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Objective: To characterize the demographic, clinical features and disease course of familial Creutzfeldt-Jakob disease (fCJD) patients homozygous to the E200K mutation., Methods: 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., Results: 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 < 0.001), had a longer disease duration (27.7 vs 8.5 months, p < 0.001) and presented more frequently with behavioral changes as initial manifestation (4/10 vs. 34/228, p = 0.05)., Conclusions: Homozygous E200K fCJD patients are characterized by a relatively younger age of onset and longer disease duration. Behavioral changes as a presenting symptom were more common in homozygous patients and cerebellar dysfunction was the most common neurological manifestation throughout the disease course.

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.

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.

The aim of the study was to examine the relationship between EEG abnormalities and the pattern of MRI changes in familial Creutzfeldt-Jakob Disease (fCJD) patients with E200K mutation. As part of a controlled, prospective study, 13 E200K fCJD patients underwent comprehensive evaluations, with EEG and an extensive MRI protocol that included one of the most prion-disease sensitive sequences, diffusion-weighted imaging (DWI). The relationship between EEG abnormalities and the pattern of DWI hyperintensities was examined. EEG demonstrated the classical CJD finding of PSWC (periodic sharp wave complexes) in five patients (38%) while in eight patients (62%) the EEG showed only slow activity. Six patients showed the typical cortical changes on MRI, and in five of them (83%) concordance between the MRI and the EEG was found. Five patients had isolated basal ganglia involvement per MRI, and in two of them (40%) concordance between the MRI and the EEG laterality was found. In the remaining two patients MRI did not show any changes suggesting CJD and EEG showed focal slow activity. The EEG of our E200K fCJD patients appears similar to that of the largest prion disease patient group, sporadic CJD (sCJD). EEG abnormalities in E200K fCJD appear to correlate mainly with cortical pathology, as revealed by DWI, rather than basal ganglia pathology. The observation that PSWC abnormalities reflect cortical rather than basal ganglia pathology is significant with respect to theories of the origins of EEG abnormalities in prion disease.

Levodopa-induced dyskinesias (LID) are commonly observed during long-term treatment of patients with Parkinson's disease (PD). The impact of non-pharmacological factors on the latency to LID appearance is not known. The aim of the paper was to identify factors associated with time to appearance of LID. Consecutive PD patients treated with levodopa (n = 155) were included in this historical prospective analysis and LID and non-LID groups were compared. The relationship between possible risk factors and the time of LID onset was explored using the Kaplan-Meier method and the Cox multivariate regression model, controlling for the confounding effects of gender, age of disease onset, time to initiation of levodopa treatment, and history of smoking. Patients with LID (57.4%) were significantly younger at disease onset and had a slightly longer latency from diagnosis to levodopa treatment than those without; disease duration and age had no effect on LID appearance. Female gender was associated with a shorter time to LID and the median time to LID was 6 years for males and 4 years for females (p = 0.004). In the multivariate survival analysis a younger age of onset of PD and a longer time from diagnosis to levodopa treatment initiation were also associated with a shorter time to LID appearance (p = 0.030 and 0.036, respectively). Female gender is associated with a significantly shorter latency to LID appearance. Younger age at PD diagnosis and a longer time until starting levodopa are associated with both higher likelihood to develop LID, and a shorter latency until LID were observed.

One of the largest clusters of genetic Creutzfeldt-Jakob disease (gCJD) is found among Jews of Libyan origin in Israel and is linked to the E200K mutation in PRNP (gCJDE200K). The aim of this study was to compare the levels of cerebrospinal fluid (CSF) biomarkers, Tau and 14-3-3 proteins, between gCJDE200K patients, sporadic CJD (sCJD) patients and non-CJD controls in Israel between the years 1996-2006. The levels of Tau and 14-3-3 proteins in CSF were measured by ELISA and immunoblotting, respectively. CSF Tau levels were similar in gCJDE200K and sCJD, both were significantly higher than in controls [1,107 ± 470 pg/ml [33/46 (72%)] of the cases >1,000 pg/ml, 1,280 ± 580 pg/ml [25/30 (83.3%)], and 354 ± 338 pg/ml [17/243 (6.9%)], respectively, p < 0.001]. 14-3-3 was detected in CSF of 41/53 (77%) of each gCJDE200K and sCJD patients tested, but only in 70/417 (16.8%) of controls (p < 0.001). An inverse correlation was found between disease duration and Tau levels in both gCJDE200K and sCJD (r = -0.464 and r = -0.284). No difference was found in Tau or 14-3-3 between the various codon 129 genotypes. We conclude that CSF biomarkers, Tau and 14-3-3, may be used in the diagnosis in both patients' populations, presenting a similar sensitivity yet Tau assay having higher specificity.

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: A single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive., Objective: To evaluate the rate of the G2019S(*) LRKK2 mutation among ethnically diverse, Jewish PD patients, MM patients, and Ashkenazi, Iraqi and Moroccan healthy controls., Patients and Methods: Overall, 242 Jewish PD patients (155 Ashkenazim and 7 of mixed origin) and 169 Jewish MM patients (142 Ashkenazim) were genotyped for the G2019S mutation. In addition, 900 healthy ethnic Jewish controls (300 Ashkenazim, 300 Moroccans and 300 Iraqis) were similarly analyzed. Genotyping was performed using PCR amplification followed by restriction digest and gel electrophoresis. Statistical analysis was done using the Chi square test., Results: Overall 19/242 (7.9 %) of the PD patients (16/155 of Ashkenazim, 10.3 %; 3/87 of non-Ashkenazim, 3.4 %) harbored the G2019S LRKK2 mutation. The age at diagnosis of PD in mutation carriers was 60.6 +/- 10.9 years compared with an age at diagnosis of 61.1 +/- 13.4 years in non-carriers (p = 0.87). Nine of 38 familial Ashkenazi PD patients (23.68 %) carried the mutation, as did 2/169 MM patients (1.2 %; 2/142, 1.4 % of the Ashkenazim). A single mutation carrier of Ashkenazi origin was detected among 900 controls (0.3 % of the Ashkenazi controls)., Conclusion: The G2019S*LRKK2 mutation is significantly more prevalent in Ashkenazi PD patients than in controls (p = 1 x 10(-6)), it is less commonly detected in non-Ashkenazi affected individuals, and its contribution to MM predisposition in Jewish individuals needs to be explored further.