionine/valine heterozygote to have slightly earlier disease onset. They note that they could not evaluate the role of RT-QuIC but report that 87.7% of the patients with the P102L mutation (found in their patient) had a positive family history, whereas 8 other single-case mutations had a negative family history.

Movement Disorders in Prionopathies: A Systematic Review

<strong>Background:</strong> Movement disorders are frequent features of prionopathies. However, their prevalence and onset remain poorly described. <strong>Methods:</strong> We performed a systematic review of case reports and case series of pathologically- and genetically confirmed prionopathies. Timing of symptom and movement disorder onset were documented. Continuous variables were compared between two groups using the Wilcoxon rank sum test and between multiple groups using Kruskal–Wallis test. Categorical variables were compared using Fisherfs exact test. <strong>Results:</strong> A total of 324 cases were included in this analysis. Movement disorders were a common feature at the onset of symptoms in most prionopathies. Gait ataxia was present in more than half of cases in all types of prionopathies. The prevalence of limb ataxia (20%) and myoclonus (24%) was lower in Gerstmann–Straussler–Scheinker disease compared to other prionopathies (p ≤ 0.004). Myoclonus was common but often a later feature in sporadic Creutzfeldt–Jakob disease (2 months before death). Chorea was uncommon but disproportionately prevalent in variant Creutzfeldt–Jakob disease (30% of cases; p &lt; 0.001). In genetic Creutzfeldt–Jakob disease, E200K <em>PRNP</em> carriers exhibited gait and limb ataxia more often when compared to other mutation carriers. <strong>Discussion:</strong> Movement disorders are differentially present in the course of the various prionopathies. The movement phenomenology and appearance are associated with the type of prion disease and the <em>PRNP</em> genotype and likely reflect the underlying pattern of neurodegeneration. Reliance on myoclonus as a diagnostic feature of sporadic Creutzfeldt.Jakob disease may delay its recognition given its relatively late appearance in the disease course.

Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from 7 Czech patients and 87 published cases suggests the existence of 4 clinical phenotypes (typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt-Jakob disease-like GSS); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, magnetic resonance imaging and real-time quaking-induced conversion may be helpful, but the results should be evaluated with respect to the overall clinical context. ANN NEUROL 2019;86:643-652.

\u201cDual Disease\u201d TgAD/GSS mice exhibit enhanced Alzheimer\u2019s disease pathology and reveal PrPC-dependent secretion of A\u03b2

To address the question of cross-talk between prion protein (PrP) and Alzheimer’s disease (AD), we generated TgAD/GSS mice that develop amyloid-β (Aβ) plaques of AD and PrP (specifically mutated PrPA116V) plaques of Gerstmann-Sträussler-Scheinker disease (GSS) and compared plaque-related features in these mice to AD mice that express normal (TgAD), high (TgAD/HuPrP), or no (TgAD/PrP−/−) PrPC. In contrast to PrPC, PrPA116V weakly co-localized to Aβ plaques, did not co-immunoprecipitate with Aβ, and poorly bound to Aβ in an ELISA-based binding assay. Despite the reduced association of PrPA116V with Aβ, TgAD/GSS and TgAD/HuPrP mice that express comparable levels of PrPA116V and PrPC respectively, displayed similar increases in Aβ plaque burden and steady state levels of Aβ and its precursor APP compared with TgAD mice. Our Tg mouse lines also revealed a predominance of intracellular Aβ plaques in mice lacking PrPC (TgAD/PrP−/−, TgAD/GSS) compared with an extracellular predominance in PrPC-expressing mice (TgAD, TgAD/HuPrP). Parallel studies in N2aAPPswe cells revealed a direct dependence on PrPC but not PrPA116V for exosome-related secretion of Aβ. Overall, our findings are two-fold; they suggest that PrP expression augments Aβ plaque production, at least in part by an indirect mechanism, perhaps by increasing steady state levels of APP, while they also provide support for a fundamental role of PrPC to bind to and deliver intraneuronal Aβ to exosomes for secretion.

Analysis of 12 Chinese Patients with Proline-to-Leucine Mutation at Codon 102-Associated Gerstmann-Sträussler-Scheinker Disease.

Background and PurposeGerstmann-Sträussler-Scheinker disease (GSS) with a proline-to-leucine mutation at codon 102 (P102L) in the PRNP gene is the most frequently reported GSS subtype worldwide. This study aimed to determine the epidemiological, clinical, genetic, and laboratory characteristics of 12 Chinese patients with P102L-associated GSS (henceforth P102L GSS).MethodsThe enrolled P102L GSS cases were analyzed according to the diagnostic criteria for Creutzfeldt-Jakob disease (CJD) issued by the China National Health Commission.ResultsThe median onset age was 50 years (range 34 to 67 years) and sex ratio was 1:2 (males:females). Most patients displayed more than one foremost symptom. Movement symptoms were frequently reported (9 of the 12 cases), followed by rapidly progressing dementia (7 cases), mental problems (5 cases), and slowly progressing dementia (2 cases). Almost all cases displayed more sporadic CJD (sCJD)-associated neurological symptoms and signs as time progressed. Five (45.5%) of 11 cases were cerebrospinal fluid 14-3-3 positive, and 2 (25%) of 8 cases exhibited periodic sharp wave complexes in electroencephalograms. MRI abnormalities were detected in all 11 of the scanned patients. Methionine homozygous genotype at codon 129 (M129M) and glutamic acid homozygous at codon 219 (E219E) homozygosity was present in 11 cases, while 1 case was M129M homozygous and glutamic acid/lysine heterozygous at codon 219 (E219K) heterozygous. Ten of the 12 cases recalled a disease-related family history during the clinical interviews. The median survival from symptom onset of the seven dead cases was 16 months (range 10 to 44 months). Patients showing the sCJD phenotype (rapidly progressing dementia) appeared to be associated with a shorter survival time.ConclusionsThe indistinguishable clinical features of P102L GSS patients with sCJD, especially in the early stage, support the importance of PRNP testing for diagnosing GSS.

IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.

A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles.

To explore pathogenesis in a young Gerstmann-Sträussler-Scheinker Disease (GSS) patient, the corresponding mutation, an eight-residue duplication in the hydrophobic region (HR), was inserted into the wild type mouse PrP gene. Transgenic (Tg) mouse lines expressing this mutation (Tg.HRdup) developed spontaneous neurologic syndromes and brain extracts hastened disease in low-expressor Tg.HRdup mice, suggesting de novo formation of prions. While Tg.HRdup mice exhibited spongiform change, PrP aggregates and the anticipated GSS hallmark of a proteinase K (PK)-resistant 8 kDa fragment deriving from the center of PrP, the LGGLGGYV insertion also imparted alterations in PrP's unstructured N-terminus, resulting in a 16 kDa species following thermolysin exposure. This species comprises a plausible precursor to the 8 kDa PK-resistant fragment and its detection in adolescent Tg.HRdup mice suggests that an early start to accumulation could account for early disease of the index case. A 16 kDa thermolysin-resistant signature was also found in GSS patients with P102L, A117V, H187R and F198S alleles and has coordinates similar to GSS stop codon mutations. Our data suggest a novel shared pathway of GSS pathogenesis that is fundamentally distinct from that producing structural alterations in the C-terminus of PrP, as observed in other prion diseases such as Creutzfeldt-Jakob Disease and scrapie.

Generation of a new infectious recombinant prion: a model to understand Gerstmann\u2013Str\xe4ussler\u2013Scheinker syndrome

Human transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative disorders that include Kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia. GSS is a genetically determined TSE caused by a range of mutations within the prion protein (PrP) gene. Several animal models, based on the expression of PrPs carrying mutations analogous to human heritable prion diseases, support that mutations might predispose PrP to spontaneously misfold. An adapted Protein Misfolding Cyclic Amplification methodology based on the use of human recombinant PrP (recPMCA) generated different self-propagating misfolded proteins spontaneously. These were characterized biochemically and structurally, and the one partially sharing some of the GSS PrPSc molecular features was inoculated into different animal models showing high infectivity. This constitutes an infectious recombinant prion which could be an invaluable model for understanding GSS. Moreover, this study proves the possibility to generate recombinant versions of other human prion diseases that could provide a further understanding on the molecular features of these devastating disorders.