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1/48. Variant Gerstmann-Straussler syndrome with the P105L prion gene mutation: an unusual case with nigral degeneration and widespread neurofibrillary tangles.

    We present here a case of variant Gerstmann-Straussler syndrome (GSS) with a codon 105 mutation of the prion protein gene. A 57-year-old woman developed dementia and gait disturbance dissimilar to the spastic paraparesis that is observed in most cases with codon 105 mutation. The clinical course of the disease in this case was 12 years. The brain weighed 900 g, and the frontal lobe, pallidum and thalamus were markedly atrophic. Severe neuronal loss was observed in the deep layer of the frontal and temporal cortices, and fibrillary gliosis and a marked loss of neurons was observed in the globus pallidus, thalamus and substantia nigra. Many amyloid plaques and some ballooned neurons were present in the frontal, temporal and parietal cortices. However, no spongiform changes were seen. The cerebellum was relatively well preserved. Numerous neurofibrillary tangles (NFTs) were recognized in the cerebral cortices, and scattered NFTs were observed in the basal nucleus of meynert, thalamus, substantia nigra, periaqueductal gray matter, raphe nuclei and locus ceruleus. The case presented here indicates the presence of variations in the pathological findings of cases with codon 105 mutation, and that the formation of cortical and brain stem NFTs might have something to do with the duration of illness and/or the degree of brain tissue destruction that had occurred. ( info)

2/48. A three-sister sibship of gerstmann-straussler-scheinker disease with a CJD phenotype.

    OBJECTIVE: To describe a rare phenotypic variant of P102L gerstmann-straussler-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. ( info)

3/48. Proton magnetic resonance spectroscopy of a patient with gerstmann-straussler-scheinker disease.

    A 23-year-old woman with gerstmann-straussler-scheinker disease (GSS) was investigated by 1H-magnetic resonance spectroscopy (1H-MRS). She developed gait ataxic at 22 years. The diagnosis was confirmed by dna analysis showing a proline-to-leucine point mutation at codon 102 of the prion protein. On 1H-MRS, she showed a remarkable reduction of the N-acetylaspartate/creatine ratio in the frontal lobe, cerebellar hemisphere and vermis and putamen. MRI revealed mild atrophy of the cerebellar hemispheres and vermis and cerebral cortex, but single-photon emission computed tomography (SPECT) with 99mHMPAO showed normal perfusion in the cerebellum. The imaging studies suggest that MRS might be superior to MRI or SPECT for detection of early neuronal degeneration. ( info)

4/48. A 7-kDa prion protein (PrP) fragment, an integral component of the PrP region required for infectivity, is the major amyloid protein in gerstmann-straussler-scheinker disease A117V.

    gerstmann-straussler-scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val(129) being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a approximately 7-kDa PrP fragment. sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148, Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the approximately 7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 217-228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85-148) readily assembled into amyloid fibrils. Peptide PrP-(191-205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23-41) and PrP-(217-228) did not. These findings suggest that the processing of mutant PrP isoforms associated with gerstmann-straussler-scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a approximately 7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation. ( info)

5/48. Report on the first polish case of the Gerstmann-Straussler-Scheinker syndrome.

    In the course of epidemiological studies on Creutzfeldt-Jakob Disease in poland, the authors found a male patient aged 54 years with dementia rapidly progressing for a year and ataxia of the extremities. EEG tracings were abnormal but without features typical of CJD. About six months after hospitalisation the patient died. Neuropathological examination of his brain demonstrated spongiform lesions of medium intensity present mainly in the cortex of frontal and occipital lobes, with slight proliferation of astroglia. In the cerebellar cortex numerous deposits of PAS-positive substance amorphous or in the shape of kuru plaques were disclosed. A smaller number of these plaques were found in the cortex of occipital and temporal lobes, and in the putamen. All deposits stained strongly with monoclonal 3F4 antibody to human prion protein (PrP). Genetic studies disclosed in the 20th chromosome, in the PrP gene, mutation at codon 102 (P102L). codon 129 was homozygous for methionine (M129M). It was established, moreover, that patient's father had at the same age a similar disease and died after one year and patient's sister died after a six-year-long neurological disease diagnosed as multiple sclerosis. On the basis of clinical, genetic and neuropathological findings the authors diagnosed the Gerstmann-Straussler-Scheinker syndrome, a familial prion disease with autosomal dominant character. This is the first report on this syndrome in poland. ( info)

6/48. A new point mutation of the PRNP gene in Gerstmann-Straussler-Scheinker case in poland.

    We report here a case of Gerstmann-Straussler-Scheinker (GSS) disease with a new mutation at the codon 232 (Met to Thr) of the PRNP gene. This case was characterized by PrP-immunopositive kuru and multicentric plaques; these plaques were also seen in the cerebral cortex, hippocampus and in the deep subcortical nuclei. Diffuse PrP depositions were also detected. In the temporal cortex, a few plaques were immunopositive for both PrP and Abeta; the latter was expressed at the periphery of the PrP-immunopositive cores. This mutation was absent from 40 healthy Polish controls and from 16 other Polish CJD cases, and we therefore believe that 232Thr is a new pathogenic mutation and not a benign polymorphism. ( info)

7/48. A new PRNP mutation (G131V) associated with gerstmann-straussler-scheinker disease.

    BACKGROUND: gerstmann-straussler-scheinker disease is a rare form of prion disease. OBJECTIVE: To determine the prion mutation in a 51-year-old man without a family history of neurologic disease who died from gerstmann-straussler-scheinker disease. PATIENT AND methods: The patient was a 51-year-old man who died after a 9-year illness characterized by dementia and eventually ataxia. Neuropathologic studies were performed, the results of which revealed abundant prion protein-immunopositive amyloid plaques in the cerebellum without spongiform degeneration. RESULTS: Genetic analysis of the prion protein gene showed a novel mutation at codon 131 that caused a valine-for-glycine substitution (G131V) and homozygosity at codon 129 (129M). Proteinase K-resistant prion protein was detected by Western blot analysis. CONCLUSIONS: This is the first mutation described in the short, antiparallel beta-sheet domain of the prion protein. This report highlights the importance of genetic analysis of patients with atypical dementia even in the absence of a family history. ( info)

8/48. Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Straussler-Scheinker syndrome P102L mutation complicated with dementia.

    Hyperphosphorylated tau (p-tau) deposition has been documented in a limited population of patients with Gerstmann-Straussler-Scheinker syndrome (GSS) with particular point mutations of the prion protein (PrP) gene. Although its pathogenesis is only poorly understood, p-tau in GSS is known to be identical to that in Alzheimer's disease (AD). We conducted immunohistochemical and quantitative image studies on the brain from a 44-year-old man with a 7-year history of dementia, diagnosed as having GSS with a point mutation of the PrP gene at codon 102 (GSS102), the commonest mutation in GSS. Severe spongiform degeneration and numerous PrP plaques were disclosed in the cerebral cortices and hippocampus, consistent with the diagnosis. However, rarely described in GSS102, prominent p-tau deposits as pretangles, neurofibrillary tangles and degenerating neurites were demonstrated adjacent to or around PrP plaques. beta-Amyloid protein (Abeta) plaques were generally sparse and appeared invariably to be of a diffuse type. Double-labeling immunohistochemistry yielded co-localization of p-tau with PrP but not with Abeta. Most PrP plaques did not contain Abeta. These results excluded a diagnosis of concomitant AD. Quantitative analysis on a fractional area density of immunoreactive pixels demonstrated that burdens of PrP and p-tau but not Abeta were significantly correlated. These results suggest that p-tau deposition in this GSS102 is secondarily induced by PrP but not by Abeta (secondary tauopathy). Our study also suggests that p-tau deposition might be a more common phenomenon in long-standing GSS. ( info)

9/48. Neuropathological features of a case with schizophrenia and prion protein gene P102L mutation before onset of gerstmann-straussler-scheinker disease.

    gerstmann-straussler-scheinker disease (GSS) is a hereditary transmissible spongiform encephalopathy associated with prion protein gene mutation P102L. The age of onset is roughly restricted to around the sixth decade; however, it is unclear whether the disease-specific pathology of GSS is already evident in the pre-clinical stage. We had a chance to examine an autopsy case with PRNP P102L mutation. The patient had died at 50 years of age before the clinical symptoms of GSS had appeared; neither neuronal loss, gliosis nor spongiform change was found anywhere in the brain. immunohistochemistry failed to detect any deposition of prion protein. It is thus considered that amyloid plaque formation in GSS probably develops in a relatively rapid fashion compared with Alzheimer's disease. Although the patient suffered from schizophrenia, no significant pathological changes were detected except for astrocytic inclusion bodies in the cerebral cortex. The nature and significance of the inclusion bodies, which are not observed in patients with GSS, remain unclear. ( info)

10/48. Variable phenotype in a P102L Gerstmann-Straussler-Scheinker Italian family.

    BACKGROUND: gerstmann-straussler-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-straussler-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. ( info)
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