Demyelinating peripheral neuropathy with Creutzfeldt-Jakob disease and mutation at codon 200 of the prion protein gene.

We performed a study of the distribution of PrP27-30, the proteinase-K-resistant form of prion protein, in the central and peripheral nervous system of a patient with a Glu200Lys mutation of the prion protein gene, cerebellar ataxia, subcortical dementia, rigidity, and demyelinating peripheral neuropathy. In the CNS, there was neuron loss and spongy degeneration, principally in the cerebellum, and with progressively lower density in the caudate nucleus, thalamus, temporal cortex, frontal cortex, and brainstem. Evaluation of the expression of PrP27-30 by Western blot showed that its distribution correlated with the intensity of the lesions in these regions. In contrast, we did not detect PrP27-30 in the peripheral nervous system where lesions consisted of demyelination, and remyelination that predominated in the proximal nerve trunks and roots.

Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies.

Human prion diseases are characterized by the accumulation in the brain of an abnormal form of the prion protein. Prion protein polymorphisms seem to play a key role in the pathogenesis of these diseases, probably by enhancing the amyloidogenic properties of the protein. We performed prion protein gene (PRNP) coding sequence analysis in 57 French subjects with Creutzfeldt-Jakob disease (CJD) and found a mutation of the PRNP coding sequence in nine subjects (15.8%); the mutation corresponded with a known family history of CJD in only three of these subjects. In 41 definite and probable cases without known PRNP mutations, codon 129 genotyping revealed an excess of the homozygous 129Met/Met genotype corresponding to a 3.4-fold increased risk of developing CJD when compared with the two other genotypes. We also found that the 129Val/Val genotype, which mainly governs susceptibility to iatrogenic CJD, does not seem to predispose to sporadic CJD.

A new point mutation in the prion protein gene at codon 210 in Creutzfeldt-Jakob disease.

We screened 16 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 28 healthy control subjects to detect possible polymorphisms in their prion protein gene (PRNP). The molecular analysis of the PRNP coding sequence was performed using denaturing gradient gel electrophoresis of polymerase chain reaction products and direct sequencing. We identified (1) a silent mutation at codon 177 in a healthy individual, (2) a codon 200 glutamate-to-lysine substitution in a 48-year-old CJD-affected Libyan Jew, and (3) a G-to-A point substitution at codon 210, leading a valine-to-isoleucine change, in a 63-year-old French CJD patient. This new mutation occurs in a highly conserved part of the PRNP coding sequence, close to the known CJD-associated codon 200 mutation, and might be linked to a symptomatologic and neuropathologic pattern of typical sporadic CJD. This mutation was also present in a sister of the patient who died at the age of 67 without neurologic symptomatology.

Familial Creutzfeldt-Jakob disease. Autosomal dominance in 14 members over 3 generations.

Discovery oa a second affected branch of a family with transmitted Creutzfeldt-Jakob disease (CJD), originally reported by Buge et al. in 1978, brings the total number of cases to 14 in 3 generations, with at least 20 members of the next young adult generation presently at risk. Complete segregation of the illness to the descendants of these 2 branches, with no skipped generations, and an overall frequency of CJD in affected sibships of 56%, clearly defines a pattern of autosomal dominance. The disease is indifferent to sex, either in terms of affected members (8 males and 6 females) or of lineage (3 fathers and 3 mothers). Acquisition of CJD virus from a point source contamination is unlikely, and case-to-case transmission, if it occurred, would have required an average minimum incubation period of 17 years.

Epidemiologic comparisons between Creutzfeldt-Jakob disease and scrapie in France during the 12-year period 1968-1979.

Systematic investigation of the occurrence of scrapie in France revealed that between 1968 and 1979 the disease has been diagnosed in a total of 145 flocks, in virtually every region where sheep are raised. The geographic distribution of scrapie-affected flocks was unrelated to the residential location of patients dying of Creutzfeldt-Jakob disease (CJD) during this period, arguing against direct contact or indirect vector transmission of the disease to humans. Regional lamb consumption was not correlated with the frequency of CJD; however, lamb consumption among nationwide categories of increasing population density (rural communities, towns, cities, the Paris metropolitan area, and the city of Paris) did correlate with an increasing frequency of CJD. Future accuracy in the reporting of scrapie, together with precise information about commercial distribution routes of lamb and other sheep products, will be required to assess the significance of this observation.

Scrapie in France: some possible predisposing factors in the naturally-acquired disease of sheep.

A nationwide survey of the occurrence of scrapie in France during the 12-year period 1968-1979 has shown the disease to be more widespread than previously thought. The data suggest that certain sheep raising practices, such as transhumance (nomadic grazing), pen and pasture alternations, and use of animals for milk production, may play a possible role in disease prevalence.

[Some demographic datas from Ixodes ricinus Linné: vector of a virus strain of central european encephalitis in Alsace (author's transl)]. / Données démographiques d'Ixodes ricinus Linné: vecteur du virus de lencéphalite à tiques d'Europe centrale (C.E.E.) en Alsace.

This work shows the montly variation in the density and stage composition of the population of the tick Ixodes Ricinus in the Rhine forest. Some factors influencing this variation are analysed. These include the locality of egg-laying and of down localisation and the main climatic variables. We also try to link these ecological data with the strains of Central European Encephalitis virus isolated from this arthropod.

[Ecology of indigenious arbovirus in Alsace. Tick Central European Encephalitis. I.--Complex Ixodes ricinus--bank voles. II.--Study of bank voles population immunity. III.--Virologic results in bank voles population (author's transl)]. / Ecologie d'un arbovirus indigène en Alsace. L'encéphalite à tiques. I.--Complexe Ixodes ricinus--campagnol roussâtre. II.--Etude de l'immunité d'une population de campagnols roussâtres. III.--Résultats virologiques observés dans une population de campagnols roussâtres.

I.--After showing that bank voles are parasited only by Ixodes ricinus larvae, the authors attempt to found different factors (demographic, biometric, and sexual) who favor individual parasitism. The authors conclude to absent of anti tick immunity for this rodent specie. II.--The search for anti-central european encephalitis antibodies (I.H.A.) are shown that 2 p. cent animals were immuns. Yearly and monthly chronologies of antibodies apparition are shown, factors favoring the growth of specific Central european encephalitis antibodies are discussed. III.--The Central european encephalitis tick viral infection of bank vole is studied according to the number of viral strains isolated from different viscera. The monthly chronology of this infection is shown.

[Analysis of the PrP gene in a Tunisian family with Creutzfeldt-Jakob disease]. / Analyse du gène PrP dans une famille d'origine tunisienne atteinte de maladie de Creutzfeldt-Jakob.

Results of PrP gene analysis in 5 of 9 members from a Jewish Tunisian family with Creutzfeldt-Jakob disease (CJD) showed a mutation at codon 200 involving substitution of lysine (Lys200) for glutamic acid (Glu200). This observation suggests that Lys200 allele probably tracks with CJD in this family and supports the possible genetic basis of the disease in the Mediterranean cluster. A second PrP variant not associated with Lys200 allele involving a short deletion in the coding sequence has also been found in only one subject.

[Creutzfeldt-Jakob disease in France: an epidemiological update (author's transl)]. / Maladie de Creutzfeldt-Jakob en France. Contribution à une recherche épidémiologique.

We report here the results of a prospective epidemiological study of Creutzfeldt-Jakob disease in continental France during the years 1978-80, extending a retrospective study of the decade 1968-1977 previously reported. The new annual mortality figures are 0.53 cases per million people for France as a whole, and 1,01 cases per million people for the paris metropolitan area. The correlation between mortality rate and population density persists in the Parisian area, and is not related to differences in age composition of the density categories. Although the geographic distribution of CJD and Scrapie and completely unrelated, there is a correlation between lamb consumption and CJD mortality rates in different nationwide population categories.

[Proteins, genes and early diagnosis of Alzheimer's disease]. / Protéines, gènes et diagnostic précoce de la maladie d'Alzheimer.

Proteic (neuritic plaques, amyloid substances...) and genetic characteristics of Alzheimer's disease are reviewed. An infectious origin appears unlikely. After production of specific antibodies, the reported abnormal Tau proteins might represent peripheral markers of the disease. Changes in olfactory neurons, accessible for biopsy specimens, might give rise to new biological diagnosis of Alzheimer's disease.

[Creutzfeldt-Jakob disease in France. Value of familial forms. Is there a gene controlling the length of the incubation period?]. / Maladie de Creutzfeldt-Jakob en France. Intérêt des formes familiales. Existe-t-il un gène gouvernant la durée de l'incubation?

An extensive search for patients who died of Creutzfeld-Jakob disease in France between 1968 and 1982 resulted in the discovery of 327 cases, 233 of which were histologically proven and 29 transmitted to animals; 17 patients belonged to 6 families. Further investigations among members of these 6 families yielded 21 additional cases, i.e. a total of 38 familial cases. Studies among sibships suggested an autosomal dominant pattern of transmission but did not exclude lateral contamination infancy. The patients' age at death was 10 to 15 years lower than that of the total of French cases and seemed to be a characteristic of each individual family. This suggests that, as in scrapie, a gene may control the length of the incubation period.

[Human transmissible dementia: prion diseases?]. / Les démences transmissibles humaines: maladies à prions?

Subacute transmissible spongiform encephalopathies (STSE) represent a cause of presenile dementias, found in man (Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, Kuru), in sheep and goats (scrapie), in cattle (bovine spongiform encephalopathy) and in various mammals. It seems that the frequency of the human spongiform encephalopathy (HSE) is more frequent than thought up to now and an alimentary origin is not to be discarded. Many discussions are held concerning the nature of the transmissible agent: virus, virino, prion? Isolation of an abnormal protein, the isoform PrPSc resulting from an unknown alteration of a protein PrPc encoded in man by the chromosome 20 is presently the basis for seeking the cause of transmissible dementias. Molecular genetic studies of the gene PrP have demonstrated the existence of many mutations: are they the actual cause of the STSE or only a favouring factor? The existence of familial sporadic or infectious forms of HSE might be explained by alterations of the conformation of PrPc into PrPSc, able to induce this structure modification to last when thereafter the synthesis of the normal protein is achieved. The "chaperone" protein model can be questioned in this respect. For the moment the research work is developed into characterization of humoral or genetic markers able to detect the predisposed subjects in high-risk families. HSE are also an interesting model for other types of dementias, especially the Alzheimer disease which is still the preferred target of research in this field.

[Bovine spongiform encephalopathy: a new entity caused by a non-conventional transmissible agent]. / L'encéphalopathie spongiforme bovine: une nouvelle entité provoquée par un agent transmissible non conventionnel.

In 1986, a new neurologic disease appeared in the Great Britain's Cattle. According to its histological lesions, this condition belongs to the group of transmissible encephalopathies known as spongiforme encephalopathies (SE). These SE are associated with no-conventional transmission agent (NCTA) or Prion. At the time of writing, over 13,000 cases of Bovine spongiforme encephalopathy (BSE) have occurred in UK. The most likely origin of this dramatic outbreak would be an oral contamination of Cattle by the feeding of sheep carcasses or of all infected with scrapie, another SE, incorporated to concentrates. Possible factors as changes (lower temperatures and reduced use of organic solvents to extract fats) in the rendering process could have preserved the very resistant Prion in these concentrates. The important lessons resulting from our present knowledge and hypothesis are there would be no species barrier to impede transmission of the NCTA through oral route. The question concerns the public health risks posed by BSE. Two related diseases of human are Kuru and Creutzfeldt-Jacob disease. At the present time, based upon epidemiological datas on scrapie, BSE is unlikely to be a major threat to humans. Nevertheless, precautionary steps to reduce a potential risk to an absolute minimum were taken by British regulations and more recently, by European directives.

[Transmissible animal spongiform encephalopathies]. / Les encéphalopathies spongiformes transmissibles animales.

Scrapie in sheep and goats was the first animal spongiform encephalopathy diagnosed. It has since been described in a large number of species (cattle, wild and exotic ruminants, mink, cat). They form an original group of diseases because they are transmissible by a specific pathogen and they depend on the genetic predisposition of the recipient animal. Transmission between species and the possibility of oral transmission underline the need to assess the risk to Man.

Sheep major histocompatibility complex OLA: gene frequencies in two French breeds with scrapie. Evidence for a linkage between OLA and resistance or susceptibility to the disease.

Gene frequencies of 13 sheep lymphocyte factors (11 factors controlled by the sheep OLA complex including three closely linked loci, and two factors by two minor loci) were compared in 189 sheep of two breeds: a. infected with scrapie, b. healthy in a contaminated environment, and c., normal. In a and c, OLA gene frequencies were similar. In healthy sheep in a contaminated environment (b), some OLA gene frequencies were higher in one breed and lower in the other. In each breed, three antigens had their frequencies significantly modified; two of them were the same in the two breeds, but they showed an inverse variation. Thus, the relative risk of clinical scrapie decreased in one breed and increased in the other for the same OLA gene. These data indicate first, that OLA antigens are not directly involved in causing scrapie, and second, that the OLA complex is linked to at least one scrapie resistance/susceptibility locus. In practice, it should be possible to select more resistent sheep, using some OLA antigens but an investigation of the OLA genes and the resistance to scrapie in a given breed is necessary before the selection.

[Scrapie in sheep and transmissible encephalopathy of the mink]. / La tremblante du mouton et l'encéphalopathie transmissible du vison.

Scrapie in sheep and goat is the prototype of the group of the transmissible spongiform encephalopathies which affect man and some animal species, notably other ruminants with bovine spongiform encephalopathy (BSE) and chronic wasting disease of wild ruminants. Transmissible mink encephalopathy (TME) is a rare disease of ranch-raised mink caused by exposure to a contaminated food ingredient in the ration scrapie, unrecognised BSE-like disease...). There is clinical and pathological similarities between TME and scrapie. These diseases share the following characteristics: a prolonged incubation period; a progressive, debilitating, neurological illness (always fatal); pathological changes confined to the central nervous system (vacuolisation, neurological loss, astrocytosis); the presence of scrapie-associated-fibrils (SAF) in brain tissue; and absence of detectable inflammatory or immune responses. The genetic origin of scrapie in sheep and the natural transmission of these spongiform encephalopathies are discussed.