Biomedical subjects

L G Goldfarb

Publications and source records attributed to L G Goldfarb.

At least 19 recordsLinked to original sources

PubMed2004

Desmin myopathy.

Desmin myopathy is a recently identified disease associated with mutations in desmin or alphaB-crystallin. Typically, the illness presents with lower limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial, bulbar and respiratory muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks and arrhythmias resulting in premature sudden death. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing amorphous eosinophilic deposits seen as granular or granulofilamentous material on electron microscopic examination. Immuno-staining for desmin is positive in each region containing abnormal structures. The inheritance pattern in familial desmin myopathy is autosomal dominant or autosomal recessive, but many cases have no family history. At least some, and probably most, non-familial desmin myopathy cases are associated with de novo desmin mutations. Age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Multiple mutations have been identified in the desmin gene: point substitutions, insertion, small in-frame deletions and a larger exon-skipping deletion. The majority of these mutations are located in conserved alpha-helical segments of desmin. Many of the missense mutations result in changing the original amino acid into proline, which is known as a helix breaker. Studies of transfected cell cultures indicate that mutant desmin is assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. Disease-associated desmin mutations in humans or transgenic mice cause accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. alphaB-crystallin serves in the muscle as a chaperone preventing desmin aggregation under various forms of stress. If mutated, alphaB-crystallin may cause a myopathy similar to those resulting from desmin mutations. Routine genetic testing of patients for mutations in desmin and alphaB- crystallin genes is now available and necessary for establishing an accurate diagnosis and providing appropriate genetic counselling. Better understanding of disease pathogenesis would stimulate research focused on developing specific treatments for these conditions.

Amino Acid Sequence↗

PubMed2004

Evaluating association and transmission of eight inflammatory genes with Viliuisk encephalomyelitis susceptibility.

Since the discovery of Viliuisk encephalomyelitis (VE) in 1887, scientists have tried to understand the natural history and aetiology of this endemic neurological disorder among the native Sakha population of Central Siberia. Familial aggregation and segregation analysis suggested a genetic influence on VE incidence. However, recent studies have implicated an unknown virus, possibly from the alpha herpesvirus family, as a possible cause for this disease. As VE is a neurological disease characterized by the inflammatory reactions systematically observed in the spinocerebellar fluid and in the brain tissue of deceased patients, we examined 17 single nucleotide polymorphisms (SNPs) across seven inflammation-related candidate gene regions, including chemokine receptors type 2 and 5 (CCR2/CCR5), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, IL-10, stromal cell-derived factor (SDF) and chemokine regulated upon activation, normal T-cell expressed and presumably secreted (RANTES). Our main objective was to analyse the degree of genetic association between VE and candidate genes that have been previously implicated in other inflammatory diseases. Samples were collected from 83 affected families comprising 88 verified VE cases, 156 family members, and an additional 69 unrelated, unaffected inhabitants of the same geographical area. This collection included substantially all of the cases that are currently on the VE Registry. The experimental design included both case-control and transmission/disequilibrium test (TDT)-based familial association analyses. None of 17 SNPs analysed was significantly associated with VE occurrence. Exclusion of these eight genes based on the lack of association has important implications for identifying the disease agent, as well as prescribing therapy and understanding Viliuisk encephalomyelitis.

Case-Control Studies↗

PubMed2004

Small de novo duplication in the repeat region of the TATA-box-binding protein gene manifest with a phenotype similar to variant Creutzfeldt-Jakob disease.

A 20-year-old North American patient developed rapidly progressive cognitive decline and pronounced ataxia, a phenotype compatible with prion disease. No structural changes were found in the PRNP gene, which excludes genetic prion disease, but the patient's PRNP codon 129 Met/Met genotype is known to predispose to variant Creutzfeldt-Jakob disease (vCJD). Further studies identified an expanded allele with 55 CAG/CAA repeats in the TBP gene. The increase of trinucleotide repeat number in the coding region of the TBP gene has previously been associated with spinocerebellar ataxia type 17 (SCA17). The patient's unaffected parents and siblings show normal-size TBP alleles with 37-38 repeats. Haplotype and nucleotide sequence analyses clearly indicate that the mutation has occurred de novo on a paternal chromosome by insertion/duplication of a (CAA)(CAG)(CAA)(CAG)(15) sequence. This report presents a second fully investigated sporadic case of SCA17 occurring as a result of a DNA rearrangement within the polymorphic TBP trinucleotide repeat region. Our findings suggest that patients suspected of vCJD should undergo testing for SCA17, Huntington's disease and other neurodegenerative disorders having phenotypic similarities with vCJD.

Adult↗

PubMed2004

Genetic studies in relation to kuru: an overview.

Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic "kuru-type" amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or "prion" diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Val genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena.

Animals↗

PubMed2002

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Chorea↗

PubMed2001

Spinocerebellar ataxia type 1 in China: molecular analysis and genotype-phenotype correlation in 5 families.

BACKGROUND: Twelve genetic types of autosomal dominant hereditary ataxia have been recently identified and the genes responsible for most of them cloned. Molecular identification of the type of ataxia is important to determine the disease prevalence and its natural history in various populations. OBJECTIVES: To perform molecular analysis of 75 Chinese families affected with spinocerebellar ataxia (SCA) and to evaluate the spectrum of mutations in these genes and the correlation between genotypes and phenotypes in Chinese patients. SETTING: Neurogenetics Unit, China-Japan Friendship Hospital, Beijing, China. METHODS: One hundred nine patients from 75 kindreds diagnosed as having autosomal dominant SCA, 16 patients with sporadic SCA or spastic paraplegia, 280 control chromosomes of the Chinese population, and 120 control chromosomes of the Sakha population were selected for this study. We conducted detailed mutational analysis by direct sequencing of polymerase chain reaction products amplified from genomic DNA. RESULTS: Spinocerebellar ataxia type 1 (SCA1) was identified in 5 families with 12 studied patients. All affected family members were heterozygous for a CAG repeat expansion in the SCA1 gene containing 51 to 64 trinucleotide repeats. Normal alleles had 26 to 35 repeats. Spinocerebellar ataxia type 1 accounted for 7% of the studied Chinese families with ataxia. In addition, we determined the frequency of a single vs double CAT interruption in 120 control chromosomes of the Siberian Sakha population, which has the highest known prevalence of SCA1, and compared this with 280 control chromosomes from the Chinese populations. The results show that 64.7% of the Siberian normal alleles contain a single CAT interruption, whereas 92% of the Chinese had more than 1 interruption. CONCLUSIONS: Spinocerebellar ataxia type 1 is responsible for 7% of affected families in the Chinese population. A correlation between the prevalence of SCA1 and the number of CAT interruptions in the trinucleotide chain suggests that a CAT-to-CAG substitution may have been the initial event contributing to the generation of expanded alleles and influencing relative prevalence of SCA1.

Adult↗

PubMed2001

Identification and functional characterization of a novel ryanodine receptor mutation causing malignant hyperthermia in North American and South American families.

Malignant hyperthermia is a pharmacogenetic disorder associated with mutations in Ca(2+) regulatory proteins. It manifests as a hypermetabolic crisis triggered by commonly used anesthetics. Malignant hyperthermia susceptibility is a dominantly inherited predisposition to malignant hyperthermia that can be diagnosed by using caffeine/halothane contracture tests. In a multigenerational North American family with a severe form of malignant hyperthermia that has caused four deaths, a novel RYR1 A2350T missense mutation was identified in all individuals testing positive for malignant hyperthermia susceptibility. The same A2350T mutation was identified in an Argentinean family with two known fatal MH reactions. Functional analysis in HEK-293 cells revealed an altered Ca(2+) dependence and increased caffeine sensitivity of the expressed mutant protein thus confirming the pathogenic potential of the RYR1 A2350T mutation.

Amino Acid Substitution↗

PubMed2001

Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease.

Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal enzyme alpha-galactosidase A, which results in a progressive multisystem disease. Most families have private mutations and no general correlation between genotype and disease manifestations has been described to date. Forty-nine patients (47 males and 2 females) from 36 affected families were selected for the study. Their evaluation included clinical examination, identification of alpha-galactosidase A gene mutations and residual enzymatic activity. For mutation detection, each exon with flanking intronic sequences was amplified by polymerase chain reaction (PCR) from the patient's genomic DNA and sequenced. Analysis of the resulting sequences was conducted to identify structural defects in the gene. Each of the Fabry patients carried a mutation in the alpha-galactosidase A gene. Fifteen mutations were novel. They included missense mutations (M51K, Y123M, G261D), nonsense point mutations (E251X) and small insertions or deletions creating a premature translational termination signal (P6X, D93X, W162X, K240X, H302X, I303X, L403X, S345X, G375X, F396X). Residual alpha-galactosidase A activity was significantly lower in patients with neuropathic pain (p=0.01) and in patients with mutations leading to a nonconservative amino acid change (p=0.04). Our findings emphasize the wide variety of genetic mechanisms leading to Fabry disease. A significant genotype-phenotype relationship was found.

Codon, Nonsense↗

PubMed2001

Gluten sensitivity in sporadic and hereditary cerebellar ataxia.

Gluten sensitivity, with or without classical celiac disease symptoms and intestinal pathology, has been suggested as a potentially treatable cause of sporadic cerebellar ataxia. Here, we investigated the prevalence of abnormally high serum immunoglobulin A (IgA) and IgG anti-gliadin antibody titers and typical human lymphocyte antigen (HLA) genotypes in 50 patients presenting with cerebellar ataxia who were tested for molecularly characterized hereditary ataxias. A high prevalence of gluten sensitivity was found in patients with sporadic (7/26; 27%) and autosomal dominant (9/24; 37%) ataxias, including patients with known ataxia genotypes indicating a hitherto unrecognized association between hereditary ataxias and gluten sensitivity. Further studies are needed to determine whether gluten sensitivity contributes to cerebellar degeneration in patients with hereditary cerebellar ataxia. Patients with hereditary ataxia (including asymptomatic patients with known ataxia genotype) should be considered for screening for gluten sensitivity and gluten-free diet trials.

Adolescent↗

PubMed2000

Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype.

Kuru reached epidemic proportions by the mid-twentieth century among the Fore people of New Guinea and disappeared after the abolition of cannibalistic rituals. To determine susceptibility to kuru and its role in the spread and elimination of the epidemic, we analyzed the PRNP gene coding sequences in 5 kuru patients; no germline mutations were found. Analysis of the PRNP 129 methionine (M)/valine (V) polymorphism in 80 patients and 95 unaffected controls demonstrated that the kuru epidemic preferentially affected individuals with the M/M genotype. A higher representation of M/M carriers was observed among the affected young Fore males entering the age of risk, whereas a lower frequency of M/M homozygotes was found among the survivors. M/V and V/V genotypes predisposed to a lower risk of disease development and longer incubation times. These findings are relevant to the current outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom, because all vCJD patients tested thus far have been M/M carriers.

Amyloid↗

PubMed2000

Inherited prion encephalopathy associated with the novel PRNP H187R mutation: a clinical study.

OBJECTIVE: To describe a variant of prion encephalopathy associated with the recently identified H187R mutation in the prion protein (PRNP) gene. METHODS: The authors studied a multigenerational American family with nine affected individuals. Clinical examination included imaging, EEG, and CSF analysis with 14-3-3 protein testing. Histopathology was characterized by examination of a brain biopsy from an H187R mutation-positive patient. RESULTS: The disease in this family is caused by the PRNP H187R mutation and characterized by autosomal dominant inheritance, median age at disease onset of 42 years (range 33 to 50 years), and median duration of illness of 12 years (range 8 to 19 years). Clinical signs include progressive dementia, ataxia, myoclonus, and seizures. Histopathologic features consist of distinctive "curly" prion protein deposits with a strictly laminar distribution in the cerebral cortex and minimal astrogliosis in the absence of amyloid plaques or spongiosis. CONCLUSION: A variant of prion encephalopathy associated with the novel H187R mutation in the PRNP gene displays distinctive clinical and immunostaining characteristics that further expand the boundaries of human prion disease.

Adult↗

PubMed2000

Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS).

Twelve cases of adult-onset progressive muscular atrophy variant of amyotrophic lateral sclerosis (PMA/ALS) were studied in a small rural population of 1500 in the Republic of Belarus (former Soviet Union). The patients were members of three apparently related kindreds, each showing autosomal dominant pattern of disease inheritance. The average age at clinical onset ranged from 26 to 57 years (mean, 40 years). Each patient suffered from skeletal muscle weakness and wasting, starting in the limbs and spreading to the trunk and neck, with very limited bulbar and no upper motor neuron involvement. Death from respiratory failure occurred from 13 to 48 months (mean, 28 months) after first symptoms. Dramatically decreased number of spinal motor neurons was the most characteristic neuropathologic feature in two autopsied cases. Most of the remaining degenerating neurons contained intracytoplasmic hyaline inclusion bodies. A D101N mutation in exon 4 of the SOD1 gene was identified in a PMA/ALS patient and in one of her three unaffected children. Our data support the view that some subtypes of familial ALS associated with SOD1 mutations may present as PMA. Diagnostic criteria of ALS should be accordingly modified to include the PMA variant of familial ALS.

Adult↗

PubMed2000

A three-sister sibship of Gerstmann-Sträussler-Scheinker disease with a CJD phenotype.

OBJECTIVE: To describe a rare phenotypic variant of P102L Gerstmann-Sträussler-Scheinker disease (GSS). BACKGROUND: Classic GSS is characterized by an early age at onset, prominent cerebellar signs with a slowly evolving dementia, and a neuropathology including multifocal PrP-positive plaques and variable but usually modest spongiform change. METHODS: Clinical, neuropathologic, immunohistochemical, and molecular genetic analysis of three sisters in a Hungarian family was performed. RESULTS: The clinical course of all three sisters was indistinguishable from sporadic Creutzfeldt-Jakob disease (CJD). Neuropathologic examination revealed spongiform changes, PrP (prion)-positive unicentric "kuru" or multicentric plaques, and abundant beta-A4-positive senile plaques. Molecular genetic analysis of the PRNP gene showed the heterozygous codon P102L mutation of classic GSS, with the methionine encoding allele of a heterozygous codon 129 coupled to the mutant 102 allele. CONCLUSION: The authors report the second recorded example of a sporadic CJD phenotype occurring in association with the P102L GSS genotype, and the first instance in which the phenotype was the rule rather than the exception, or was associated with prominent beta-A4 plaque formation.

Aged↗

PubMed2000

Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene.

BACKGROUND: Myofibrillar myopathies, often referred to as desmin-related myopathies, are a heterogeneous group of inherited or sporadic distal-onset skeletal myopathies associated with cardiomyopathy. Among the myofibrillar proteins that characteristically accumulate within the muscle fibers of affected patients, the one found most consistently is desmin, a muscle-specific intermediate-filament protein responsible for the structural integrity of the myofibrils. Skeletal and cardiac myopathy develops in mice that lack desmin, suggesting that mutations in the desmin gene may be pathogenic. METHODS: We examined 22 patients from 8 families with dominantly inherited myofibrillar or desmin-related myopathy and 2 patients with sporadic disease and analyzed the desmin gene for mutations, using complementary DNA (cDNA) amplified from muscle-biopsy specimens and genomic DNA extracted from blood lymphocytes. Restriction-enzyme analysis was used to confirm the mutations. Expression vectors containing normal or mutant desmin cDNA were introduced into cultured cells to determine whether the mutant desmin formed intermediate filaments. RESULTS: Six missense mutations in the coding region of the desmin gene that cause the substitution of an amino acid were identified in 11 patients (10 members of 4 families and 1 patient with sporadic disease); a splicing defect that resulted in the deletion of exon 3 was identified in the other patient with sporadic disease. Mutations were clustered in the carboxy-terminal part of the rod domain, which is critical for filament assembly. In transfected cells, the mutant desmin was unable to form a filamentous network. Seven of the 12 patients with mutations in the desmin gene had cardiomyopathy. CONCLUSIONS: Mutations in the desmin gene affecting intermediate filaments cause a distinct myopathy that is often associated with cardiomyopathy and is termed "desmin myopathy." The mutant desmin interferes with the normal assembly of intermediate filaments, resulting in fragility of the myofibrils and severe dysfunction of skeletal and cardiac muscles.

Adult↗

PubMed2000

Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation.

Desmin myopathy is a familial or sporadic disorder characterized by intracytoplasmic accumulation of desmin in the muscle cells. We and others have previously identified desmin gene mutations in patients with familial myopathy, but close to 45% of the patients do not report previous family history of the disease. The present study was conducted to determine the cause of desmin myopathy in a sporadic patient presenting with symmetrical muscle weakness and atrophy combined with atrioventricular conduction block requiring a permanent pacemaker. A novel heterozygous R406W mutation in the desmin gene was identified by sequencing cDNA and genomic DNA. Expression of a construct containing the patient's mutant desmin cDNA in SW13 (vim-) cells demonstrated a high pathogenic potential of the R406W mutation. This mutation was not found in the patient's father, mother or sister by sequencing and restriction analysis. Testing with five microsatellite markers and four intragenic single nucleotide polymorphisms excluded alternative paternity. Haplotype analysis indicates that the patient's father was germ-line mosaic for the desmin mutation. We conclude that de novo mutations in the desmin gene may be the cause of sporadic forms of desmin-related cardiac and skeletal myopathy.

Adult↗

PubMed2000

Desmin splice variants causing cardiac and skeletal myopathy.

Desmin myopathy is a hereditary or sporadic cardiac and skeletal myopathy characterised by intracytoplasmic accumulation of desmin reactive deposits in muscle cells. We have characterised novel splice site mutations in the gene desmin resulting in deletion of the entire exon 3 during the pre-mRNA splicing. Sequencing of cDNA and genomic DNA identified a heterozygous de novo A to G change at the +3 position of the splice donor site of intron 3 (IVS3+3A-->G) in a patient with sporadic skeletal and cardiac myopathy. A G to A transition at the highly conserved -1 nucleotide position of intron 2 affecting the splice acceptor site (IVS2-1G-->A) was found in an unrelated patient with a similar phenotype. Expression of genomic DNA fragments carrying the IVS3+3A-->G and IVS2-1G-->A mutations confirmed that these mutations cause exon 3 deletion. Aberrant splicing leads to an in frame deletion of 32 complete codons and is predicted to result in mutant desmin lacking 32 amino acids from the 1B segment of the alpha helical rod. Functional analysis of the mutant desmin in SW13 (vim-) cells showed aggregation of abnormal coarse clumps of desmin positive material dispersed throughout the cytoplasm. This is the first report on the pathogenic potentials of splice site mutations in the desmin gene.

Adult↗

PubMed1999

Novel PRNP sequence variant associated with familial encephalopathy.

Human transmissible spongiform encephalopathies (TSEs) are a group of chronic progressive neurodegenerative disorders that may be hereditary, infectious, or sporadic. Hereditary TSEs are associated with mutations in the PRNP gene on chromosome 20p12-pter. We report on a family in which seven patients developed limb and truncal ataxia, dysarthria, myoclonic jerks, and cognitive decline. The age of onset in the 30s, 40s, or 50s, prolonged disease duration, cerebellar atrophy on imaging, and the presence of synchronic periodic discharges on electroencephalogram suggested a familial encephalopathy resembling Gerstmann-Sträussler-Scheinker disease. A novel H187R mutation has been identified in affected, but not in unaffected, family members or unrelated controls suggesting a pathogenic role for this mutation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:653-656, 1999. Published 1999 Wiley-Liss, Inc.

Adult↗

PubMed1999

Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation-associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the basis of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation.

Amyloid↗