Pseudo-anticipation in Creutzfeldt-Jakob disease is due to a rhomboid-shaped artifact.

BACKGROUND AND PURPOSE: Previous studies have reported conflicting results regarding possible anticipation in familial E200K Creutzfeldt-Jakob disease (fCJD). Our objective was to use a large database to assess the age of disease onset (AODO) in CJD. METHODS: The study population included 477 CJD patients [266 with fCJD, 145 with sporadic CJD (sCJD) and 66 patients of Libyan origin but negative family history] from the Israeli registry of CJD conducted since 1954. In all patients, AODO in relatives and family trees was documented. Comparison of AODO was done using a paired t test and regression using Pearson correlation for birth and year of onset. RESULTS: The initial analysis in 52/73 families in which more than one generation was affected revealed an AODO of 63.30 ± 9.44 in the first generation compared to 56.96 ± 8.99 in the second generation (P < 0.001). However, inspection of individual AODO values plotted by year of birth showed a clear rhomboid methodological artifact generated by missing data of many young onset CJD patients who died before the database began to function in 1954 and of many late onset CJD patients missing at the present time since they will only develop the disease in the future. The 'generation' effect completely disappears if analysis is performed by year of disease onset or for the periods in which complete data are available. CONCLUSIONS: In this very large dataset, true anticipation in fCJD patients was not detected. It is plausible that previous reports supporting the presence of anticipation are biased by a rhomboid-shaped data availability artifact.

Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease.

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.

CSF tau correlates with CJD disease severity and cognitive decline.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans. The clinical diagnosis of CJD is supported by a combination of electroencephalogram, MRI, and the presence in the CSF of biomarkers. CSF tau is a marker for neuronal damage and tangle pathology, and is correlated with cognitive status in Alzheimer's disease (AD). OBJECTIVES: The aim of this study was to test whether tau levels in the CSF also correlate with the degree of the neurological deficit and cognitive decline in patients with CJD as reflected by various clinical scales that assess disease severity and cognitive performance. METHODS: Consecutive patients with familial CJD (fCJD) were examined by a neurologist who performed several tests including minimental status examination (MMSE), frontal assessment battery (FAB), NIH stroke scale (NIHSS), CJD neurological scale (CJD-NS), and the expanded disability status scale (EDSS). CSF tau was tested as part of the workout, and the correlation was tested using Pearson correlation. RESULTS: Fifty-two patients with fCJD were recruited to the study (35 males, mean age 59.4 ± 5.7, range 48-75 years). A significant negative correlation was found between CSF tau levels and the cognitive performance of the patients as reflected by their MMSE and FAB scores. In addition, a significant positive correlation was found between tau levels and the clinical disease severity scales of CJD-NS, NIHSS, and EDSS. CONCLUSION: The correlation between tau levels and the disease severity and degree of cognitive decline in patients with fCJD suggests that tau can be a biomarker reflecting the extent of neuronal damage.

Health professions and risk of sporadic Creutzfeldt-Jakob disease, 1965 to 2010.

In 2009, a pathologist with sporadic Creutzfeldt-Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue.

The Creutzfeldt-Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression.

OBJECTIVES: To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). METHODS: A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). RESULTS: The mean TSS (±SD) was significantly higher in patients with CJD (13.19 ± 5.63) compared with normal controls (0.41 ± 0.78) and PD patients (9.71 ± 3.05). The mean SIS was also significantly different between the CJD (5.19 ± 1.22) and PD (2.78 ± 1.18 P ≤ 0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS > 4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time-dependent increase in both the TSS and the SIS reflecting the scale's ability to track disease progression. CONCLUSIONS: The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients.

Rapidly progressive Creutzfeldt-Jakob disease in patients with Familial Mediterranean Fever.

BACKGROUND: The largest cluster of familial Creutzfeldt-Jakob disease (fCJD) exists in Jews of Libyan origin. Familial Mediterranean fever (FMF) is an inflammatory disease also common in this population. OBJECTIVES: We hypothesized that FMF, as a pro-inflammatory condition, may affect the course of CJD. METHODS: Three hundred and seventy-two consecutive patients diagnosed clinically and genetically as CJD were included in the study. Two hundred and thirty-six had fCJD, and 136 had sporadic disease (sCJD). Review of the patient's records revealed three patients with FMF-CJD co-morbidity. In addition, 50 DNA samples of patients with CJD were genotyped as homozygote, heterozygote, and non-carriers of the FMF mutation. The demographic and clinical variables of the groups were compared. RESULTS: The three patients with FMF had an earlier age of onset and significantly shorter disease duration than the patients without FMF. Heterozygote carriers did not differ in disease onset and duration from patients without FMF. CONCLUSIONS: The shorter disease duration of CJD patients with FMF may indicate the importance of pro-inflammatory factors in the disease.

Creutzfeldt-jakob disease: focus among Libyan Jews in Israel.

A countrywide search for Creutzfeldt-Jakob disease in Israel disclosed 29 cases with onset between 1963 and 1972. Incidence in various ethnic groups varied in the narrow range of 0.4 to 1.9 per million population except among Jewish immigrants from Libya, among whom the incidence was 31.3 per million. An extraordinary excess of Creutzfeldt-Jakob disease exists in this ethnic group.

Fast collapse but slow formation of secondary structure elements in the refolding transition of E. coli adenylate kinase.

The various models proposed for protein folding transition differ in their order of appearance of the basic steps during this process. In this study, steady state and time-resolved dynamic non-radiative excitation energy transfer (FRET and trFRET) combined with site specific labeling experiments were applied in order to characterize the initial transient ensemble of Escherichia coli adenylate kinase (AK) molecules upon shifting conditions from those favoring denaturation to refolding and from folding to denaturing. Three sets of labeled AK mutants were prepared, which were designed to probe the equilibrium and transient distributions of intramolecular segmental end-to-end distances. A 176 residue section (residues 28-203), which spans most of the 214 residue molecule, and two short secondary structure chain segments including an alpha-helix (residues 169-188) and a predominantly beta-strand region (residues 188-203), were labeled. Upon fast change of conditions from denaturing to folding, the end-to-end distance of the 176 residue chain section showed an immediate collapse to a mean value of 26 A. Under the same conditions, the two short secondary structure elements did not respond to this shift within the first ten milliseconds, and retained the characteristics of a fully unfolded state. Within the first 10 ms after changes of the solvent from folding to denaturing, only minor changes were observed at the local environments of residues 203 and 169. The response of these same local environments to the shift of conditions from denaturing to folding occurred within the dead time of the mixing device. Thus, the response of the CORE domain of AK to fast transfer from folding to unfolding conditions is slow at all three conformational levels that were probed, and for at least a few milliseconds the ensemble of folded molecules is maintained under unfolding conditions. A different order of the changes was observed upon initiation of refolding. The AK molecules undergo fast collapse to an ensemble of compact structures where the local environment of surface probes seems to be native-like but the two labeled secondary structure elements remain unfolded.

A simple spectroscopic method for studying erythrocyte ghost resealing.

A novel spectroscopic method is described for following the kinetics of resealing of hemolysed erythrocyte ghosts. The procedure is based on the broadening of the EPR spectrum of nitroxyl radicals by paramagnetic ions. The method is used to study the effect of Ca2+, Mg2+ and dimethonium ion on the kinetics of resealing.

EPR study of the hydrophobic interaction of spectrin with fatty acids.

The hydrophobic interaction between spin-labelled stearic acid and spectrin was studied by electron paramagnetic resonance (EPR) and fluorescence quenching. The results are quantitatively interpreted in terms of two types of binding site on spectrin. A comparison between the results of the EPR and fluorescence experiments show the drawback of the fluorescence method in binding studies.

The role of electrostatic forces in the interaction between the membrane and cytoskeleton of human erythrocytes.

Evidence is presented that electrostatic forces play a major role in the interaction between the cell membrane and cytoskeleton of human erythrocytes. Experiments were carried out on the effects of ionic strength variation, Ca2+ and Mg2+ ions, dimethonium ion and lipophilic ions on the release of spectrin from the erythrocyte ghost. In addition it was shown that the release of spectrin for fixed Ca2+ or Mg2+ concentration shows a maximum as a function of Na+ concentration. All results are consistent with the existence of a repulsive electrostatic force between membrane and cytoskeleton.

The natively helical chain segment 169-188 of Escherichia coli adenylate kinase is formed in the latest phase of the refolding transition.

The refolding transition of Escherichia coli adenylate kinase (AK) was investigated by monitoring the refolding kinetics of a selected 20 residue helical segment in the CORE domain of the protein. Residues 169 and 188 were labeled by 1-acetamido-methyl-pyrene, and by bimane, respectively. The experiment combines double-jump stopped-flow fast mixing initiation of refolding and time-resolved Förster energy transfer spectroscopy for monitoring the conformational transitions (double-kinetics experiment). Two kinetic phases were found in the denaturant-induced unfolding of AK. In the first phase, the fluorescence quantum yields of both probes decreased. The distribution of the distances between them transformed from the native state's narrow distribution with the mean distance corresponding to the distance in the crystal structure, to a distribution compatible with an unordered structure. In the second, slow step of denaturation, neither the fluorescence parameters of the probes nor the distance distribution between them changed. This step appeared to be a transformation of the fast-folding species formed in the first phase, to the slow-folding species. Refolding of the fast-folding species of the denatured state of AK was also a two-phase process. During the first fast phase, within less than 5ms, the fluorescence emission of both probes increased, but the distance distribution between the labeled sites was unchanged. Only during the second slow refolding step did the intramolecular distance distribution change from the characteristic of the denatured state to the narrow distribution of the native state. This experiment shows that for the case of the CORE domain of AK, the large helical segment of residues 169-188 was not formed in the first compaction step of refolding. The helical conformation of this segment is established only in the second, much slower, refolding phase, simultaneously with the completion of the native structure.

Association of structural repeats in the alpha-actinin rod domain. Alignment of inter-subunit interactions.

Fragments of the rod domain of chicken alpha-actinin, which comprises four spectrin-like repeat sequences, have been prepared by expression in Escherichia coli. Electron microscopy reveals that all products containing three or four complete repeats are rod-like. Self-association of fragments was detected by chemical cross-linking and analytical equilibrium sedimentation. The intact rod domain forms a stable dimmer, which does not dissociate measurably in the accessible concentration range. Elimination of either terminal repeat (repeat 1 or repeat 4) greatly diminishes the extent of dimerisation. The fragment comprising repeats 1-3 dimerises appreciably, with an association constant estimated from the sedimentation equilibrium distribution of approximately 5 x 10(5) M-1. The fragment made up of repeats 2-4 dimerises to a small extent, but also forms aggregates at high concentrations. The results are most easily reconciled with an aligned structure for the rod domain in solution, in which repeat 1 associates with repeat 4 of the partnering chain, and repeat 2 with repeat 3, rather than with a staggered structure, in which one of the terminal repeats does not participate in dimerisation. Possible explanations for the apparent difference observed between the alpha-actinin rod structure in solution and in two-dimensional crystalline arrays are examined.

conformation and phasing of dystrophin structural repeats.

The presumptive rod domain of dystrophin contains a series of degenerate repeating sequences with homology to those of spectrin. To determine the relation of the implied structural repeating units to the sequence repeat (the phasing), recombinant fragments of the domain of dystrophin were prepared by expression in Escherichia coli. The phasing was established by identifying the minimum sequence element that would form a stable fold of high (approx. 75%) alpha-helicity: by contrast, incorrectly phased fragments had labile structure with an average alpha-helicity of about 40%. The isolated folded structural repeat showed high stability towards proteolysis and a urea-denaturation profile with a plateau at low denaturant concentration, indicative of a unique folded conformation. The phasing is consistent with a structure inferred from analysis of the amino acid sequence and also found in spectrin, in which each structural repeat comprises a three-stranded coiled-coil, made up of one short helix (approx. 30 residues) and the N and C-terminal halves of two separate long helices, such that each long helix participates in the formation of two contiguous structural units.

Changes in the incidence of amyotrophic lateral sclerosis in Israel.

The incidence of amyotrophic lateral sclerosis (ALS) in Israel was determined for the period 1959 through 1974. A total of 246 patients with ALS was ascertained. The male-female ratio was 1.62:1. The average annual age-adjusted incidence per 100,000 persons increased during this period by 41%. The increase was almost entirely due to a higher rate in persons more than 60 years of age and was greater in women than in men. This led to a decrease in the male-female ratio. The mean age of onset increased from 52.8 to 58.6 years during the same period. The increment in incidence could not be explained by better case ascertainment or increased life expectancy, but greater precision in diagnosis of ALS in the aged may have partially contributed to the increase.

Presenile dementia in Israel.

A nationwide epidemiologic study of presenile dementia of the Alzheimer type (PDAT) with onset through age 60 years was carried out in Israel. The Israeli National Neurologic Disease Register and clinical records of all patients discharged from hospitals between 1974 and 1983 with a neurologic or psychiatric diagnosis suggestive of dementia were reviewed. A total of 71 Jewish patients with onset of PDAT between 1974 and 1978 was ascertained. The age at onset in these patients ranged from 43 to 60 years. The median survival was 8.1 years, with slightly longer survival if onset occurred before age 55 years, even after correction for expected mortality according to age and sex. The average annual incidence rate per 100,000 population at risk was 2.4 in the population aged 40 through 60 years. Although the incidence rates were slightly greater for women, the difference between the rates by sex was not statistically significant. The age- and sex-adjusted incidence of PDAT per 100,000 population was significantly higher in those born in Europe or America (2.9) than in those born in Africa or Asia (1.4). No significant difference in survival was found between these two groups. The curve of the incidence rates by age for PDAT in Israel is continuous with that for senile dementia of the Alzheimer type collected by similar methods elsewhere, which suggests that one disease process may account for both conditions.

The Libyan Creutzfeldt-Jakob disease focus in Israel: an epidemiologic evaluation.

In a country-wide study of Creutzfeldt-Jakob disease (CJD) in Israel, we diagnosed 114 cases, among them 49 Libyan-born, with onset of their disease during the years 1963-1987. After age adjustment, the mean annual incidence rate per million population was 43 among Libyan-born and 0.9 in the rest of the population. Among Jews born in Egypt and Tunisia, neighboring countries of Libya, the adjusted rates were higher than in the other Israelis (3.5 and 2.3 per million, respectively). Among Libyan Jews, there was no association between incidence rate of CJD and age at immigration, ie, duration of exposure to hypothetical infectious factor in Libya. The percent of familial cases among Libyan Jews (41 to 47%) is one of the highest ever published. Genetic factors seem to be important for the high incidence of CJD among Libyan Jews.

Do Creutzfeldt-Jakob disease patients of Jewish Libyan origin have unique clinical features?

A focus of Creutzfeldt-Jakob disease is present in Israel among Jews born in Libya. The present study examines the clinical features in this particular group of patients. In a country-wide study of Creutzfeldt-Jakob disease, we identified 114 patients; 49 were Libyan immigrants, and 65 (three of whom had Libyan ancestors) were born in other countries. The clinical presentation and evolution of the disease is very similar in patients born in Libya and others without Libyan ancestors, but it tends to be more classical in the Libyan patients, with higher frequency of myoclonic jerks and periodic EEG and a progressive course of shorter duration. The Libyan patients tend to complain more often of headache, which is most probably an ethnic expression for depression and loss of concentration. There was no difference between the familial and nonfamilial cases.

Measles, measles vaccination, and risk of subacute sclerosing panencephalitis (SSPE).

Between the years 1968 and 1979, 87 cases of subacute sclerosing panencephalitis (SSPE) appeared among the Israeli-born population. The incidence of SSPE dropped sharply in 1977, 10 years (the median age at onset of SSPE) after introduction of mass antimeasles vaccination, and remained low in 1978 and 1979. Most of the SSPE cases reported measles at an age significantly younger than that of the general population. This pattern did not change after introduction of antimeasles vaccination. Incidence was significantly lower (p less than 10(-9) in the vaccinated population than in the unvaccinated population. Occurrence of SSPE in some children who were vaccinated against measles could be explained by incomplete vaccine efficacy, or by older age at vaccination, which allows the possibility of prior exposure to measles. There was no indication that measles vaccine can induce SSPE.

Acute transverse myelitis: incidence and etiologic considerations.

There have been few population-based studies of acute transverse myelitis (ATM). Therefore, incidence and population selectivity of this disorder in different regions is not well known. Data on all Jewish patients with ATM throughout Israel were collected for the period 1955 through 1975. Based on 62 patients who satisfied rigid diagnostic criteria, the average annual incidence rate was 1.34 per million population. No significant difference in incidence was noted between European/American-born and Afro/Asian-born populations. There was no significant seasonal or annual fluctuation in frequency. In 37% of the patients, a history of infection prior to ATM was reported, more commonly among younger patients. ATM rarely evolved into multiple sclerosis. More than one-third of the patients with ATM made a good recovery; in another one-third recovery was only fair; 14 patients failed to improve and 3 died. If other population-based studies of ATM were undertaken, comparison with our results might shed further light on the causes of this disorder.