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.

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

In 1974-1984 30 patients died with a diagnosis of Creutzfeldt-Jakob disease (CJD) in Finland (annual mortality rate of CJD 0.9 per million population for the years 1979-1984). Six of these patients (20%) were familial, all belonging to the same kindred. The pedigree now includes 15 affected members in four generations, and the occurrence of disease is consistent with an autosomal dominant mode of inheritance. The clinical features of CJD in this family are in most respects typical of the familial disease described elsewhere. However, the mean age at onset is 47, periodic EEG activity has not been observed, and the mean duration of illness of 27.5 months is longer than usual for either familial or sporadic CJD. Neuropathological examination of brain biopsy and autopsy specimens revealed spongiform change without amyloid plaques, and brain tissue from one patient transmitted disease to a capuchin monkey. In an analysis of the histocompatibility antigens of the family, CJD was not linked with a single haplotype, but at least 12 out of 13 CJD patients shared the HLA antigen A28. Molecular genetic studies disclosed a new G-to-A mutation in codon 178 of the PRNP gene (resulting in a substitution of asparagine for aspartic acid) in the DNA of eight family members with CJD but not in any of ten currently healthy first degree relatives of the patients, or 86 controls. The codon 178 mutation thus seems to co-segregate with CJD in this family. Linkage analysis gave a LOD score value of 3.6.

Creutzfeldt-Jakob disease is a transmissible neurodegenerative disorder that occurs more than 100 times more frequently among Libyan Jews than in the worldwide population. We examined 11 patients with the disease--10 Libyan Jews from Israel and 1 Libyan Jew from Italy--to determine whether abnormalities of the prion protein could be detected in them. Abnormal forms of this host-encoded protein are the predominant if not sole components of the transmissible agent that causes the disease.The prion-protein open-reading frame in peripheral-leukocyte DNA from the Italian patient was amplified with the polymerase chain reaction and sequenced. Allele-specific oligonucleotide hybridization was used to assess a prion-protein codon 200 lysine mutation in the 10 Israeli patients and 37 control subjects.The prion-protein sequence in DNA from the Italian patient revealed a single nucleotide change (G----A) at the first position of codon 200 that resulted in a substitution of lysine for glutamate. This substitution was detected in all 10 Israeli patients, 8 of whom had a positive family history of Creutzfeldt-Jakob disease. One patient was homozygous for the lysine mutation, and her clinical course did not differ from that of the patients heterozygous for the mutation. The lysine mutation was not found in one Moroccan Jew from Israel with Creutzfeldt-Jakob disease.The codon 200 lysine mutation of the prion-protein gene is consistently present among Libyan Jews with Creutzfeldt-Jakob disease, strongly supporting a genetic pathogenesis of their illness. The similarity of the clinical courses of the patient homozygous for this mutation and the patients heterozygous for it argues that familial Creutzfeldt-Jakob disease is a true dominant disorder.

BACKGROUND AND PURPOSE: The E200K mutation of the PRNP (prion protein) gene is the most common cause of familial Creutzfeldt-Jakob disease (fCJD), which has imaging and clinical features that are similar to the sporadic form. The purpose of this study was to conduct a controlled and blinded evaluation of the sensitivity and specificity of MR imaging in this unique population. MATERIALS AND METHODS: We compared the MR imaging characteristics of 15 early stage familial CJD patients (age, 60 ± 7 years) with a group of 22 healthy subjects from the same families (age, 61 ± 8 years). MR imaging included diffusion-weighted imaging (DWI), T2-weighted fast spin-echo imaging, and a fluid-attenuated inversion recovery (FLAIR) sequence. The scans were rated for abnormalities by an experienced neuroradiologist blind to diagnosis, group assignment, age, and sex. RESULTS: Thirteen of 15 fCJD subjects had abnormal MR imaging. FLAIR signal intensity abnormality in the caudate or putamen nuclei demonstrated a sensitivity of 87% and specificity of 91%. DWI abnormality in the caudate nucleus showed a sensitivity of 73% and a specificity of 100%. Abnormalities in the thalamus (6 patients), cingulate gyrus (6 patients), frontal lobes (4 patients), and occipital lobes (3 patients) were best detected with DWI. No signal intensity abnormalities were demonstrated in the cerebellum. T2-weighted and T1-weighted sequences were uninformative. CONCLUSIONS: FLAIR and DWI abnormalities in the caudate nucleus and putamen offer the best sensitivity and specificity for diagnosing fCJD. Our findings support recent recommendations that MR imaging should be added to the diagnostic evaluation of CJD.

The clinical features of familial Creutzfeldt-Jakob disease with a codon 200 point mutation [fCJD (E200K)] are similar to those of sporadic CJD (sCJD). MRI diffusion-weighted imaging (MRI-DWI) has been reported to be useful for the early diagnosis of CJD. We describe a Japanese fCJD (E200K) case in which thalamic symptoms were the initial manifestations. On admission, electroencephalography (ECG) showed no periodic synchronous discharge (PSD), and MRI showed no abnormalities. However, single photon emission computed tomography (SPECT) using (99m)Tc-ethyl cysteinate dimer ((99m)Tc-ECD) revealed hypoperfusion in the right thalamus. We conclude that the thalamic form of CJD tends to show no high-intensity area (HIA) by MRI-DWI, and that SPECT may be more useful for visualizing the affected area responsible for the thalamic symptoms at an early stage.

Four members of a kindred with Creutzfeldt-Jakob disease are reported, in whom myoclonus did not develop and in whom serial electroencephalograms performed late in their illness failed to show periodic sharp wave complexes. Otherwise, the patients' disease duration, clinical features, and neuropathological findings were similar to those described in sporadic cases of Creutzfeldt-Jakob disease. Our findings and those reported by others suggest that periodic electroencephalographic activity may be rare in familial forms of Creutzfeldt-Jakob disease, as it is in other slow transmissible encephalopathies.

Familial occurrence of three definitive and two possible cases of Creutzfeldt-Jakob disease (CJD) with temporal and spatial separation in the area of focal CJD accumulation in Slovakia is reported. Incubation period is 51 and 53 years respectively, if spatial and temporal separation of affected siblings is considered, and 51 years when the time interval between the death of the affected mother and the clinical onset in the first affected child is determined. Affected children tend to die at the same time (mean difference 3.3 years) and not at the same age (mean difference 6 years). Due to separation of the affected children, a possible common exposure to CJD infection was limited to approximately seven years during their childhood. Potential endo- and exogenous risk factors and a possible mode of CJD transmission in the described family, as well as in the CJD focus, is discussed.

A 5 5-year-old woman who had no family history of dementia developed insomnia followed by somnolence, intellectual deterioration, unsteady gait, psychiatric symptoms and myoclonus. Two months after the onset, she was admitted to our hospital because of severe dementia. EEG showed periodic sharp and wave complexes (PSWC) and diffusion-weighted MRI (DWI) demonstrated a high intensity lesion in the bilateral striatum. 14-3-3 protein immunoassay in CSF was positive. Prion protein gene (PRNP) analysis revealed M232R and methionine homozygosity at codon 129 (MM 129). Three months after the onset she became akinetic and mute.

A pedigree of familial CJD with five octapeptide repeat insert (50RI) is reported. In this family seven out of nine members from one generation had dementia. Three showed slowly progressive course, two with typical clinical features of CJD, and two without details. The probaband is a 62 year old man, who initially presented with abnormal behavior at age 52. The symptoms gradually deteriorated into a bed-ridden state with no verbal expression at age 59. There was no 14-3-3- protein in CSF or PSD in EEG. MRI showed cerebral atrophy with T2 high intensity of the white matter. At age 62, he still responds to a call for his name. The proband’s oldest brother showed similar clinical features, starting difficulty in word recall around age 64, followed by progressive mental deterioration but was ambulatory even just prior to death. He died unexpectedly and no autopsy was done. The other two brothers showed typical clinical features of CJD, with onset at age 41 and 51, respectively. Their clinical course was about one year, accompanying myoclonus, PSD and akinetic mutism. The brain weight was 1,320g and 1,260g respectively. In the cerebral cortex, severe neuronal loss and gliosis with spongiformic changes were present. Hippocampus was relatively spared. The cerebellum showed severe depletion of granular cells. Immunocytochemically the deposition of prion protein was of synaptic pattern in the cerebral cortex and confluent granular one in the cerebellar cortex. In addition, degeneration of the cerebral white matter was diffuse in one case but focal in another. In the latter case, 5ORI was detected. So far, the results of the sequence analysis differ in two other reported families with 5ORI. A current family may provide a direct evidence that two distinct phenotypes of rapidly or slowly progressive clinical course may arise from the same 5ORI sequence abnormality.

Fatal familial insomnia (FFI) is a prion disease clinically characterised by progressive insomnia and dysautonomia, and associated with an aspartic acid to asparagine mutation at the codon 178 (D178N) of the prion protein gene ( PRNP ).1 This mutation is also associated with familial Creutzfeldt-Jakob disease (CJD). These phenotypes have been held to depend on the polymorphism at the codon 129. FFI and CJD phenotypes are associated with methionine (129M) and valine (129V) polymorphisms, respectively.2 However, the diverse phenotypes can be associated with D178N-129M genotype.3 4 We here report on a Japanese family with D178N-129M genotype presenting cerebellar ataxia without overt insomnia. Pedigree of the family and genotypes. (A) Pedigree of the family. Squares, males; circles, females; triangles, either sex (to protect the confidentiality of the family, the sexes of these people are not shown). Filled symbols, affected; shaded symbols, genotype only examined; slashed symbols, deceased; numbers, ages of onset. (B) Tth 111I and Nsp I restriction analyses of the 848 bp open reading frame of PRNP. The Tth 111I-non-digested band of 848 bp indicates D178N mutation. The Nsp I-non-digested band of 502 bp indicates 129V polymorphism and the 427 bp …

Fatal Familial Insomnia (FFI) is a new entry into the group of the prion diseases (MEDORI et al. 1992). FFI is characterized clinically by marked decrease or loss of ability to sleep, dysautonomia and motor signs, and pathologically by preferential atrophy of thalamic nuclei (GAMBETTI et al. 1993). FFI is linked to a mutation a codon 178 of the prion protein gene (PRNP) resulting in the substitution of aspartic acid with asparagine (D178N) (MEDORI et al. 1992).

A research study to identify the priori gene mutation in a family with familial Creutzfeldt-Jakob disease (FCJD) evolved into presymptomatic diagnostic testing. Our experience with one case raises concerns regarding similar studies that will ensue as a result of the Human Genome Project. Technological advances in human molecular genetics make it difficult for Institutional Review Boards (IRB) to adequately evaluate proposed studies. Additionally, changes in the implications of the study may occur after initial IRB approval, due to technological progress. While FCJD, like Huntington's disease (HD), has adult onset and causes progressive dementia and ataxia, protocols established for presymptomatic testing of HD were not included in the FCJD study design. It is thus recommended that IRB committees include a genetics professional and that IRB-approved research studies be reevaluated on a regular basis to monitor the impact that technological advances may have on participating human subjects.