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1/22. Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype.

    Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). As the other sporadic or infectious prion disease forms, they are almost all characterized by the accumulation in the brain of an abnormal misfolded form of the patient's PrP. Brain extracts can often transmit the disease once inoculated in a recipient animal. Inherited prion diseases with Creutzfeldt-Jakob disease (CJD) phenotype are autosomal forms, although sporadic cases have been reported. We report three novel mutations of the PRNP gene in unrelated patients with clinical and histopathologic features of CJD. The three mutations were missense: c635G>A (E196K), c656G>A (V203I) and c680G>C (E211Q). Familial history of neurologic disorders was evidenced for patients carrying the E196K and E211Q mutations. E196K would be predicted to have more severe effects on protein stability than V203I and E211Q. These mutations expand the spectrum of mutations in PRNP and reduce the proportion of CJD patients in whom genetic alterations have not been found.
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2/22. Novel prion protein gene mutation in an octogenarian with Creutzfeldt-Jakob disease.

    BACKGROUND: The transmissible spongiform encephalopathies constitute a fascinating and biologically unique group of invariably fatal neurodegenerative disorders that affect both animals and humans. Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia represent the more common human phenotypes. Excluding the small number of iatrogenically transmitted cases, approximately 85% to 90% of patients develop CJD without identifiable explanation, with an increasing number of different mutations in the prion protein gene (PRNP) recognized as probably causative in the remainder. OBJECTIVE: To report on an 82-year-old woman with pathologically confirmed CJD found unexpectedly to harbor a novel mutation in PRNP. methods: Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient, including magnetic resonance imaging of the brain, electroencephalography, and cerebrospinal fluid analysis for the 14-3-3 beta protein. Standard postmortem neuropathological examination of the brain was performed, including immunocytochemistry of representative sections to detect the prion protein. Posthumous genetic analysis of the open reading frame of PRNP was performed on frozen brain tissue using polymerase chain reaction and direct sequencing. RESULTS: Concomitant with the exclusion of alternative diagnoses, the presence of characteristic periodic sharp-wave complexes on the electroencephalogram in combination with a positive result for 14-3-3 beta protein in the cerebrospinal fluid led to a confident clinical diagnosis of CJD, confirmed at autopsy. There was no family history of dementia or similar neurological illness, but patrilineal medical information was incomplete. Unexpectedly, full sequencing of the PRNP open reading frame revealed a single novel mutation consisting of an adenine-to-guanine substitution at nucleotide 611, causing alanine to replace threonine at codon 188. CONCLUSIONS: In addition to expanding the range of PRNP mutations associated with human prion diseases, we believe this case is important for the following reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerative disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Second, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a genetic basis. Finally, as a corollary, this case highlights problematic issues in human transmissible spongiform encephalopathies, as illustrated by disease penetrance and age of onset in genotype-phenotype correlations.
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3/22. Cucumber shaped and 35 nm particles in Creutzfeldt-Jakob disease.

    A 63 year old female with the ataxic form of Creutzfeldt-Jakob disease (CJD) is presented. In addition to amyloid plaques which were not associated with Alzheimer's neurofibrillary tangles, rare profiles similar to those reported in scrapie were also seen. To our knowledge, these profiles have never been observed in CJD and their presence in this condition adds a further morphologic similarity between the human and animal forms of subacute spongiform "viral" encephalopathies.
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4/22. 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.
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5/22. The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease.

    Prion epizoonoses spread from animals consumed by humans raise the question of which pathways lead to prion neuroinvasion after oral exposure of humans. Here we show that neurons of sympathetic ganglia of patients with variant Creutzfeldt-Jakob disease (vCJD) accumulate the abnormal isoform of the protein prion. This observation shows the involvement of the sympathetic nervous system in the pathogenesis of vCJD and suggests a role for GUT-associated sympathetic neurons in prion propagation in humans after oral contamination.
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6/22. Progressive neurodegenerative disease in presumed spinal cord injury: case report of a patient with prion disease.

    BACKGROUND: prion diseases or transmissible spongiform encephalopathies (TSEs) are neurodegenerative syndromes caused by proteinaceous infectious particles (or "prions"), are fatally progressive, and affect humans and animals. Human prion disease may be familial, sporadic, or due to iatrogenic causes. The signs and symptoms include dementia, ataxia, myoclonus, dysautonomia, pyramidal and extrapyramidal tract signs, and akinesia. The incubation period of iatrogenic TSE ranges from 15 months to 30 years, and clinical presentations may be atypical. DESIGN: Case report. FINDINGS: This article presents the case study of a 39-year-old man who fell at work and subsequently complained of subjective lower extremity weakness, followed by onset of ataxia, bowel and bladder incontinence, and progressive decline in ambulation over 6 months. In the absence of a unifying diagnosis, the patient was presumed to have had a spinal cord injury (SCI). Because neuro-axis imaging studies failed to explain his symptoms, the patient's complaints were thought to have a large psychologic component. The patient then developed neurologic abnormalities proximal to the presumed SCI. Somatosensory evoked potentials were suggestive of a thoracic or lumbar cord myelopathy and cerebrospinal fluid analysis was suggestive of prion disease. family members eventually revealed that the patient had had injections of growth hormones derived from cadaveric human pituitary glands as a child. Postmortem brain examination later revealed definitive Creutzfeldt-Jakob disease.
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7/22. Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Straussler-Scheinker diseases.

    A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Straussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE, present in abundance after 18 and 22 months incubation, were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.
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8/22. Spongiform encephalopathies: the physician's responsibility.

    The spongiform encephalopathies encompass several diseases affecting humans and animals. In the united states, the most common of these disorders in humans is Creutzfeldt-Jakob disease. The most frequent manifestations include dementia, pyramidal tract signs, and extrapyramidal movement disorder. Several clinically distinct syndromes can be identified. Often the diagnosis is confused with other forms of dementia, and the only definitive method for establishing the diagnosis is autopsy evaluation of brain tissue. Unfortunately, since the recognition of the infectious etiology of Creutzfeldt-Jakob disease, fear has often unreasonably interfered with clinical care and autopsy evaluation of affected patients. In actuality, because of the low and restricted infectivity of the responsible agent, affected individuals present minimal risks to clinical caretakers, and handling of patient specimens is not dangerous if appropriate precautions are taken. These precautions are well established, and physicians and other health care workers should not refuse care of appropriate evaluation (including autopsy) to individuals with suspected Creutzfeldt-Jakob disease.
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9/22. purkinje cells in degenerative diseases of the cerebellum and its connections: a Golgi study.

    The cellular pathology of purkinje cells in several degenerative diseases of the cerebellum and its connections was studied with the rapid Golgi method. Purkinje cells from a patient with Creutzfeldt-Jakob disease (case 1) showed decreased numbers of spiny branchlets. In a patient with a cystic infarct of the cerebellar white matter and chronic deafferentation of the cerebellar cortex (case 2) there was a striking increase in the density of spines on the primary dendrites. No abnormalities were observed in purkinje cells from two patients with hereditary spinocerebellar degeneration (cases 3 and 4). purkinje cells in two patients with olivopontocerebellar atrophy (OPCA) had severely reduced numbers of dendritic branches. Ballooned proximal axons were found in purkinje cells with severely damaged dendrites (cases 5 and 6). In contrast to experimental olivary degeneration in laboratory animals, purkinje cells from patients with OPCA did not have increased numbers of stubby spines in stout proximal dendrites but few spines with long pedicles were observed in the proximal segment of the primary dendrites and in the cellular body.
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10/22. Familial presenile dementia with CJD-like lesions: preliminary results.

    A case of an unknown type of familial presenile dementia is reported. The patient was a 56-year-old female, whose main clinical symptom was a gradually progressive dementia over 16 years. She had no myoclonus or periodic synchronous discharge in the EEG. The CT scans revealed marked cerebral atrophy with prominent atrophy of the cerebral white matter. One of her sisters is thought to suffer from the same disease, and is now in an apallic state. The patient was clinically diagnosed as having familial Alzheimer's disease. The neuropathological features consisted of severe cerebral cortical degeneration with conspicuous proliferation of gemistocytic astrocytes as well as severe cerebral white matter degeneration. These cerebral lesions are most similar to those of the panencephalopathic type of Creutzfeldt-Jakob's disease (CJD). However, our case differs from it in that the cerebellar degeneration was very mild. Transmission experiments of frozen tissue from the patient into animals are being tried. The neurochemical data suggested cholinergic deficits. As far as we know, such a case has never been reported in the literature.
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