Variable phenotype in a P102L Gerstmann-Sträussler-Scheinker Italian family

BACKGROUND: Gerstmann-Str?ussler-Scheinker disease is an autosomal dominant prion disease. The clinical features include ataxia, dementia, spastic paraparesis and extrapyramidal signs. METHODS: We report a new large Italian family affected by Gerstmann-Str?ussler-Scheinker disease. RESULTS: The four generation pedigree includes 11 patients. The mean age at onset +/- SD was 41.4 +/- 16.2 years. Mean disease duration to death in four patients was 5.5 +/- 1.7 years. Two clinical patterns were evident: cognitive impairment with scarce neurological features or ataxia followed by cognitive impairment. Molecular analysis showed P102L mutation in PRNP gene. CONCLUSION: Three Italian families have been reported to date. The variable phenotype has already been reported, and does not appear related to the codon 129 polymorphism.     

A three-sister sibship of Gerstmann-Sträussler-Scheinker disease with a CJD phenotype

OBJECTIVE: To describe a rare phenotypic variant of P102L Gerstmann-Str?ussler-Scheinker disease (GSS). BACKGROUND: Classic GSS is characterized by an early age at onset, prominent cerebellar signs with a slowly evolving dementia, and a neuropathology including multifocal PrP-positive plaques and variable but usually modest spongiform change. METHODS: Clinical, neuropathologic, immunohistochemical, and molecular genetic analysis of three sisters in a Hungarian family was performed. RESULTS: The clinical course of all three sisters was indistinguishable from sporadic Creutzfeldt-Jakob disease (CJD). Neuropathologic examination revealed spongiform changes, PrP (prion)-positive unicentric "kuru" or multicentric plaques, and abundant beta-A4-positive senile plaques. Molecular genetic analysis of the PRNP gene showed the heterozygous codon P102L mutation of classic GSS, with the methionine encoding allele of a heterozygous codon 129 coupled to the mutant 102 allele. CONCLUSION: The authors report the second recorded example of a sporadic CJD phenotype occurring in association with the P102L GSS genotype, and the first instance in which the phenotype was the rule rather than the exception, or was associated with prominent beta-A4 plaque formation.     

Gerstmann-Sträussler-Scheinker: a new phenotype with 'curly' PrP deposits

Gerstmann-Str?ussler-Scheinker (GSS) is a hereditary prion disease typically associated with prion protein (PrP)-containing plaques. The protease-resistant, scrapie PrP (PrPSc) is represented by internal fragments, whereas the C-terminal fragments associated with the other prion diseases are generally underrepresented. Different histopathologic and PrPSc features associated with at least 13 PrP gene (PRNP) mutations have been described in GSS. We report the histopathology and PrP characteristics in a father and son carrying a mutation at PRNP codon 187 that substitutes histidine (H) with arginine (R) and is coupled with valine (V) at position 129 (H187R-129V). The PrP plaques were present in both cases but with different structure and topography and minimal spongiform degeneration. A distinctive, "curly" PrP immunostaining was prominent in one case. The protease-resistant PrPSc differed in amount in the 2 cases, possibly depending on whether plaques or the curly immunostain was present. Two protease-resistant PrP fragments of 14 kDa and 7 kDa with, in at least one case, N-terminus between residues 90-99 and 82-90, respectively, codistributed with the plaques, whereas only very small amounts of the PK-resistant PrP were present in the curly staining regions. PK-resistant PrP recovered from the plaque and curly staining regions appeared to be full length.     

Morbus Gerstmann-Sträussler-Scheinker

Zusammenfassung Befunde von drei Patienten aus einer Familie mit einem Morbus Gerstmann-Sträussler-Scheinker (M-GSS) werden mitgeteilt. Die Diagnose wurde zweimal autoptisch gesichert. Klinisch und morphologisch handelt es sich um eine seltene familiäre subakute spongiöse Encephalopathie mit besonderem Befall des Kleinhirns, deren Vorkommen bisher nur in vier Familien mit insgesamt 52 Kranken gesichert ist. In der hier untersuchten Familie begann die Erkrankung durchschnittlich im fünften Dezennium und führte innerhalb von fünf Jahren zum Tode. Cerebellare Funktionsstörungen, später Demenz, bulbäre und Pyramidenbahn-Symptome sowie Hör- und Sehminderung bei zwei Patienten, charakterisierten das klinische Bild. Die biochemischen Befunde, einschließlich deren des Liquors, waren unauffällig. Neurophysiologisch zeigte sich mit fortschreitender Erkrankung eine Allgemeinveränderung im EEG ohne periodische paroxysmale Abläufe. Für eine Demyelinisierung ergaben die evozierten Potentiale keinen Hinweis. Nur durch die histologischen Befunde mit den nicht immer nachweisbaren Kuru-Plaques, aber stets unterschiedlich ausgeprägten multizentrischen Plaques, spongiösen Verderungen wechselnder Ausprägung war die Erkrankung sicher vom M. Alzheimer und M. Creutzfeldt-Jakob (M-CJ) abzugrenzen. Nach ersten positiven Übertragungsversuchen auf Primaten und ähnlichen histologischen Veränderungen beim M-CJ und Kuru wird eine slow-virus-Infektion durch ein nichtkonventionelles, möglicherweise dem M-CJ-, Kuru- und Scrapie-Virus verwandtes Virus diskutiert. Die unterschiedliche Manifestation der beim Menschen beobachteten Erkrankungen könnte auch durch verschiedene dispositionelle Faktoren beim Wirt erklärt werden, die nach den bisherigen humangenetischen Befunden beim M-GSS autosomal dominant weitergegeben werden.     

Gerstmann-Sträussler-Scheinker syndrome masquerading as multiple sclerosis

Gerstmann-Str?ussler-Scheinker syndrome (GSS) is a rare degenerative disorder of the central nervous system that belongs to the family of human spongiform encephalopathies, or prion diseases. GSS is almost always inherited and mostly carried in an autosomal dominant pattern. Nevertheless, GSS is genetically and phenotypically heterogeneous; among the different prion diseases GSS has the longest clinical course thereby has the potential to mimic the clinical course of different neurological disorders. Here, we report of a patient with a progressive ataxic syndrome, with MRI and CSF findings suggestive of a demyelinating-inflammatory process as multiple sclerosis and the cues that prompted to a final diagnosis of GSS.     

Gerstmann-Sträussler-Scheinker disease showing β-protein type cerebellar and cerebral amyloid angiopathy

Cerebral amyloid angiopathy is observed in several brain degenerative disorders, but this pathological condition has received little attention in Gerstmann-Sträussler-Scheinker disease (GSS). We report a 69-year-old man who showed the cardinal features of GSS together with typical and extensive congophilic angiopathy. Immunohistochemical studies revealed that the vast majority of the amyloid plaques present in the brain of this patient were consistently labeled by anti-prion protein (PrP) antibody. Double immunostaining disclosed many additional -protein immunoreactive plaque-like lesions, including a special type of hybrid plaque with colocalization of PrP and -protein (-PrP). The vascular amyloid deposits seen in both the cerebellum and cerebrum were immunoreactive only to anti--protein antibody. It seems likely that the extensive deposition of -protein amyloid (including brain vascular amyloidosis) seen in this and other similar cases is part of pathology of GSS, although the possibility that this finding is due to ageing or concomitant Alzheimer's disease cannot be completely ruled out.Supported by a research grant from the Intractable Disease Division, Ministry of Health and Welfare, Primary Amyloidosis Research Committee, Japan     

Ultrastructural study of florid plaques in variant Creutzfeldt-Jakob disease: a comparison with amyloid plaques in kuru, sporadic Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease

Background: Although the histological features of the amyloid plaques in variant Creutzfeldt–Jakob disease (vCJD) are distinct from those in other forms of prion disease [kuru, sporadic Creutzfeldt–Jakob disease (sCJD) and Gerstmann–Sträussler–Scheinker disease (GSS)], their ultrastructural features have only been described in a single case report. Aims: To study vCJD plaques systematically and compare them with plaques in kuru, sCJD, GSS and Alzheimer disease (AD). Methods: Amyloid plaques were studied by transmission electron microscopy and image analysis in five cases of vCJD, three cases of GSS, two cases of sCJD, one case of kuru and five cases of AD. Immunohistochemistry was performed on paraffin sections from one case of vCJD, two cases of GSS, one case of kuru and two cases of sCJD. Results: The florid plaques in vCJD were either compact or more diffuse; in both forms, the radiating fibrils were organized into thick 'tongues', in contrast to kuru plaques. Dystrophic neurites (DNs) containing lysosomal electron-dense bodies or vesicles surrounded florid plaques. Microglial cells were found within florid plaques; occasional amyloid fibrils were identified in membrane-bound pockets of microglial cells. In vCJD, there was significant tau immunoreactivity in DNs around florid plaques while, in sCJD, GSS and kuru, minimal tau immunoreactivity was observed around plaques. Conclusions: The ultrastructure of the florid plaques and DNs in vCJD is more reminiscent of neuritic plaques in AD than kuru or multicentric plaques. These findings may reflect differences both in the strains of the transmissible agents responsible for these disorders and in host factors.     

Prion protein (PrP) deposits in the tectum of experimental Gerstmann-Sträussler-Scheinker disease following intraocular inoculation

The abnormal misfolded isoform of prion protein (PrPd; "d" for disease) is considered as a surrogate marker for infectivity in the transmissible spongiform encephalopathies (TSEs) or prion diseases, including Creutzfeldt-Jakob disease (CJD). In this experiment, we used intraocular inoculation to study PrPd deposition in the visual system of the brain of mice infected with the Fujisaki (K.Fu) strain of Gerstmann-Str?ussler-Scheinker (GSS) disease. We report here that PrPd is deposited in the superior colliculus following contralateral intraocular inoculation and thus follows neuronal connections when it spreads into the brain. Until 26 weeks postinoculation, no PrPd-specific immunostaining was observed in the brain. At 27 weeks postinoculation, PrPd targeted to the contralateral superior colliculus as delicate granular synaptic deposits located in the superficial part of this structure. As already reported, a few spongiform vacuoles were visible in the same area by conventional H and E staining. In several other sections, vacuoles were visible but no PrPd staining could be detected.     

Sleep and temperature rhythms in two sisters with P102L Gerstmann-Sträussler-Scheinker (GSS) disease

BackgroundSleep disorders are increasingly recognized in the symptomatology of many neurodegenerative diseases. Gerstmann-Sträussler-Scheinker (GSS) disease is a hereditary prion disease featuring cerebellar ataxia, akinetic parkinsonism, pyramidal signs and cognitive decline.MethodsWe performed a polysomnographic study (PSG) of sleep and body core temperature (BcT°) in two sisters with GSS.ResultsOur study showed protracted nocturnal awakenings, reduced sleep efficiency and brief daytime naps but also qualitatively preserved slow-wave and REM sleep and substantially normal arousal and periodic limb movements in sleep indices and BcT° rhythm.ConclusionsThese findings conflict with those in multiple system atrophy and other prion diseases such as fatal familial insomnia, which enter the differential diagnosis of GSS and are characterized by prominently disrupted sleep-wake and BcT° cycles.     

Gerstmann-Sträussler-Scheinker disease- the dilemma of molecular and clinical correlations

Gerstmann-Str?ussler-Scheinker disease (GSSD) is a hereditary as well as transmissible human prion disease, restricted to families carrying point mutations of the PRPN gene on chromosome 20. To date 7 different causative mutations have been found. In this review the results of molecular biology with regard to the clinical course are discussed. As the findings of the disorder are very variable, the clinical picture and the neuropathology are extensively reported. An attempt has been made to define the disease, and filter out atypical non-GSSD cases. Finally, a comprehensive bibliography and tabulation of cases reported in the Western and Japanese literature are provided.     

Gerstmann-Strussler-Scheinker病1例报告

正朊蛋白病,又称感染性海绵状脑病,是由一种缺少核酸但具有感染性的朊蛋白引起的致死性的神经变性疾病,分为散发性、遗传性及获得性。在人类,遗传性朊蛋白病占朊蛋白病的5%~15%,包括家族性Creutzfeldt-Jakob病(Creutzfeldt-Jakob disease,CJD)、Gerstmann-Strussler-Scheinker(GSS)病以及家族性致死性失眠症(fatal familial insomnia,FFI)~([1])。其中,GSS病(人类孟德尔遗传137440)是常染色     

A second case of Gerstmann-Sträussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient

A rare case of Gerstmann-Str?ussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed by ataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrP(Sc)). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was no spongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising an unglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrP(Sc). Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Str?ussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia.     

Microglia is a component of the prion protein amyloid plaque in the Gerstmann-Sträussler-Scheinker syndrome

Summary The microglial cell has been demonstrated as component of the cerebral amyloid plaque of Alzheimer's disease. Involvement of microglia in plaques of another cerebral amyloidosis, the Gerstmann-Sträussler-Scheinker syndrome (GSS), has found little attention. We examine here the presence of microglia in GSS plaques by immunohistochemistry and transmission electron microscopy. Paraffin sections from five brains of patients with GSS were immunolabelled with antibodies against prion protein, A4/ amyloid protein, ferritin, leukocyte common antigen, HLA-DR, CD 68, and the MAC387 epitope for microglia and monocytes/macrophages; microglia was also labelled with the Ricinus communis agglutinin-1 lectin. Such (immuno)labelling demonstrated many delicate cell processes and occasional somata within and around prion protein plaques in all GSS brains. Microglial immunoreactivity was strongest with anti-ferritin and variable with anti-macrophage antibodies. Ultrastructural examination of brain tissue from one autopsy and one biopsy of GSS identified microglial cells in close proximity of amyloid plaque fibrils. Our observations demonstrate microglia as an important component of the amyloid plaque in GSS and suggest a major role for microglia in processing and deposition, or at least organization, of prion protein amyloid. Thus, plaques in both transmissible and nontransmissible cerebral amyloidoses seem to develop via similar pathogenetic mechanisms, irrespective of differences in etiology and molecular composition of the amyloid.Supported in part by the Austrian Fund for the Advancement of Scientific Research (P8196-MED). This study is part of the EC BIOMED I Project The human prion diseases led by H. Budka     

Lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive of Gerstmann-Sträussler-Scheinker disease Pro102Leu

Gerstmann-Str?ussler-Scheinker disease Pro102Leu (GSS102) is a rare autosomal dominant inherited prion disease due to a substitution of proline for leucine at codon 102 in the Prion Protein gene, and characterized by early walking difficulties and much later occurring dementia. We report clinical, electrophysiological and neuroradiological features of seven novel Italian cases of GSS102. The findings in our series support the thesis that early signs of GSS102 (including areflexia, ataxia, lower limb weakness, and painful dysesthesias) are likely due to a caudal myelopathic process, and suggest that GSS102 should be included among the causes of ataxia with areflexia. Moreover, our observations show that in patients with GSS102, as opposed to Friedreich's ataxia and other forms of ataxia with areflexia, nerve conduction studies and somato-sensory evoked potentials are normal, despite the presence of lower limb areflexia. Hence, in subjects with walking difficulties, the presence of lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive or possibly pathognomonic of GSS102, and can easily guide the clinicians to make the diagnosis of this rare neurodegenerative disease.