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S Capellari

Publications and source records attributed to S Capellari.

At least 19 recordsLinked to original sources
PubMed2002

Creutzfeldt-Jakob disease associated with a deletion of two repeats in the prion protein gene.

A two-octapeptide repeat deletion of the prion protein gene has been recently observed in a patient with a 2-year history of dementia and a clinical diagnosis of possible Creutzfeldt-Jakob disease (CJD). The authors report a similar deletion in a patient with a definitive diagnosis of CJD. Since the two-repeat deletion has not been observed in large, population-based studies, the two cases suggest that this deletion is a new pathogenic mutation associated with CJD.

Autopsy↗
PubMed2002

Insomnia associated with thalamic involvement in E200K Creutzfeldt-Jakob disease.

BACKGROUND: Insomnia with predominant thalamic involvement and minor cortical and cerebellar pathologic changes is not characteristic of familial Creutzfeldt-Jakob disease (CJD) but is a hallmark of fatal familial insomnia. OBJECTIVE: To report a 53-year-old woman with intractable insomnia as her initial symptom of disease. METHODS: The authors characterized clinical, pathologic, and molecular features of the disease using EEG, polysomnography, neurohistology, Western blotting, protein sequencing, and prion protein (PrP) gene (PRNP) analysis. RESULTS: The patient developed dysgraphia, dysarthria, bulimia, myoclonus, memory loss, visual hallucinations, and opisthotonos, as well as pyramidal, extrapyramidal, and cerebellar signs. Polysomnographic studies showed an absence of stages 3 and 4, and REM. She died 8 months after onset. On neuropathologic examination, there was major thalamic involvement characterized by neuronal loss, spongiform changes, and prominent gliosis. The inferior olivary nuclei exhibited chromatolysis, neuronal loss, and gliosis. Spongiform changes were mild in the neocortex and not evident in the cerebellum. PrP immunopositivity was present in these areas as well as in the thalamus. PRNP analysis showed the haplotype E200K-129M. Western blot analysis showed the presence of proteinase K (PK)-resistant PrP (PrP(sc)) with the nonglycosylated isoform of approximately 21 kd, corresponding in size to that of type 1 PrP(sc). N-terminal protein sequencing demonstrated PK cleavage sites at glycine (G) 82 and G78, as previously reported in CJD with the E200K-129 M haplotype. CONCLUSIONS: Insomnia may be a prominent early symptom in cases of CJD linked to the E200K-129M haplotype in which the thalamus is severely affected.

Amino Acid Sequence↗
PubMed2002

A French cluster of Creutzfeldt-Jakob disease: a molecular analysis.

We report the molecular and phenotypic analysis of a French cluster of three cases of Creutzfeldt-Jakob disease (CJD), two of them occurring in 1998 in the same village and the other in 1995 in a neighboring village. Analyses of the occurrence of these events in a close area with less than 3000 inhabitants over the 1992-1999 notification period confirmed that they are rare. This could be explained either by a common source of contamination or by the coincidental occurrence of either sporadic or genetic CJD. We applied genetic analysis and brain PrPres typing to explore these CJD cases. The three patients did not carry any mutation in their prion protein gene coding sequence. All were homozygous for methionine at the polymorphic codon 129. Brain tissue was available from two cases that died in 1998. The two patients showed different PrPres profiles on Western blot and distinct clinico-pathological features. These findings do not support the conclusion that in these three cases, CJD was acquired from a unique source of contamination and suggest that concurrent occurrence of sporadic CJD accounted for this CJD cluster.

Aged↗
PubMed2001

Inherited prion disease caused by the V210I mutation: transmission to transgenic mice.

OBJECTIVE: To describe the clinical and neuropathologic profile and determine the strain characteristics of familial Creutzfeldt-Jakob disease (fCJD) caused by a point mutation of the PRNP gene at codon 210 that results in a valine-to-isoleucine substitution in the prion protein (PrP). METHODS: The clinicopathologic features of four individuals from the United States who died of fCJD(V210I) were compared. Transgenic (Tg) mice expressing a chimeric human-mouse PrP transgene were inoculated with brain extracts from three fCJD(V210I) cases, sporadic CJD (sCJD), fCJD(E200K), and fatal familial insomnia (FFI), to compare prion strain characteristics. RESULTS: The clinicopathologic profile of fCJD(V210I) was variable among cases but shared similarities with sCJD. The pattern of PrP(Sc) deposition in the brains of Tg mice was similar to that caused by sCJD but different from that associated with fCJD(E200K) or FFI. CONCLUSIONS: Each of these prion diseases is characterized by a rapidly progressive dementia with myoclonus, periodic complexes on EEG, and spongiform change without PrP plaque deposition in the brain. The occurrence of a different PrP(Sc) phenotype with each PRNP mutation argues that each respective amino acid sequence substitution produces a different prion strain.

Animals↗
PubMed2001

Creutzfeldt-Jakob disease after receipt of a previously unimplicated brand of dura mater graft.

BACKGROUND: Iatrogenic Creutzfeldt-Jakob disease (CJD) transmission via dura mater grafts has been reported in many countries. In September 1998, a 39-year-old Colorado woman was reported as having suspected CJD after receiving a dura mater graft 6 years earlier. METHODS: An investigation was initiated to confirm the diagnosis of CJD and assess the possible source of CJD transmission. The authors determined the presence or absence of other known CJD risk factors, checked for epidemiologic evidence of possible CJD transmission via neurosurgical instruments, and evaluated the procedures used in the collection and processing of the graft, including whether the donor may have had CJD. RESULTS: The CJD diagnosis was confirmed in the dural graft recipient by neuropathologic and immunodiagnostic evaluation of the autopsy brain tissue. She had no history of receipt of cadaveric pituitary hormones or corneal grafts or of CJD in her family. The authors found no patients who underwent a neurosurgical procedure within 6 months before or 5 months after the patient's surgery in 1992 who had been diagnosed with CJD. The dura mater was obtained from a 57-year-old man with a history of dysarthria, ataxia, and behavioral changes of uncertain origin. The graft was commercially prepared by use of a process that included treatment with 0.1 N sodium hydroxide and avoided commingling of dura from different donors. CONCLUSIONS: The patient's age, absence of evidence for other sources of CJD, the latent period, and the report of an unexplained neurologic illness in the donor of the dura mater indicate that the graft was the most likely source of CJD in this patient.

Adult↗
PubMed2001

Creutzfeldt-Jakob disease in unusually young patients who consumed venison.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) in humans and chronic wasting disease (CWD) in deer and elk occur in the United States. Recent reports of 3 unusually young patients with CJD who regularly consumed deer or elk meat created concern about the possible zoonotic transmission of CWD. OBJECTIVE: To examine the possible transmission of CWD to humans. PATIENTS: Three unusually young patients (aged 28, 28, and 30 years) with CJD in the United States during 1997-2000. METHODS: We reviewed medical records and interviewed family members and state wildlife and agriculture officials. Brain tissue samples were tested using histopathologic, immunohistochemical, immunoblot, or prion protein gene analyses. MAIN OUTCOME MEASURES: Presence or absence of established CJD risk factors, deer and elk hunting in CWD-endemic areas, and comparison of the evidence for the 3 patients with that of a zoonotic link between new variant CJD and bovine spongiform encephalopathy. RESULTS: None of the patients had established CJD risk factors or a history of travel to Europe. Two patients hunted game animals and 1 was a daughter of a hunter. Unlike patients with new variant CJD, the 3 patients did not have a unique neuropathologic manifestation, clinicopathologic homogeneity, uniformity in the codon 129 of the prion protein gene, or prion characteristics different from those of classic variants. CONCLUSIONS: Although the occurrence of 3 unusually young patients with CJD who consumed venison suggested a possible relationship with CWD, our follow-up investigation found no strong evidence for a causal link. Ongoing CJD surveillance remains important for continuing to assess the risk, if any, of CWD transmission to humans.

Adult↗
PubMed2000

Genetic influence on the structural variations of the abnormal prion protein.

Prion diseases are characterized by the presence of the abnormal prion protein PrP(Sc), which is believed to be generated by the conversion of the alpha-helical structure that predominates in the normal PrP isoform into a beta-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of PrP(Sc), type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of PrP(Sc) in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrP(Sc), respectively, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in PrP(Sc): one N-terminal (residues 23-73) that is invariably PK-sensitive, one C-terminal (residues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the beta-sheet structure, varies mostly as a function of the PrP genotype at codon 129.

Brain Chemistry↗
PubMed2000

Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia.

Molecular genetics and protein chemistry have led to major advances in our understanding of the molecular basis of phenotypic variability of prion diseases. A large body of evidence indicates that a common methionine/valine polymorphism at codon 129 in the prion protein gene (PRNP), alone or in conjunction with PRNP mutations, modulates both disease susceptibility and phenotypic expression of human prion diseases. In addition, there are physicochemical properties of the abnormal isoform of the prion protein (PrP(sc)), such as relative molecular mass and glycosylation, that correlate with distinct phenotypes even in subjects carrying the same PRNP genotype. Different PrP(sc) "type"-PRNP genotype combinations are found associated with pathological phenotypes that differ in the relative severity of lesions among distinct brain regions, the presence and morphology of certain lesions such as amyloid plaques, and the pattern of intracerebral and tissue deposition of PrP(sc). This review summarizes the currently available data on the molecular pathology of sporadic Creutzfeldt-Jakob disease, the most common human prion disease, and fatal insomnia, a more recently defined entity that has rapidly become one of the best characterized of the human prion diseases.

Blotting, Western↗
PubMed2000

Effect of the E200K mutation on prion protein metabolism. Comparative study of a cell model and human brain.

The hallmark of prion diseases is the cerebral accumulation of a conformationally altered isoform (PrP(Sc)) of a normal cellular protein, the prion protein (PrP(C)). In the inherited form, mutations in the prion protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrP(M)) engendering its conversion into PrP(Sc). We used a cell model to study biosynthesis and processing of PrP(M) carrying the glutamic acid to lysine substitution at residue 200 (E200K), which is linked to the most common inherited human prion disease. PrP(M) contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrP(M) showed impaired transport of the unglycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrP(M) displayed some characteristics of PrP(Sc), the PrP(Sc) found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrP(M) in the cell model and in the brain. However, in the brain, PrP(M) undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrP(Sc) and the development of the disease.

Amino Acid Substitution↗
PubMed1999

Prion protein glycosylation is sensitive to redox change.

The conversion of soluble prion protein into an insoluble, pathogenic, protease-resistant isoform is a key event in the development of prion diseases. Although the mechanism by which the conversion engenders a pathogenic event is unclear, there is increasing evidence to suggest that this may depend on the function of the prion protein in preventing oxidative damage. Therefore, in this study, we assessed the interrelationship between redox-sensitive cysteine, glycosylation, and prion metabolism. Cells were treated with a thioreductant, dithiothreitol, to assess the effect of the cellular oxidation state on the synthesis of the prion protein. This change in redox balance affected the glycosylation of the prion protein, resulting in the sole production of glycosylated forms. The role of the single disulfide bridge in mediating this effect within the prion protein was confirmed by mutating the cysteine residues involved in its formation. These data suggest that conditions that increase the rate of formation of the disulfide bridge favor formation of the unglycosylated prion protein. Thus, since the presence of glycans on the prion protein is protective against its pathogenic conversion, a change in the redox status of the cell would increase the risk of developing a prion disease by favoring the production of the unglycosylated form.

Cysteine↗
PubMed1999

A subtype of sporadic prion disease mimicking fatal familial insomnia.

OBJECTIVE: To establish a variant of sporadic prion disease as the sporadic form of fatal familial insomnia (FFI). BACKGROUND: FFI is a recently described prion disease characterized clinically by severe sleep impairment, dysautonomia, and motor signs, and pathologically by atrophy of thalamic nuclei, especially the medial dorsal and anterior ventral, and of the inferior olive. FFI is linked to the D178N mutation coupled with the methionine codon at position 129 in the prion protein gene (PRNP). It is also identified by the properties of the abnormal prion protein (PrP(Sc)), which has the relative molecular mass of 19 kDa, corresponding to the so-called type 2, and a marked underrepresentation of the unglycosylated form relative to the diglycosylated and monoglycosylated forms. METHODS: Clinical, pathologic, PrP(Sc), and PRNP data from 5 subjects with a sporadic prion disease phenotypically similar to FFI were collected and analyzed. RESULTS: All 5 subjects had a disease clinically similar and histopathologically virtually identical to FFI. PrP(Sc) type 2 was present in all subjects in amount and distribution similar to those of FFI. However, the PrP(Sc) did not show the striking underrepresentation of the unglycosylated isoform of the protein that is characteristic of FFI. Moreover, none of the subjects had the D178N PRNP mutation but all were homozygous for methionine at codon 129. CONCLUSION: This condition is likely to represent the sporadic form of FFI and the term "sporadic fatal insomnia" is proposed.

Adult↗
PubMed1999

Type 1 protease resistant prion protein and valine homozygosity at codon 129 of PRNP identify a subtype of sporadic Creutzfeldt-Jakob disease.

A man was studied with sporadic Creutzfeldt-Jakob disease (sCJD) who had serial cortical syndromes evolving over 15 months without significant ataxia, prominent myoclonus, or periodic complexes on EEG examinations. This clinical phenotype correlated with a predominantly cortical and striatal distribution of lesions and accumulation of protease resistant prion protein with relative sparing of the brainstem or cerebellum. No amyloid plaques were seen and prion protein (PrP) immunohistochemistry only demonstrated very faint granular deposits in the cerebral cortex. Molecular analysis showed homozygosity for valine at codon 129 in the prion protein gene (PRNP) and protease resistant prion protein type 1 deposition. The comparison of molecular and clinicopathological features of the present case with those previously reported in sCJD, indicates that valine homozygosity at codon 129 and type 1 protease resistant prion protein are associated with a distinct phenotypic variant of sCJD. The data also support the view that the PRNP codon 129 polymorphism and the physicochemical properties of the protease resistant prion protein are major determinants of phenotypic variability in sCJD.

Codon↗
PubMed1999

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.

Adult↗
PubMed1998

Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease.

The clinicopathological phenotype of the Gerstmann-Sträussler-Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of approximately 21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt-Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and "synaptic" pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion diseases largely depends on the type of PrP-res fragment that forms in vivo. Because the formation of PrP-res fragments of 7-8 kDa with ragged N and C termini is not a feature of Creutzfeldt-Jakob disease or fatal familial insomnia but appears to be shared by most GSS subtypes, it may represent a molecular marker for this disorder.

Adult↗
PubMed1998

Prion encephalopathy with insertion of octapeptide repeats: the number of repeats determines the type of cerebellar deposits.

We studied modifications of the molecular layer of the cerebellum in three patients with octapeptide repeat insertion (OPRI). Two brothers carrying a six-OPRI showed only spongiosis in haematoxylin & eosin preparations (H&E), whereas immunocytochemical examination (ICC) with an antiprion protein (PrP) antibody revealed numerous elongated PrP deposits. The third patient from a family with an eight-OPRI had numerous plaques visible in H&E preparations and had been diagnosed as Gerstmann-Straüssler-Scheinker syndrome. So far, 15 other cases from seven families and three individual cases with OPRI have undergone neuropathological examination. Characteristic PrP deposits were seen in six other cases, two isolated cases with a four- and a seven-OPRI, whereas four cases with a six-OPRI came from three different families. Such deposits have never been reported in other cases of prion encephalopathy, without OPRI. Genuine plaques were observed in five out of the 15 other patients. Interestingly, four had an eight-OPRI and one a nine-OPRI. Cases with OPRI are prone to develop different PrP deposits: those only visible on ICC are not to be confused with genuine plaques visible in H&E preparations. Elongated PrP deposits are present in cases with a four- to seven-OPRI, whereas plaques are present when there is an eight- or a nine-OPRI. All these cases should be termed prion encephalopathy with OPRI.

Adult↗
PubMed1998

Molecular pathology of fatal familial insomnia.

Fatal familial insomnia (FFI) is linked to a mutation at codon 178 of the prion protein gene, coupled with the methionine codon at position 129, the site of a methionine/valine polymorphism. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease (CJD178) with a different phenotype. Two protease resistant fragments of the pathogenic PrP (PrPres), which differ in molecular mass, are associated with FFI and CJD178, respectively, suggesting that the two PrPres have different conformations and hence they produce different disease phenotypes. FFI transmission experiments, which show that the endogenous PrPres recovered in affected syngenic mice specifically replicates the molecular mass of the FFI PrPres inoculated and is associated with a phenotype distinct from that of the CJD178 inoculated mice, support this idea. The second distinctive feature of the FFI PrPres is the underrepresentation of the unglycosylated PrPres form. Cell models indicate that the underrepresentation of this PrPres form results from the PrP dysmetabolism caused by the D178N mutation and not from the preferential conversion of the glycosylated forms. Codon 129 on the normal allele further modifies the FFI phenotype determining patient subpopulations of 129 homozygotes and heterozygotes: disease duration is generally shorter, insomnia more severe and histopathology more restricted to the thalamus in the homozygotes than in the heterozygotes. The allelic origin of PrPres fails to explain this finding since in both cases FFI PrPres is expressed only by the mutant allele. Despite remarkable advances, many issues remain unsolved precluding full understanding of the FFI pathogenesis.

Brain↗
PubMed1998

Creutzfeldt-Jakob disease with long duration and panencephalopathic lesions: molecular analysis of one case.

A 49-year-old woman presented with isolated aphasia followed by dementia and ataxia with a duration of 4 years. Histopathologically there was panencephalic involvement, status spongiosus, and kuru-type plaques. Molecular analysis showed heterozygosity at codon 129 in the prion protein (PrP) gene, and type 2 protease-resistant PrP. The comparison between this case and those previously reported suggests that the panencephalopathic variant of Creutzfeldt-Jakob disease (CJD) is an aspecific end-stage condition displayed by most if not all CJD variants in individual patients with an unusually prolonged course.

Biopsy↗