Search

To characterize the demographic, clinical features and disease course of familial Creutzfeldt–Jakob disease (fCJD) patients homozygous to the E200K mutation. The Israeli National CJD Database was screened for patients homozygous to the E200K mutation. Patients' demographic data, clinical presentation and neurological findings, tau protein levels in the cerebrospinal fluid (CSF) and EEG, were assessed. Ten homozygous E200K patients were identified (80% males). Average age of onset was 47.5 ± 6.1 years (range 40–56) and the average age of death was 49.3 ± 7. 7 years (range 42–63) with average disease duration of 27.7 ± 9.7 months (range 2–97). Initial clinical presentation included behavioral change in 4/10 patients, cognitive decline in 3/10 patients and focal neurological deficits in 2/10 patients. Throughout the disease course, the clinical signs in descending order of prevalence included cerebellar (70%), brainstem (60%), extrapyramidal (50%), pyramidal (50%), frontal lobe signs (30%), and disturbances of ocular motility (30%) Compared to the 228 heterozygous E200K fCJD patients, the 10 homozygous patients were significantly younger at disease onset (47.5 vs 59.7 years, p

It is now known that the inherited prion disease is caused by over 60 different mutations in the Prion protein (PRNP) gene. Four missense mutations at codons 102, 178, 200 and 210, account for over 95% of these cases. In this study we describe, a large Indian family with familial Creutzfeldt Jakob Disease (fCJD). One affected member presented with a presenile dementia, a protracted clinical course and characateristic MRI features. Genetic analysis revealed a D178N mutation in the 2 affected individuals and 7 unaffected members. The neuropathological examination of the brain of one of the affected member was conspicuous by spongiform degeneration, neuronal loss and gliosis. This is a detailed report of a genetically and neuropathologically proven fCJD from India.

Unusual clinical presentations in patients with E200K familial Creutzfeldt-Jakob Disease (fCJD) have been rarely reported. Herein, we described a case of E200K fCJD presenting with subacute cranial multiple neuropathy, initially suspected to be paraneoplastic or due to a leptomeningeal carcinomatosis, considering the neoplastic comorbidity of the patient. Surprisingly, brain MRI was highly suggestive of CJD. Brain histological examination confirmed the diagnosis. Genetic tests led to the definite diagnosis of E200K fCJD. To the best of our knowledge, the current case provides the first report of a histologically-confirmed E200K fCJD starting with cranial multiple neuropathy and may widen the spectrum of the clinical variability of CJD, also in its genetic variant. Unusual presentations may lead, as in this case, to incorrect diagnostic hypothesis and unuseful therapeutic attempts in the first phase of the diagnostic process. Also in the genetic variant of CJD, brain MRI demonstrated a very high sensitivity to detect the typical abnormalities since the earliest phases of the disease.

ObjectiveThe objective of the study was to explore patterns of white matter (WM) alteration in preclinical stage familial Creutzfeldt–Jakob disease (fCJD) using diffusion tensor imaging (DTI).MethodsSeven asymptomatic carriers of the PRNP G114V mutation and six non-carriers were recruited from the same fCJD kindred and follow-up obtained from all asymptomatic carriers and two non-carriers 2 years later. Overlapping WM patterns were also explored in asymptomatic carriers and symptomatic CJD patients. All participants underwent clinical and neuropsychological assessments and DTI at baseline and follow-up. DTI data were subjected to whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) in WM using tract-based spatial statistics. Three comparisons were conducted: baseline carriers against non-carriers (baseline analysis), changes after 2 years in carriers (follow-up analysis), and differences between patients with symptomatic CJD and healthy controls (CJD patient analysis).ResultsNeither carriers nor non-carriers developed any neurological symptoms during 2 years of follow-up. Baseline analysis showed no differences between the carrier and non-carrier groups in MD and FA. Follow-up analysis showed significantly increased MD in multiple WM tracts, among which increased MD in the bilateral superior longitudinal fasciculus, bilateral anterior thalamic radiation, bilateral cingulate gyrus, and left uncinate fasciculus overlapped the patterns observed in patients with symptomatic CJD.ConclusionChanges in integrity within multiple WM tracts can be detected during the preclinical stage of fCJD.

Highlights: E200K-PRNP mutation is the most common cause of fCJD. The typical presentation includes rapidly progressive dementia, myoclonus, cerebellar manifestations, and other motor signs. Early sensory disturbances and seizures are infrequent symptoms. We described 4(out of 5) cases of fCJD manifesting ESD and seizures as dominant clinical features. The present findings further underline the clinical variability of fCJD

A 38-year-old male presented with a three-week history of bilateral lower extremity choreiform movements. History included sleep abnormalities, rushed and unintelligible speech, with delusions two to six months prior to presentation. He also developed mild dysphagia, staring spells, and anterograde amnesia. On examination, he had pressured speech, asynchronous cycling movements of the bilateral lower extremities persisting during sleep, occasional ballistic movements of the upper extremities, and ataxia. Magnetic resonance imaging (MRI) of the brain showed high cortical signal change in bilateral parieto-occipital cortices with evidence of medullary olive hypertrophy bilaterally. Electroencephalography showed generalized slowing without periodic spikes. Cerebrospinal fluid was positive for protein 14-3-3 and real-time quaking-induced conversion. Genetic testing was positive for autosomal dominant prion protein gene (PRNP) genetic mutation. The patient passed away three months after discharge. This case provides previously undescribed imaging and movement abnormalities in a patient with familial Creutzfeldt-Jakob disease (CJD), and suggests that CJD should not be removed from the differential in patients with these atypical findings.

Background: Pathologic processes in Creutzfeldt-Jakob disease (CJD) are not fully understood. Familial CJD (fCJD) gives opportunities to discover pathologic changes in the preclinical stage. Objective: To investigate cerebral glucose metabolism in the preclinical stage via 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in fCJD. Methods: Seven asymptomatic carriers of G114V mutation and six family members without PRNP mutation from the same fCJD kindred were included, and were followed for 2 years. Ten symptomatic CJD patients were also recruited. All subjects underwent standardized clinical examinations and 18F-FDG PET scans. Results were compared in three groups: baseline carriers against non-carriers (baseline analysis), changes after 2 years in carriers (follow-up analysis), and differences between symptomatic CJD patients and healthy controls (CJD patients analysis). Results: No carriers developed any neurological symptoms during 2-year follow-up. Baseline analysis: carriers demonstrates decreased metabolism (p

Previous studies have suggested that disease duration in Creutzfeldt-Jakob disease (CJD) may be related to the radiological findings or cerebrospinal fluid (CSF) tau levels; however, it is not yet established whether clinical, radiological, and laboratory findings at diagnosis can predict survival or have a prognostic value. The aim of this study was to examine whether the disease duration is correlated with clinical, radiological, and laboratory variables. The study population consisted of consecutive familial CJD (fCJD) patients that were assessed within 1 week from the diagnosis including the CJD neurological scale (CJD-NS), Minimental Status Examination, Frontal Assessment Battery, NIH Stroke Scale, and the expanded disability status scale. In addition, a single MRI study was done and measurements of the extent of the cortical and subcortical involvement were performed. CSF was examined as part of the workout, and tau levels were determined. Sixty-nine fCJD patients were included in the study (43 males, mean age 59.3 ± 8.4, range 44-79 years). The mean disease duration was 7.3 ± 6.9 months (median 5.6 months, range 2-20 months). A significant correlation was found between the disease duration and the CJD-NS, the disease burden as reflected by the degree of cortical involvement by DWI, and the CSF tau levels. The findings of the current study reveal that several findings at disease onset including the disease severity, the cortical changes, and the tau levels are each individually correlated with disease duration and can be used by the clinician as a tool to predict the disease course and prognosis.

The familial Creutzfeldt-Jakob disease (fCJD) usually has similar clinical and neuroimaging features as sporadic CJD (sCJD). A 57-year-old man presented with a four-month history of rapidly progressive dementia (RPD). Laboratory tests for RPD were all normal. Brain MRI demonstrated diffuse cortical atrophy and no abnormal cortical or striatal hyperintensities on fluid-attenuated inversion recovery (FLAIR)/diffusion weighted imaging (DWI). Electroencephalography revealed intermittent slow waves in the bilateral hemispheres. Cerebrospinal fluid (CSF) examination showed elevated cell counts and protein concentrations. After 10 days of empirical treatment with antiviral agents, the patient was eventually diagnosed with fCJD with M232R mutation based on the results of positivity for 14-3-3 protein, CSF PrPsc in real-time quaking-induced conversion assay and genetic test for PRNP gene. The striatal or cortical FLAIR/DWI hyperintensities are reliable radiographic markers in the diagnosis of both sCJD and fCJD. However, this case suggests that clinical work-up for CJD including genetic test is essential to do a differential diagnosis of RPD, regardless of FLAIR/DWI findings.

Prion diseases are a group of neurodegenerative diseases caused by prion protein (PrP) conformational changes. More than 30 PRNP gene mutations have been associated with familial prion diseases. E200K-associated familial Creutzfeldt-Jakob disease (fCJD) is the most common inherited prion disease. One of the hallmarks of prion diseases is the accumulation of oxidative damage. The mechanism by which oxidative modification of methionine (Met) residues influence the E200K PrP misfolding remains unclear. Here, we examined the stability, structural change, oligomerization and proteinase K resistance of unoxidized/oxidized E200K PrP and Met-to-Leu mutants. We found that oxidation of surface-exposed Met109/112/129/134/154/166 residues significantly destabilized E200K PrP but had a limited impact on the protein's structure. The oxidation of Met213 was the initial step in the conformational conversion of E200K PrP and facilitated the further oxidation of Met205/206. The oxidation of Met213/205/206 led to the exposure of the inner hydrophobic core, disrupted the overall structure of E200K PrP and induced the formation of large soluble multimers at low pH. In addition, the aggregation behavior of oxidized E200K PrP at the cellular level was investigated using E200K PrP Met-to-Ser mutants. The results showed that M109/112/129/154S or M134/166S mutants were efficiently localized on the cell membrane, whereas the M213/205/206S mutant generated many of aggregated fluorescent dots in the cytoplasm. The present work provides important clues for understanding the special roles of methionine oxidation in E200K PrP misfolding and links oxidative stress and consequent misfolding of oxidative damaged E200K PrP with the pathogenic mechanism of E200K-associated fCJD.

Background and propose Familial Creutzfeldt−Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. The typical presenting symptoms include cognitive decline, behavioral changes and gait disturbances; however, some patients may have an unusual presentation such as a stroke-like presentation, alien hand syndrome or visual disturbances. The aim of this paper is to describe uncommon presentations in our series of consecutive patients with E200K fCJD. Methods The study group included consecutive fCJD patients followed up as part of a longitudinal prospective study ongoing since 2003 or hospitalized since 2005. The clinical diagnosis of probable CJD was based on accepted diagnostic criteria and supported by typical magnetic resonance imaging, electroencephalographic findings, elevated cerebrospinal fluid tau protein levels and by genetic testing for the E200K mutation. Disease symptoms and signs were retrieved from the medical files. Results The study population included 77 patients (42 men) with a mean age of disease onset of 60.6 ± 7.2 years. The most prevalent presenting symptoms were cognitive decline followed by gait impairment and behavioral changes. However, six patients had an unusual presentation including auditory agnosia, monoparesis, stroke-like presentation, facial nerve palsy, pseudobulbar syndrome and alien hand syndrome. Conclusions Our case series illustrates the wide phenotypic variability of the clinical presentation of patients with fCJD and widens the clinical spectrum of the disease. A high level of clinical suspicion may prove useful in obtaining early diagnosis and therefore avoiding costly and inefficient diagnostic and therapeutic strategies.

The largest cluster of E200K familial Creutzfeldt-Jakob disease (fCJD) which occurs is in Jews of Libyan origin in Israel. Insomnia is a very common early complaint in those patients and may even be the presenting symptom. The aim of this study was to assess and characterize sleep pathology in E200K fCJD patients. To do so, sleep studies of 10 consecutive fCJD patients were compared with those of 39 age and gender-matched controls. All patients presented pathological sleep characterized by fragmentation of sleep, loss of sleep spindles and reduced REM sleep amount. Respiration was characterized by irregular rhythm, periodic breathing, apneas and hypopneas, either central or obstructive. EMG recordings revealed repeated movements in sleep, with loss of REM atonia. Comparing to controls, a significant decrease of total sleep time, sleep efficacy and slow-wave sleep as well as a significant increase in the number of awakenings, apnea-hypopnea index and mixed and central apneas were evident in CJD patients. Comparison of two sequential sleep studies in one patient revealed a 40 % reduction of the total sleep time, a 40 % reduction in sleep efficacy and a 40-fold increase of the number of arousals in the second study. A significant correlation was found between the disease severity, as reflected by the CJD Neurological Scale and Periodic leg movement index. These definite and characteristic sleep pathologies in patients with fCJD associated with the E200K mutation may serve as a new diagnostic tool in the disease.

Familial Creutzfeldt-Jakob disease (fCJD) results from inheritance of mutations in the prion protein gene. Confirming fCJD diagnosis is essential for informing persons of their potential hereditary risk and for genetic counseling to support personal decisions for genetic testing and family planning. We describe a case of fCJD that was linked to a large cluster of African Americans with fCJD identified through a public health investigation, including 8 confirmed cases and 13 suspected cases involving 7 generations in 1 family. Genetic counseling is an important component of fCJD management for families coping with genetic prion diseases.

Dear Editor-in-Chief, Creutzfeldt–Jakob disease (CJD) mimicked various neurodegenerative diseases among them corticobasal syndrome (CBS) is very rare as an initial manifestation of CJD. There are some cases of sporadic CJD (sCJD) presented as CBS, but none of familial CJD (fCJD) case is reported yet. In addition, the only one case of M232R mutation in fCJD was reported in South Korea [1]. We report a case of 73-year-old woman who diagnosed CBS with dystonic posturing of unilateral arm and finally confirmed as fCJD. A 73-year-old right-handed South Korean woman visited with severe gait disturbance, bradykinesia and dystonic posturing of left arm. Three months before the admission, she diagnosed parkinsonism with bradykinesia and gait disturbance at another hospital. Brain magnetic resonance image (MRI) was normal and has been taking levodopa constantly. But levodopa was not effective and her parkinsonism was getting worse rapidly. At the time of admission, she showed gait disturbance, postural instability, stuttering, swallowing difficulty, severe rigidity of axial and limb muscles, and jerky dystonic tremor and posturing of left arm. In addition, bilateral esotropia and vertical gaze palsy were observed. Ideomotor and buccofacial apraxia, alien hand syndrome, right-left disorientation, frontal lobe releasing sign were also observed. Laboratory studies including cerebrospinal fluid (CSF) examination were all Table 1 Results of neuropsychological test

Gerstmann-Sträussler-Scheinker syndrome is a rare autosomal dominant disease caused by a mutation in the prion gene, usually manifesting as progressive ataxia with late cognitive decline. A 44-year-old woman with a positive family history developed early personality and behavior changes, followed by paresthesias and ataxia, later associated with memory problems, pyramidal signs, anosognosia and very late myoclonus, spasticity, and severe dysexecutive impairment. Magnetic resonance showed caudate, mesio-frontal, and insular hyper-intensities, electroencephalography revealed generalized triphasic periodic complexes. A pathogenic P102L mutation in the prion gene was detected. Our case differed from classical Gerstmann-Sträussler-Scheinker syndrome by rapid progression, severe dementia, abnormal electroencephalography and magnetic resonance findings, which were highly suggestive of familial Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is an untreatable rare human prion disease characterized by rapidly progressive dementia along with various neurological features, including myoclonus and sometimes other movement disorders. The clinical course is typically insidious and rapid, leading to an early death. In general, the most common form is sporadic CJD; however, Slovakia is typical for a high percentage of genetic cases. We present an unusual case report of a 65-year-old man with a sudden, stroke-like onset of motor aphasia with right-sided levodopa unresponsive parkinsonism, alien hand, and other characteristic features of corticobasal syndrome (CBS), with rapid deterioration and death on the 32nd day of the disease. Various neurodegenerative disorders are manifested with CBS as a clinical phenotype, including corticobasal degeneration (CBD), progressive supranuclear palsy, Alzheimer’s disease, and CJD. In our patient, mutation E200K and M129M polymorphism of the PRNP gene and typical immunohistochemical findings pointed to a diagnosis of CJD. The patient’s mother died of CJD many years ago. Several CBS-CJD cases were described, but the atypical stroke-like onset of CBS-CJD, an extremely rare presentation of CJD, makes our case unique worldwide.

Cerebrospinal fluid (CSF) tau was found to correlate with disease severity and cognitive status in E200K familial Creutzfeldt-Jakob disease (fCJD) patients. The objective of the present study was to test whether tau levels in the CSF also correlate with the disease burden as reflected by the degree of cortical involvement in DWI MRI. Forty-four consecutive E200K fCJD patients (25 males, mean age 58.6±7.5, range 48-75 years) were recruited to the study and had a CSF tau examination as well as measurements of the extent of the cortical involvement in the DWI axial MRI. Correlation was tested using Pearson test. A significant correlation (r=0.617 p0.0001) was found between CSF tau levels and the extent of cortical involvement. This correlation between tau levels and the disease burden reinforce the notion that tau can be used as a biomarker reflecting the extent of disease in patients with E200K fCJD.

The use of diffusion MRI improved the accuracy of diagnosis in Creutzfeldt–Jakob disease (CJD) and expanded our knowledge of the changes occurring in the brain during the disease. The aim of this study was to test whether in patients with E200K familial CJD (fCJD) the clinical severity correlates with the disease burden as reflected by the extent of cortical involvement in DWI MRI. Consecutive fCJD patients were examined by a neurologist who performed several tests including the CJD neurological scale (CJD-NS), MiniMental status examination (MMSE), Frontal Assessment Battery (FAB), NIH Stroke Scale (NIHSS), and the expanded disability status scale (EDSS). A simultaneously acquired MRI was analyzed by measuring the extent of cortical involvement in the DWI axial sequence. Correlations were tested for using Pearson test. Fifty-two fCJD patients (35 males, mean age 59.4 ± 5.7 years) were recruited to the study. Significant negative correlation was found between the extent of cortical involvement and the cognitive performance of the patients as reflected by their MMSE and FAB scores. In addition, a significant positive correlation was found between the MRI and the clinical disease severity scales CJD-NS and EDSS. The correlation between clinical scales of severity and cognitive dysfunction and the disease burden confirms the reliability of the CJD-NS scale. Further studies are warranted to examine whether MRI may serve not only for diagnosis but also as a biomarker for follow-up of disease progression and the efficacy of potential treatments.

BACKGROUND: Diffusion-weighted imaging (DWI) has been reported to be a useful technique for diagnosing Creutzfeldt-Jakob disease (CJD). The present study reported DWI results in cases of familial CJD with a V180I mutation (CJD180) in the prion protein gene as well as neurological findings. METHODS: A retrospective analysis of 3 patients with V180I was performed. Cerebrospinal fluid (CSF) analysis, brain MRI, single-photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS) were included. CSF was analyzed for biochemical markers, and each patient underwent brain MRI, SPECT, and MRS analysis. A brain biopsy from the frontal cortex, which corresponded to the area of increased DWI signals, was utilized for neuropathological analysis. RESULTS: CSF analysis results revealed elevated total tau protein and the absence of 14-3-3 protein, as well as decreased concentrations of neuron-specific enolase, S100 protein, and prostaglandin E(2). All patients presented with unique MRI features. Brain biopsy showed severe spongiform morphology, but comparatively preserved neurons and mild astrocytic gliosis. Accumulations of PrP(Sc) were not detected using the 3F4 antibody, and microglial activation was subtle. SPECT revealed hypoperfusion throughout both hemispheres. MRS revealed a reduced N-acetyl aspartate/creatine ratio. CONCLUSION: Results from this study suggested that increased DWI signals could reflect severe spongiform changes in CJD180 patients., Dementia and geriatric cognitive disorders, 28(6), pp.550-557; 2009

Contains fulltext : 80427.pdf (Publisher’s version ) (Open Access) In sporadic Alzheimer's disease (AD), cerebrospinal fluid (CSF) analysis is becoming increasingly relevant to establish an early diagnosis. We present a case of familial AD due to a presenilin-1 mutation in which CSF studies suggested appropriate DNA diagnostics. A 38 year old Dutch man presented with dementia, spastic paraparesis, and frontal executive function impairments, mimicking familial Creutzfeldt Jakob disease and frontotemporal dementia. CSF studies, revealing increased total tau and phosphorylated-tau levels with decreased amyloid-beta42, distinguished familial AD from Creutzfeldt Jakob disease and frontotemporal dementia. A causative p.L424R PSEN1 mutation was subsequently identified.

Creutzfeldt-Jakob Disease (CJD) is considered to be a sudden and fatal degenerative brain disorder that leads to death within a few months. In the last decade, we have studied the course of familial CJD (fCJD) among Jews of Libyan descent, one of the largest clusters of fCJD in the world. Recently, we published results that included the identification of abnormal anxiety levels in healthy CJD E200K mutation carriers that were significantly different from those of healthy non-carriers from the same families. All participants were first-degree relatives of patients known to have been carriers of the E200K mutation and had died from CJD, and none of the participants was aware of his/her genetic make-up. In the current review, it is suggested that an abnormality in anxiety levels among the healthy fCJD mutation carriers may reflect the clinical presentation of the disease onset especially during and after any stressful experience. This hypothesis is supported by a summary of relevant literature, dealing with psychological, physiological, and cellular aspects.

In this study, we aimed to assess sleep function in patients with recent-onset familial Creutzfeldt-Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene (PRNP) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow-wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease.

Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) has been reported to be a useful tool for early diagnosis of sporadic Creutzfeldt–Jakob disease (CJD). We report MRI findings with DWI, as well as with fluid-attenuated inversion recovery (FLAIR) and T1-weighted imaging (T1WI), in a case of familial CJD with a mutation at codon 200 of the prion protein gene. DWI in this patient showed high signal intensity in the basal ganglia and the cerebral cortex, similar to findings in sporadic CJD. In addition, T1WI showed areas of high signal intensity bilaterally in the globus pallidus. Despite the clinical diversity and atypical laboratory findings seen in familial CJD with the codon 200 mutation, these neuroimaging studies suggest that common regional distributions and a common pathogenesis might underlie the clinical progression both in sporadic CJD and in familial CJD with the codon 200 mutation in the prion protein gene. DWI abnormalities may be characteristic features that should be considered in the diagnosis of familial as well as of sporadic CJD.

The clinical features of familial Creutzfeldt-Jakob disease (fCJD) with a mutation at codon 180 (V180I) are less typical than those of patients with sporadic CJD. We describe a patient with pathologically confirmed CJD carrying the V180I mutation who had atypical cerebrospinal fluid and electroencephalography findings. Similar to other prion protein mutations, this report suggests that the V180I mutation is not the exclusive determinant of the phenotype.

Right cerebral and contralateral cerebellar hypermetabolism were observed on FDG PET in a 68-year-old woman with familial Creutzfeldt-Jakob disease (CJD) at an early stage before seizures occurred. The disease progressed with frequent seizures, myoclonus, and a startle reaction. In all past reports, FDG PET studies demonstrated hypometabolism in the cerebrum, cerebellum, and thalamus in patients with CJD. Focal hypermetabolism corresponding with epileptic foci is a common finding in ictal epilepsy patients, and hypometabolism is common in patients with myoclonus or the startle reaction. This finding may reflect a prodromal pathophysiology of epilepsy. Attention should be paid to the diagnosis of CJD while using FDG PET.

Background: Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K. Methods: Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software. Results: Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis. Conclusion: Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K.

Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. While carriers are born with this mutation, they usually remain asymptomatic until middle age. Early detection of conversion is crucial for understanding and eventually for the treatment of the disease. The aim of this study was to report longitudinal MRI data in E200K individuals who eventually converted from healthy mutation carriers to clinically symptomatic CJD. As a part of a prospective study, asymptomatic E200K mutation carriers were scanned annually until their conversion to symptomatic disease. Standardized diffusion and anatomical MR sequences were performed before and after clinical conversion in the subjects and those were compared to 15 non-carrier siblings ("healthy controls"). Blinded radiological readings and region of interest analyses were performed. Radiological readings of individual cases failed to detect characteristic changes in the scans taken before the conversion. Region of interest analysis of diffusion changes in pre-symptomatic stage was inconclusive; however, ADC reduction was found in early and late stages of the disease. Computerized volumetric analysis revealed monotonic volume reductions in thalamus, putamen and caudate following conversion, and the lateral ventricles showed dilatation of up to 62 % after clinical conversion. Although the clinical manifestations at disease onset are variable, the diffusion abnormalities and/or volume changes in the thalamus and basal ganglia during conversion may indicate early involvement of the thalamostriatal neuronal circuit.

Creutzfeldt-Jakob disease (CJD), the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT) have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.

Diffusion-weighted magnetic resonance imaging (DWI) has been described as a useful tool for the diagnosis of sporadic Creutzfeldt–Jakob disease (CJD). To our knowledge, DWI abnormalities have not previously been reported in familial CJD. In two patients with familial CJD associated with distinct mutations at codon 183 and at codon 210 of the prion protein gene, DWI showed a high signal in the basal ganglia and in the cerebral cortex. These abnormalities are similar to those described in sporadic CJD. This observation expands the value of DWI for the diagnosis of some forms of familial CJD. It remains to be investigated whether this finding also holds for CJD associated with other mutations of the prion protein gene.

Creutzfeldt-Jakob disease (CJD) belongs to a group of chronic, progressive, neurodegenerative disorders that may be hereditary, infectious, or sporadic. Hereditary CJDs are associated with mutations in the PRNP gene on chromosome 20p12-pter. We report a family in which four patients developed classical clinical signs of CJD, including severe cognitive decline, cerebellar signs, myoclonic jerks, and synchronic periodic discharges on electroencephalogram. The E211Q mutation has been identified in family members, but not in 97 sporadic CJD patients referred to the Italian registry of CJD nor in 205 healthy normal subjects, suggesting a pathogenic role for this mutation.

We describe a patient who was clinically diagnosed with familial early-onset Alzheimer disease (AD) carrying both the E318G substitution in presenilin 1 (PSEN1) and an insertion of 7 octapeptide coding repeats in the prion protein gene (PRNP). Neuropathological examination revealed elongated cerebellar prion protein deposits in the absence of AD pathology. Further analysis of other family members showed that the Creutzfeldt-Jakob disease phenotype in this family was caused solely by the PRNP insertion. This observation is consistent with our previous finding that PSEN1 E318G is not causally related to AD.

The spectrum of neuropsychological features of familial Creutzfeldt-Jakob disease (CJD) have seldom been reported, possibly because of (a) the rarity of this hereditary form of prion disease; (b) frequent delays in diagnosis, and; (c) the typically rapid demise of the patient, which affords little opportunity for comprehensive testing or serial analysis. Here we describe the neurobehavioral characteristics of a 48-year-old right-handed male (JD) who presented with complaints of poor depth perception, unsteady gait, and unusual sensory experiences in his face and neck. JD was followed serially over the final 4 months of his 5-month illness. Immediately following hospital admission, he underwent a neuropsychological evaluation that revealed moderate to severe impairment of delayed (30-minute) verbal memory, tactual performance in his right hand, and word-finding ability. In contrast, other abilities that are commonly classified within the verbal, visuospatial, and memory domains showed minimal or no compromise. Parallel studies of electroencephalographic activity revealed diffuse slowing and, later, 1-Hz rhythmical discharges over the left hemisphere, and mild prominence of the lateral ventricles and cerebral sulci on magnetic resonance imaging. Autopsy revealed spongiform changes and reactive astrocytosis, and genetic testing demonstrated a codon 200 mutation in the prion protein gene. These findings indicate that CJD can result in clinical manifestations compatible with multifocal asymmetric cerebral involvement before more diffuse neurodegeneration ensues, providing a strong impetus for the study of additional cases. This long-term understanding can help to determine whether the multiple loci of clinical involvement are specified by genetic or epigenetic factors, or both.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.

SummaryCreutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation–associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the bais of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation.

Creutzfeldt-Jakob disease (CJD) is the most prevalent of the human prion diseases, a group of fatal neurodegenerative disorders afflicting both humans and animals. The unique characteristic of these diseases, whether sporadic, dominantly inherited, or acquired by transmission, is the accumulation in the brain of an abnormal isoform (PrPSc) of the cellular prion protein (PrPc). Progress has been made in understanding inherited prion diseases by genetically linking clusters of familial CJD (fCJD) to mutations of the PrP gene (PRNP). One of the largest clusters of fCJD exists among Jews of Libyan origin. The clinical and pathologic manifestations of CJD in this community resemble those seen with sporadic CJD (sCJD), but the incidence is about 100 times higher than in the general population. Initially, this high incidence was attributed to infection via consumption of sheep brains or eyeballs, but a mutation at codon 200 in PRNP resulting in the substitution of lysine (K) for glutamate (E), designated E200K, was identified in this population. The onset of fCJD (E200K) is age dependent and shows nearly complete penetrance by age 85 years. fCJD in Libyan Jews is invariably associated with accumulation of the pathologic isoform PrPSc in the central nervous system. Using mutation-specific antibodies, it was shown that most PrPSc in the brain of these patients originated from the mutant protein. Some studies suggest that mutant PrP may accumulate in brain and other organs due to an impaired degradation, and its accumulation has been postulated to promote conversion into PrPSc. fCJD (E200K) has been transmitted to primates and transgenic mice, highlighting the need to address ethical and public health issues surrounding the possibility of human to human transmission.

Four point mutations and one insertion within the prion protein (PrP) gene have been tightly linked to the development of inherited prion disease.We developed a denaturing gradient gel electrophoresis system that allowed us to screen the entire open reading frame of the PrP gene. Using this system, we found a new mutation of the PrP gene in a patient with pathologically confirmed Creutzfeldt-Jakob disease and a negative family history for dementia. DNA sequencing revealed an adenine substitution for guanine at the second position of codon 208, which results in the nonconservative substitution of histidine for arginine. The same PrP mutation was identified in another younger member of the pedigree but was not present in more than 200 alleles tested. Such findings suggest that the frequency of inherited prion disease might be higher than ascertained by clinical history alone.NEUROLOGY 1996;47: 1305-1312

We report a familial form of Creutzfeldt-Jakob disease, associated with a unique insert mutation of the PRNP gene in an American family of Ukrainian origin. Ten family members exhibited early age at onset and longduration illnesses characterized primarily by personality changes, cognitive impairment, and spasticity. The proband, presenting at age 42 years, exhibited a fairly stable, nonprogressive course over 7 years, followed by precipitous decline and death in the eighth year. Other affected family members exhibited marked clinical heterogeneity. Each tested affected member had an insert mutation consisting of five extra octapeptide repeats between codons 51 and 91 of the PRNP gene on chromosome 20. Examination of two autopsy cases showed classic spongiform change, neuronal loss and astrocytosis in one case, and minimal pathologic abnormality in the other case. This report documents a new insert mutation of the PRNP gene, and confirms the early age of onset, characteristically prolonged clinical course, and clinical and pathologic heterogeneity seen in such mutations.NEUROLOGY 1996;47: 727-733

Fatal familial insomnia (FFI) has been exclusively associated with a pathogenic mutation at codon 178 in the PRNP gene coupled with methionine (Met) at codon 129. We now describe a subject with familial Creutzfeldt-Jakob disease, heterozygous for the pathogenic lysine (Lys) mutation at codon 200 and homozygous for Met at codon 129 of the PRNP gene, who was affected by severe insomnia. At autopsy the patient had significant involvement of the thalamus, as previously described in subjects affected by FFI with the codon 178 mutation. This case demonstrates the wide variability of the clinical expressions in patients with the codon 200 mutation, that may include insomnia and thalamic pathology.

Introduction The familial form of Creutzfeldt-Jakob disease (fCJD) is a dominantly inherited prion disease caused by mutations in the prion protein gene. We describe the sleep structure assessed by night v-polysomnography in a patient with Glu200Lys mutation. Patient A 53 y/o bus driver man came to hospital because of loss of memory. Seven months later disartria appeared, followed by ataxia and generalized myoclonus; the illness progressed to stupor and unresponsiveness and finally death after ten months. Results The first EEG showed a continuous focal right parietal epileptiform activity, with normal background activity. Two months later, a pattern of generalized synchronous periodic sharp waves appeared in the awake state. An all night video-polysomnography showed an abnormal sleep structure with no recognition of asleep stages; there were no vertex sharp waves nor spindles or K complex; with no REM sleep during awakenings the background activity was a diffuse low amplitude theta-delta activity, with generalized periodic bi-triphasic sharp waves. Abnormal respiratory events, were present with an apnea-hypopnea index of 79. Conclusion Night polysomnography in fCJD shows a very abnormal sleep structure, with a significant decrease in total sleep time, sleep efficiency, fragmentation, loss of normal sleep graphoelements, loss of REM sleep and periodic breathing with abnormal arousals.

Background We report a female patient with familial Creutzfeldt-Jakob disease with V180I mutation (fCJD with V180I), who was serially followed up with magnetic resonance imaging (MRI) and electroencephalogram (EEG) for up to four years. Case presentation At 6 months after the onset, diffusion-weighted images (DWI) and fluid-attenuated inversion recovery (FLAIR) of brain MRI revealed an increased signal intensity in the bilateral frontal, temporal, and parietal cerebral cortex with left dominancy except for the occipital lobe. However, her follow-up MRI at four years showed the high-signal regions spreading to the occipital cerebral cortex in DWI and FLAIR images, and bilateral frontal cerebral white matter in FLAIR images. EEG showed a progressive and general slow high-voltage rhythm from 7–8 to 3–5 c/s over four years, without evidence of periodic synchronous discharge. These findings correspond to the symptom progression even after akinetic mutism at 18 months. Conclusion We suggest that serial MRI and EEG examinations are useful for early diagnosis of fCJD with V180I and for monitoring disease progression.

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asp-178-->Asn) but segregate with different genotypes determined by this mutation and the methionine-valine polymorphism at codon 129 of the prion protein gene. The abnormal isoforms of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the two diseases. These differences are likely to be responsible for the type and location of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing two altered conformations of the prion protein.

Pruritus, a common feature of animal prion diseases such as scrapie, is rarely reported in humans with Creutzfeldt–Jakob disease (CJD), and its anatomical background is not well defined. The present study was undertaken to carry out a methodical prospective search for the prevalence of pruritus in CJD patients and investigate its anatomical substrate by MRI. The study group included consecutive familial and sporadic CJD patients carrying the E200K PRNP mutation followed up in a longitudinal prospective study between the years 2005 and 2008. Pruritus was prospectively screened for and diffusion-weighted imaging (DWI) was used to correlate brain diffusion abnormalities with pruritus in CJD patients. Pruritus was present in 6/31 (19.35%) patients with familial disease (fCJD) and in none of the patients with sporadic disease (sCJD). Pruritus was a presenting symptom in one patient and evolved during the course of the disease in the other five patients. The pruritus was generalized in three patients, regional in two and localized in one patient. It was transient in one patient and continued throughout the disease in five patients. DWI showed that pruritus was significantly associated with reduced diffusion in the several areas known to be affected by CJD, but most significantly in the midbrain periaqueductal grey matter. Pruritus is relatively common in patients with familial CJD carrying the E200K mutation. Our findings point to a central origin that involves damage to the inhibitory gating mechanism for itch in the periaqueductal grey matter.

Background Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene ( PRNP ) is the most frequent cause of familial CJD. Coexistent amyloid β (Aβ) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation. Objective To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration. Design Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype. Setting Alzheimer disease research center. Participants Two generations of a family. Main Outcome Measures Clinical, biochemical, and neuropathologic observations in 2 generations of a family. Results In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE e4 carrier but not in the APOE e4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children. Conclusions To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrP E200K may result in increased Aβ deposition.