Zeev Meiner

Mutation of the Prion Protein in Libyan Jews with Creutzfeldt–Jakob Disease

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone

Humoral and cellular immune responses were followed in multiple sclerosis patients treated with Copolymer 1 (Cop1, glatiramer acetate, Copaxone) who participated in three different clinical trials. All patients (130) developed Cop1 reactive antibodies, which peaked at 3 months after initiation of treatment, decreasing at 6 months and remaining low. IgG1 antibody levels were 2-3-fold higher than those of IgG2. The proliferative response of Peripheral Blood Mononuclear Cells (PBMC) to Cop1 was initially high and gradually decreased during treatment. Antibodies and T cell responses to MBP were low and did not change significantly during the treatment. The humoral and cellular immunological responses to Cop1 do not correlate with the side effects and do not affect its therapeutic activity. The preferential production of IgG1 over IgG2 antibodies may indicate that Th2 responses are involved in mediating the clinical effect of Cop1.

The Effectiveness of Locomotor Therapy Using Robotic-Assisted Gait Training in Subacute Stroke Patients: A Randomized Controlled Trial

To evaluate the effectiveness of early and prolonged locomotor treatment with the use of a robotic‐assisted gait training (RAGT) device (Lokomat; Hocoma Inc., Zurich, Switzerland) on the functional outcomes of patients after subacute stroke.

FAMILIAL CREUTZFELDT-JAKOB DISEASE : CODON 200 PRION DISEASE IN LIBYAN JEWS

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.

Detection of circulating antibodies against tau protein in its unphosphorylated and in its neurofibrillary tangles-related phosphorylated state in Alzheimer's disease and healthy subjects.

While the presence of naturally occurring antibodies (Abs) against amyloid-beta in AD patients and healthy subjects have been repeatedly reported, no data on the presence of naturally occurring Abs against tau protein, in its unphosphorylated as well as its pathologically phosphorylated state, has been reported so far. We describe here the detection of circulating Abs against unphosphorylated and pathologically phosphorylated tau protein in sera of 17 aged subjects: nine Alzheimers disease (AD) patients and eight healthy individuals. An ongoing autoimmune process may take place, as is suggested by the presence of both IgM class anti-tau Abs, as well as IgG. A preliminary evidence for higher anti-phosphorylated-tau Abs of IgM class in AD patients relative to controls is indicated, but demands further confirmation in a larger sample. Detection of naturally occurring anti-tau antibodies may point to the possibility that some autoimmune process may take place against the tau neuronal protein, including its pathologically phosphorylated state which compose the neurofibrillary tangles. Whether these Abs are neuroprotective or neurotoxic - is unknown, as it is with anti-amyloid-beta Abs.

Acute Disseminating Encephalomyelitis in Neuromyelitis Optica: Closing the Floodgates

OBJECTIVE To report the clinical and radiological features of 2 patients with neuromyelitis optica (NMO) associated with severe acute disseminating encephalomyelitis. The first patient had anti-aquaporin 4 antibodies (NMO-IgG) but no lesion enhancement, in contrast to the second patient who was seronegative for NMO-IgG but had clear lesion enhancement on magnetic resonance imaging. DESIGN Clinical, laboratory, and radiological analysis of 10 patients presenting with features compatible with an NMO-spectrum disorder, 2 of whom developed acute disseminating encephalomyelitis. SETTING Inpatient ward at the Department of Neurology, Hadassah University. PATIENTS Patients admitted during a 1-year period with features compatible with an NMO-spectrum disorder. INTERVENTIONS Medical histories and imaging data were reviewed and serum samples were analyzed for the presence of NMO-IgG. MAIN OUTCOME MEASURES Clinical and paraclinical evidence of brain involvement. RESULTS Of 10 patients tested, 5 were positive for NMO-IgG. One seropositive and 1 seronegative patient had an acute disseminating encephalomyelitis-like episode. In both cases, the clinical, laboratory, and electroencephalographic findings supported a diagnosis of acute disseminating encephalomyelitis. Magnetic resonance imaging demonstrated extensive bilateral white matter lesions in both patients. Lesions in the seropositive patient were notably lacking in enhancement following gadolinium injection, whereas robust lesion enhancement was observed in the seronegative patient. CONCLUSIONS Acute disseminating encephalomyelitis without lesion enhancement on magnetic resonance imaging may represent a childhood manifestation of seropositive NMO. The lack of enhancement suggests an intact blood-brain barrier and supports a unique mechanism of edema induction due to dysfunction of water channels.

Detection of 14-3-3 protein in the CSF of genetic Creutzfeldt-Jakob disease

The 14-3-3 protein, a protein involved in signal transduction, is present in the CSF of patients with Creutzfeldt-Jakob disease (CJD) and not in patients with other dementing diseases. We show here that this is also true for patients with E200K CJD, but not for healthy carriers of the mutation.

Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

Presence of prion protein in peripheral tissues of Libyan Jews with Creutzfeldt‐Jakob disease

The prion protein (PrP) gene on chromosome 20 encodes a protein designated PrPC. An abnormal, protease-resistant isoform of PrPC, denoted PrPCJD or PrPSc, is present in the brains of patients with Creutzfeldt-Jakob disease (CJD). In Libyan Jews, CJD segregates with a point mutation at codon 200 of the PrP gene, resulting in the substitution of lysine for glutamate. In the present study, we examined the presence of PrP in fibroblasts and leukocytes derived from eight CJD patients with the codon 200 mutation. In cultured fibroblasts as well as in leukocytes, there was a significant increase in PrP as judged by immunocytochemistry in addition to immunoblotting. Most of the PrP in fibroblasts and leukocytes could be released from the external surface by phosphatidylinositol-specific phospholipase C, a property characteristic of PrPC. In leukocytes only, part of the protein was protease resistant, resembling PrPCJD. The concentration of PrP mRNA was similar in fibroblast lines derived from controls and CJD patients. These results suggest that in CJD patients carrying a mutation at codon 200 of the PrP gene, the metabolism of PrP, rather than PrP synthesis, is abnormal.

Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family

Abstract.Background: Frontotemporal dementia with parkinsonism linked to chromosome 17q21–22 (FTDP-17) is an autosomal dominant tauopathy manifested by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in the tau gene. Among others, the P301S mutation has been previously reported in three families of European and one of Japanese origin presenting with different clinical phenotypes. Objectives To report a three-generation family of Jewish-Algerian origin with FTDP-17 due to the P301S tau mutation. Methods: Clinical, neuropsychological and neuroimaging evaluation of 3 patients, tau genotyping, and pathological study of the proband. Results: The 3 affected family members had a fairly stereotyped clinical course with early personality changes from their late 30s followed within a period of 1–2 years by a progressive cognitive and motor deterioration eventually leading to a state of akinetic mutism or death 3–5 years after the initial symptoms. The main clinical manifestations included severe dementia and hypokinetic-rigid movement disorder associated with supranuclear gaze impairment, pyramidal signs and frontal release signs. Brain imaging disclosed a variable degree of frontotemporal atrophy, ventriculomegaly and regional cerebral hypoperfusion or glucose hypometabolism. Frontal lobe biopsy in the proband revealed weak tau immunoreactivity in a few cortical neurons, in rare neurites and in some glial cells with no neurofibrillary tangles. Molecular DNA analysis identified a P301S mutation in exon 10 of the tau gene. Conclusions: The observed clinical features further expand the reported P301S phenotype and confirm a more aggressive course of the disease than in the other known tau mutations.