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L G Goldfarb

Publications and source records attributed to L G Goldfarb.

At least 55 records · Page 3Linked to original sources
PubMed1995

Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy.

Accumulation of beta-amyloid protein (A beta) occurs in some muscle fibers of patients with inclusion body myopathy and resembles the type of amyloid deposits seen in the affected tissues of patients with Alzheimer's disease and cerebrovascular amyloidosis. Because mutations in exons 16 and 17 of the beta-amyloid precursor protein (beta APP) gene on chromosome 21 have been identified in patients with early-onset familial Alzheimer's disease and Dutch-type cerebrovascular amyloidosis, we searched for mutations of the same region in patients with familial inclusion body myopathy. Sequencing of both alleles in 8 patients from four unrelated families did not reveal any mutations in these exons. The amyloid deposition in familial forms of inclusion body myopathy may be either due to errors in other gene loci, or it is secondary reflecting altered beta APP metabolism or myocyte degeneration and cell membrane degradation.

Adult↗
PubMed1995

The transmissible spongiform encephalopathies.

The human transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of rapidly progressive disorders characterized by a spectrum of clinical abnormalities that include cognitive impairment, ataxia, myoclonus, and visual, pyramidal, and extrapyramidal signs. They share a spongiform (vacuolar) degeneration and variable amyloid plaque formation. Examples of TSEs are kuru, an infectious disease; Creutzfeldt-Jakob disease (CJD), which may take an infectious, genetic, or sporadic form; and Gerstmann-Sträussler-Scheinker disease (GSS) and fatal familial insomnia (FFI), rare familial disorders. With the exception of FFI, all of these disorders have been experimentally transmitted to nonhuman primates and laboratory rodents. The pathogenic PrP protein accumulating in the brain of TSE patients is a protease-resistant and insoluble product of a precursor protein molecule of unknown function that is encoded by the PRNP gene on chromosome 20. Different mutations in this gene are responsible for various phenotypes of TSE in its familial form, and a polymorphism at codon 129 controls susceptibility to the infectious and perhaps sporadic forms of disease. TSEs are transmissible amyloidoses in which the host-encoded protein has the propensity to acquire a beta-sheet conformation and produce amyloid; the accumulation of amyloid eventually destroys the neurons and induces the deadly disease.

Animals↗
PubMed1995

Clinical and genetic studies of fatal familial insomnia.

We report a 42-year-old man who, for 8 months, had intermittent motor abnormalities and mild difficulty falling asleep. A diagnosis of fatal familial insomnia (FFI) became evident over the next 6 months when he developed progressive insomnia, myoclonus, sympathetic hyperactivity, and dementia. The amyloid or prion protein (PrP) genotype showed features typically seen in FFI, with a 178Asn mutation and a 129Met polymorphism. There was also a deletion of one octapeptide repeat, suggesting that the association of 178Asn mutation with the 129Met polymorphism is not due to "founder effect." Western immunoblot showed a trace of protease-resistant PrP in the thalamus--which had the most significant neuronal loss and gliosis--a moderate amount of PrP in the fronto-temporal area, and no detectable protein elsewhere in the brain. Endocrine studies showed that a circadian modulation of hormonal levels could be maintained despite a near-total absence of sleep. Administration of gamma-hydroxybutyrate induced a remarkable increase in slow-wave sleep.

Adult↗
PubMed1994

Infectious amyloid precursor gene sequences in primates used for experimental transmission of human spongiform encephalopathy.

Based on the analysis of genomic DNA from single healthy animals of each of five primate species, nucleotide and predicted amino acid sequences of the infectious amyloid precursor gene of higher apes (Gorilla and Pan) and Old World (Macaca) and New World (Ateles, Saimiri) monkeys showed 95-99% homology to the human sequences, corresponding to their phylogenetic distance from humans. Two of 18 amino acids that differed from humans resulted from nucleotide changes at sites of mutations in humans with familial forms of spongiform encephalopathy (a deleted codon within the codon 51-91 region of 24 bp repeats and a substitution at codon 198). In each of the five animals, codon 129 specified methionine, the more common of the two polymorphic genotypes in humans. Because genotypic homology did not correlate with experimental transmission rates of human spongiform encephalopathy, primary structural similarity of the infectious amyloid precursor protein in humans and experimental primates may not be an important factor in disease transmissibility.

Amino Acid Sequence↗
PubMed1994

Genetic analysis of Creutzfeldt-Jakob disease and related disorders.

Genetic studies of over 200 cases of Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru have brought a reliable body of evidence that the familial forms of CJD and all known cases of GSS and FFI are linked to germline mutations in the coding region of the PRNP gene on chromosome 20, either point substitutions or expansion of the number of 24-nucleotide repeat units. Phenotypic expression of FFI and familial CJD, clinically and pathologically distinct syndromes linked to the 178Asp-->Asn substitution, is dependent on a polymorphism at codon 129. Synthetic peptides homologous to several regions of PrP spontaneously form insoluble amyloid fibrils with unique morphological characteristics and polymerization tendencies. Peptides homologous to mutated regions of PrP exhibit enhanced fibrillogenic properties and, if mixed with the wild-type peptide, produce even more abundant and larger fibrous aggregates. A similar process in vivo may be the primary event leading to amyloid accumulation and disease.

Adult↗
PubMed1994

Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease.

We present a synthesis of clinical, neuropathological, and biological details of the National Institutes of Health series of 300 experimentally transmitted cases of spongiform encephalopathy from among more than 1,000 cases of various neurological disorders inoculated into nonhuman primates during the past 30 years. The series comprises 278 subjects with Creutzfeldt-Jakob disease, of whom 234 had sporadic, 36 familial, and 8 iatrogenic disease; 18 patients with kuru; and 4 patients with Gerstmann-Strüssler-Scheinker syndrome. Sporadic Creutzfeldt-Jakob disease, numerically by far the most important representative, showed an average age at onset of 60 years, with the frequent early appearance of cerebellar and visual/oculomotor signs, and a broad spectrum of clinical features during the subsequent course of illness, which was usually fatal in less than 6 months. Characteristic spongiform neuropathology was present in all but 2 subjects. Microscopically visible kuru-type amyloid plaques were found in 5% of patients with Creutzfeldt-Jakob disease, 75% of those with kuru, and 100% of those with Gerstmann-Sträussler-Scheinker syndrome; brain biopsy was diagnostic in 95% of cases later confirmed at autopsy, and proteinase-resistant amyloid protein was identified in Western blots of brain extracts from 88% of tested subjects. Experimental transmission rates were highest for iatrogenic Creutzfeldt-Jakob disease (100%), kuru (95%), and sporadic Creutzfeldt-Jakob disease (90%), and considerably lower for most familial forms of disease (68%). Incubation periods as well as the durations and character of illness showed great variability, even in animals receiving the same inoculum, mirroring the spectrum of clinical profiles seen in human disease. Infectivity reached average levels of nearly 10(5) median lethal doses/gm of brain tissue, but was only irregularly present (and at much lower levels) in tissues outside the brain, and, except for cerebrospinal fluid, was never detected in bodily secretions or excretions.

Adolescent↗
PubMed1994

Autosomal dominant spinocerebellar ataxia (SCA) in a Siberian founder population: assignment to the SCA1 locus.

In seven families from a Siberian founder population with autosomal dominant spinocerebellar ataxia (SCA) genetic analysis of the polymorphisms flanking the SCA1 locus on chromosome 6p showed allelic association with disease inheritance. While the association was absolute in the case of microsatellite D6S274, an allele switch was observed for D6S89 in two families, suggesting a historic recombinant. Further genetic and physical study of this recombinant event could be instrumental for the precise localization and identification of the SCA1 gene.

Alleles↗
PubMed1994

Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between ancient genes and modern medicine.

We tested DNA from 15 centrally infected cases of iatrogenic Creutzfeldt-Jakob disease (CJD) (dura mater or corneal homografts and stereotactic EEG electrodes), 11 peripherally infected cases (native human growth hormone or gonadotrophin), and 110 control individuals for the presence of mutations in the chromosome 20 amyloid gene. No patient or control had any of the known pathogenic point or insert mutations found in familial disease, but allelic homozygosity at polymorphic codon 129 was present in all but two (92%) of the 26 patients, compared with 54 (50%) of the 110 controls (p < 0.001). Pooled data from all identified and tested cases of iatrogenic disease yielded a worldwide total of 56 patients, of whom all but four were homozygous at codon 129 (p < 0.001). These findings support the thesis that homozygosity at codon 129 enhances susceptibility to iatrogenic infections of both central and peripheral origin, with evident implications for the population of dura mater homograft and pituitary hormone recipients whose lives have been complicated by the possibility of exposure to the infectious agent of CJD.

Amyloid↗
PubMed1993

Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically different amyloid fibrils.

We synthesized polypeptides corresponding to sequences encoded by normal and mutant alleles in the regions of codon 178 (Asp-->Asn) and codon 200 (Glu-->Lys) of the chromosome 20 amyloid gene that have been linked to familial Creutzfeldt-Jakob disease. Peptide suspensions from both regions spontaneously formed amyloid fibrils with different morphological characteristics and aggregation tendencies. Fibrillar arrays were denser and more profuse in mutant than in normal peptide suspensions and were even more marked when the homologous mutant and normal peptides were mixed together. Preparations from the region of codon 200 were in all cases more fibrillogenic than corresponding peptides from the region of codon 178. These in vitro observations support the hypothesis that amino acid changes from pathogenic single-allele point mutations in Creutzfeldt-Jakob disease may nucleate the in vivo folding behavior of the normal host protein to favor formation of insoluble amyloid fibrils.

Amino Acid Sequence↗
PubMed1993

Real and imagined clinicopathological limits of "prion dementia".

The term "prion dementia" has been proposed to replace "spongiform encephalopathy", to accommodate the existence of atypical forms of these "prion protein" (PrP) cerebral amyloidoses that may not show spongiform changes in the brain. We tested brain tissue extracts for the presence of PrP from 46 cases (including 13 familial cases) of non-spongiform dementias with a variety of associated neurological signs, referred to our laboratory for primate transmission studies. None of the cases transmitted disease to primates, and none had PrP detectable by western immunoblots of extracted brain tissue. We conclude that prion dementias are not lurking undetected within the larger landscape of neurodegenerative disorders, and that their clinicopathological limits are, except for a small number of previously reported familial cases, essentially those of spongiform encephalopathy.

Adult↗
PubMed1993

Belgrade virus, a cause of hemorrhagic fever with renal syndrome in the Balkans, is closely related to Dobrava virus of field mice.

Belgrade virus is a recently described hantavirus that causes severe hemorrhagic fever with renal syndrome (HFRS) in people living in various parts of the Balkan Peninsula. Nucleotide sequencing of the G2-encoding region in the medium (M) segment of the viral genome, reverse transcribed and amplified by the polymerase chain reaction, revealed the Belgrade virus to be substantially different from Hantaan virus and other major serotypes of hantavirus but identical to Dobrava virus, a virus isolated from a field mouse (Apodemus flavicollis) in Slovenia. Belgrade virus may be an important cause of HFRS in the Balkan Peninsula, extending north toward the Alps. It poses a special danger to humans who have close contact with field rodents.

Animals↗
PubMed1993

Clinical heterogeneity and unusual presentations of Creutzfeldt-Jakob disease in Jewish patients with the PRNP codon 200 mutation.

The cluster of Creutzfeldt-Jakob disease among Jews of Libyan origin is the largest in the world. It was found that the disease in this ethnic group is linked to a point mutation in codon 200 of the prion protein precursor gene. In this study the clinical data from 14 such patients are described, demonstrating wide phenotypic heterogeneity. The age of onset ranged from 34 to 65 years and the duration of disease from 2 to 66 months. Clinical features included cerebral, basal ganglia, brainstem, cerebellar, and spinal cord dysfunction. Uncommon features included fatal insomnia in one patient, pruritus in another, and demyelinating peripheral neuropathy in two.

Adult↗
PubMed1993

A new (two-repeat) octapeptide coding insert mutation in Creutzfeldt-Jakob disease.

We report a family in which the proband died of clinically typical, neuropathologically verified Creutzfeldt-Jakob disease; her still-living mother suffers from a progressive dementia of many years' duration, and her maternal grandfather died after a similar illness. The proband, her mother, and two of three young first-degree relatives all have an identical insert mutation in the PRNP gene consisting of a twice-repeated 24-nucleotide sequence in the region between codons 51 and 91.

Aged↗
PubMed1992

Familial Creutzfeldt-Jakob disease (codon 200 mutation) with supranuclear palsy.

OBJECTIVE: To identify a possible gene defect in a large kindred with atypical Creutzfeldt-Jakob disease (CJD). SUBJECTS: Over 360 kindred members, with and without progressive dementia. METHODS: Family, hospital, and clinic records were reviewed. The DNA was extracted from paraffin-embedded brain tissue of two deceased patients, and from blood leukocytes of nine healthy persons at risk. DNA was subjected to polymerase chain reaction and then analyzed by restriction endonuclease and single nucleotide primer extension. RESULTS: Nine family members had progressive fatal neurological disease consistent with CJD without myoclonus or typical electroencephalographic findings. Supranuclear gaze palsy was present in all five patients who underwent eye examinations. Two neuropathologically confirmed cases and five of nine at-risk family members had an identical mutation (GAG to AAG, glutamic acid to lysine) in codon 200 of the amyloid gene (PRNP) on chromosome 20. CONCLUSIONS: Clinically atypical CJD with early supranuclear gaze palsy but without myoclonus or characteristic electroencephalographic periodicity patterns is associated with the codon 200Lys mutation in the largest CJD kindred yet reported. The clinical concept of familial CJD should be enlarged to include this unusual phenotype.

Adult↗
PubMed1992

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD), two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asn178) of the prion protein gene. The possibility that a second genetic component modified the phenotypic expression of the Asn178 mutation was investigated. FFI and the familial CJD subtype segregated with different genotypes determined by the Asn178 mutation and the methionine-valine polymorphism at codon 129. The Met129, Asn178 allele segregated with FFI in all 15 affected members of five kindreds whereas the Val129, Asn178 allele segregated with the familial CJD subtype in all 15 affected members of six kindreds. Thus, two distinct disease phenotypes linked to a single pathogenic mutation can be determined by a common polymorphism.

Adult↗