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L G Goldfarb

Publications and source records attributed to L G Goldfarb.

At least 73 records · Page 4Linked to original sources
PubMed1992

Creutzfeldt-Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin.

We recently discovered an amino acid-altering heterozygous mutation in codon 178 of the PRNP amyloid precursor gene in patients with familial Creutzfeldt-Jakob disease. This mutation is now shown to be associated with the occurrence of disease in 7 unrelated families of Western European origin, among which a total of 65 members are known to have died from Creutzfeldt-Jakob disease. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control individuals. Linkage analysis in two informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggests that codon 178Asn is the actual disease mutation.

Adult↗
PubMed1992

Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178Asn PRNP mutation.

A group of 43 patients from seven families affected by Creutzfeldt-Jakob disease (CJD) with the codon 178Asn mutation of the PRNP amyloid precursor gene is compared to a group of 211 patients with the sporadic form of the disease. As a group, the patients with the codon 178Asn mutation had an earlier age at onset of illness (almost always presenting as an insidious loss of memory), a longer duration of illness, and an absence of periodic electroencephalographic activity. Transmission of disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings are interpreted and discussed in terms of possible differences in the temporospatial evolution of damage to the brain, and of accelerated induction of polymerized amyloid protein by its mutationally altered template precursor.

Age Factors↗
PubMed1992

An insert mutation in the chromosome 20 amyloid precursor gene in a Gerstmann-Sträussler-Scheinker family.

We report the finding of an insert mutation in the chromosome 20 amyloid precursor gene in a family with neuropathologically-verified, experimentally-transmitted Gerstmann-Sträussler-Scheinker syndrome (GSS). The insert consisted of 8 extra copies of a repeating octapeptide coding sequence in the region between codons 51 and 91; it was identified in the proband and a presently unaffected at-risk niece by full sequencing of the open reading frame, and was visualized electrophoretically in the proband and 6 of 12 at-risk relatives. Although affected members in this French-Breton family have shown a variety of clinical profiles, including durations of illness that ranged from 3 months to 13 years, all autopsied cases (including the patient with the shortest illness) have had the distinctive multicentric amyloid plaques that define GSS as a nosologic entity.

Adult↗
PubMed1992

Familial Creutzfeldt-Jakob disease in Chile is associated with the codon 200 mutation of the PRNP amyloid precursor gene on chromosome 20.

We have found the codon 200Lys mutation in 6 Chilean CJD families, including a family in the rural case cluster in Chillán. Thus, all 3 of the known clusters of CJD, in Slovakia, Libyan-born Israeli Jews, and Chile, are linked to the presence of the same mutation. The phenotypic features of the disease in these families are similar to those reported for other clustered or individual families elsewhere in the world. The heterogeneous genetic composition of the Chilean population interpreted in light of historical migration patterns suggests that the mutation may have entered Chile by Jewish emigration from Spain.

Adult↗
PubMed1992

Viliuisk encephalomyelitis in the Iakut people of Siberia.

Viliuisk encephalomyelitis (VE), a progressive neurological disorder with a fatal outcome usually in several months to 6 yrs after disease onset, is seen only among the Iakut people of Siberia. The acute meningoencephalitic phase of the disease is followed by progressive dementia, rigidity and spastic tetraparesis. The disease is characterized by multiple micronecrotic foci with marked inflammatory reactions and gliosis in the grey matter. The acute febrile onset, with cerebrospinal fluid (CSF) pleocytosis and increased protein in the CSF, the epidemiology and the inflammatory neuropathology suggest the disease is infectious. Studies on household spread indicate an incubation time of up to several years. Viliuisk encephalomyelitis was restricted to an ethically distinct group of Iakut people of the Middle Viliui region, but in recent decades, with migration from this region, it has been spreading into previously unaffected Iakut populations. The occurrence of multiple VE cases in households and introduction of the disease by migrants into new populations indicate horizontal transmission in a setting of long intimate contact.

Acute Disease↗
PubMed1992

Atypical Creutzfeldt-Jakob disease in an American family with an insert mutation in the PRNP amyloid precursor gene.

An American family of English origin with an unusually early onset and long-duration form of Creutzfeldt-Jakob disease (CJD) had a heterozygous insert mutation in the region of repeating octapeptide coding sequences between codons 51 and 91 of the PRNP gene on chromosome 20. Affected members were 23 to 35 years old at the onset of illnesses that lasted from 4 to 13 years, yet experimental transmission of disease from the proband (11-year duration) produced a typically brief incubation period and duration of illness in each of three inoculated primates. Also, the PrP amyloid protein that accumulates in CJD brain was only barely detectable in extracted brain tissue from one case with massive spongiform change and was undetectable in another case with no spongiform change, perhaps because of epitope shielding by a configurational change in the protein induced by the mutation. Analysis of this and other families with similar inserts suggests that such mutations in the PRNP gene not only predispose to CJD, but also modify its phenotypic expression.

Adult↗
PubMed1991

Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene.

The PRNP gene, encoding the amyloid precursor protein that is centrally involved in Creutzfeldt-Jakob disease (CJD), has an unstable region of five variant tandem octapeptide coding repeats between codons 51 and 91. We screened a total of 535 individuals for the presence of extra repeats in this region, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurological and non-neurological patients, and normal controls. We identified three CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had "wobble" nucleotide substitutions. We also found one individual with 9 repeats and no nucleotide substitutions who had no evidence of neurological disease. These observations, together with data on published British patients with 11 and 14 repeats, strongly suggest that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD.

Adult↗
PubMed1991

Detection of flaviviruses by reverse-transcriptase polymerase chain reaction.

RNA sequences of five flaviviruses were detected by a modified polymerase chain reaction (PCR) that incorporated a reverse transcriptase and RNase inhibitor. Oligonucleotide primer pairs were synthesized to amplify sequences from St. Louis encephalitis (SLE), Japanese encephalitis (JBE), yellow fever (YF), dengue 2 (DEN-2), and dengue 4 (DEN-4) viruses. The amplified products were visualized as bands of appropriate size on ethidium bromide-stained agarose gels. The identity of these products was confirmed by restriction endonuclease cleavage to generate fragments of predicted lengths. The reverse-transcriptase PCR (RT-PCR) successfully amplified flavivirus sequences from cell cultures, frozen brain tissue, and formalin-fixed, paraffin-embedded brain tissue. The reactions were highly specific, and the method compared favorably to two conventional assays of viral infectivity. RT-PCR followed by PCR with nesting primers (N-PCR) was 1,000-fold more sensitive in detecting virus than classical infectivity titration by intracerebral inoculation of suckling mice and nearly 1,000-fold more sensitive than amplification of virus in cell culture followed by inoculation of mice.

Aedes↗
PubMed1991

The phenotypic expression of different mutations in transmissible familial Creutzfeldt-Jakob disease.

Cases of familial Creutzfeldt-Jakob disease (CJD) with mutations in the PRNP gene were analyzed for distinctive clinico-pathological and experimental transmission characteristics. An insert mutation within the region of codons 51 to 91 was associated with a markedly early age at onset and prolonged course of illness. Point mutations at codons 178 and 200 were also associated with ages at onset, durations of illness, and clinical symptom profiles that differed from sporadic CJD. The age at onset of illness in each group was correlated with the length of incubation periods in primates inoculated with their brain tissue, suggesting that the early onset of familial CJD results not from a time shift of the initiating event, but from an accelerated pre-clinical (incubation) phase of disease, perhaps due to a more rapid formation of amyloid induced by a mutationally-altered precursor protein template.

Adult↗
PubMed1991

Creutzfeldt-Jacob disease associated with the PRNP codon 200Lys mutation: an analysis of 45 families.

200Lys mutation in the human PRNP coding region has been identified in 45 of the 55 CJD-affected families thus far presented to our NIH laboratory. These codon 200Lys families have a total of 87 patients, and originate from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Forty-seven patients were neuropathologically verified, and brain tissue from 14 patients transmitted disease to experimental primates. The mutation was found by direct sequencing in 4 patients, and it was detected by restriction endonuclease analysis with BsmA 1 and/or the single nucleotide extension reaction in 36 other patients and 45 of 109 first degree relatives (1 parent, 14 siblings, and 30 children). The mutation is associated with all known geographical clusters of CJD (Slovakia, Libyan Jews, Chile) in which the annual mortality rate is tens or hundreds of times higher than the world average of 1 per million. All patients originating from the cluster areas carried the mutation, but it was seen in only 1 of 103 unrelated control individuals from the same areas, and in none of 102 controls from other areas, indicating a strong association between the mutation and disease. The penetrance of the mutation was estimated to be 0.56. Branches of some families migrating from cluster areas to other countries continue to have CJD over several generations, suggesting that CJD in these families is a genetic disorder, in which the 200Lys mutation is responsible for the disease.

Africa↗
PubMed1991

Familial Creutzfeldt-Jakob disease in Finland: epidemiological, clinical, pathological and molecular genetic studies.

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.

Adult↗
PubMed1991

The molecular genetics of familial Creutzfeldt-Jakob disease in France.

Five French families with Creutzfeldt-Jakob disease (CJD) were found to have either of 2 different point mutations (at codons 178 and 200) in the amyloid precursor gene (PRNP) on chromosome 20. The ancestry of these and other CJD families outside of France suggests that the codon 178 mutation had a northern European origin, while the codon 200 mutation originated in central Europe and the Mediterranean basin. Evidence is presented that the mutations either cause or predispose to familial forms of CJD, and also influence their phenotypic expression, although considerable clinical and neuropathological heterogeneity may occur between and even within families having the same mutation. Experimental transmission of disease was successful in 4 of 5 inoculated cases, comparable to the transmission rate in sporadic CJD.

Amyloid beta-Protein Precursor↗
PubMed1991

Support of linkage of Gerstmann-Sträussler-Scheinker syndrome to the prion protein gene on chromosome 20p12-pter.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a human transmissible spongiform encephalopathy recently linked to the human analog of the prion protein gene (PRNP) on chromosome 20p. We have studied a large German GSS family for linkage to PRNP and have obtained a peak lod score of 1.15 at a recombination fraction (theta) of 0.00. This result provides additional evidence that GSS is linked to a mutation in codon 102 of the PRNP gene. Combining our data with linkage data previously reported yields a peak lod score of 4.52 at theta = 0.0. No evidence for linkage heterogeneity was found in the combined data set.

Chromosomes, Human, Pair 20↗
PubMed1991

A mutation in the prion protein gene in Creutzfeldt-Jakob disease in Jewish patients of Libyan, Greek, and Tunisian origin.

A modified host protein encoded by the gene specifying the scrapie amyloid precursor is critically involved in the pathogenesis of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker's syndrome, and Kuru. A mutation in the open reading frame of this gene was recently described in a cluster of patients with CJD in Slovakia. This mutation at codon 200 changes glutamic acid coded by GAG to lysine coded by AAG. We examined the prevalence of this mutation in the cluster of patients with CJD among Sephardic Jews of Libyan descent in Israel. A polymerase chain reaction was used to amplify the open reading frame of the prion protein gene from DNA extracted from frozen brain tissue of five Israeli residents (four of Libyan and one of Greek origin) and two familial cases in Jews born in Greece and Tunisia who later emigrated to France. The existence of the codon 200 mutation was detected by digestion of the open reading frame fragments with the BsmA1 restriction enzyme. All patients had the same codon 200 mutation. These findings implicate this mutation in the high prevalence of CJD among Libyan and Sephardic Jews from other Mediterranean countries.

Creutzfeldt-Jakob Syndrome↗