RESUMO
The article presents results of investigation of certain unclear aspects of mortality of patients with spinocerebellar ataxia type I including patients with the same number of CAG-repetitions. The analysis of mortality of patients observed from 1993 to nowadays was implemented. Sampling included 112 patients during that period 53 patients died. The comparative analysis was implemented concerning received data and results of analysis of mortality of patients died prior to 1980. According received data, average value of CAG-repetitions of normal allele was equal to 30.2, and ofpathologic allele--48.7. The average life span made up to 52.8 years, average age of disease onset--38 years and natural duration of disease--14.8 years. The analysis of life span of patients with equal length of repetitions demonstrated that range of life span of patients makes up to from 8 to 23 years. It is established that life of patients becomes shorter because of accidents, cancer and concomitant diseases of cardiovascular system. The presence of such concomitant disease as tuberculosis of lungs results in no shortening of life of patients. The comparative analysis of mortality during the period over 34 years demonstrated that age of disease onset turned out to be more conservative and stable indicator of morbidity. Despite of lacking of effective methods of treatment of disease, the natural duration of disease increased statistically reliable up to 1.8 times during period of observation. The analysis of life span ofpatients with spinocerebellar ataxia type I demonstrated that their life span except length of CAG-expansion depends on a number of factors accelerating and retarding development of disease. At that, life span of patients with the same number of CAG-repetitions can significantly differ The malignant neoplasms, diseases of cardiovascular system and external causes are to be referred to factors accelerating and retarding development of main disease. The addition oftuberculosis in our case resulted in no alteration of natural course of disease. The other factors exist prolonging life of patients, including factors of social economic and medical character They require additional specification and thorough investigation with the purpose of developing methods ofpreventive correction of neuro-degeneration processes.
Assuntos
Progressão da Doença , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/mortalidade , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idade de Início , Comorbidade , Humanos , Estudos Longitudinais , Fatores de Risco , Federação Russa/epidemiologia , Fatores Socioeconômicos , Ataxias Espinocerebelares/epidemiologiaRESUMO
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.
Assuntos
Doença de Fabry/genética , alfa-Galactosidase/genética , Códon sem Sentido , Estudos de Coortes , DNA/química , DNA/genética , Análise Mutacional de DNA , Doença de Fabry/enzimologia , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto , Fenótipo , Deleção de SequênciaRESUMO
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.
Assuntos
Hipertermia Maligna/genética , Mutação de Sentido Incorreto , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Substituição de Aminoácidos , Argentina , Saúde da Família , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Ensaio Radioligante , Rianodina/metabolismo , Rianodina/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Trítio , Estados UnidosRESUMO
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.
Assuntos
Substituição de Aminoácidos/genética , Amiloide/genética , Mutação/genética , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Precursores de Proteínas/genética , Adulto , Idade de Início , Amiloide/metabolismo , Atrofia/etiologia , Atrofia/patologia , Progressão da Doença , Evolução Fatal , Feminino , Genes Dominantes , Ligação Genética , Humanos , Escore Lod , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Parietal/metabolismo , Lobo Parietal/patologia , Linhagem , Penetrância , Fenótipo , Doenças Priônicas/patologia , Proteínas Priônicas , Príons , Precursores de Proteínas/metabolismoRESUMO
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.
Assuntos
Desmina/genética , Doenças Musculares/genética , Mutação de Sentido Incorreto , Miofibrilas/patologia , Adulto , Sequência de Bases , Cardiomiopatias/genética , Linhagem Celular , Análise Mutacional de DNA , DNA Complementar , Feminino , Humanos , Filamentos Intermediários/genética , Filamentos Intermediários/patologia , Filamentos Intermediários/ultraestrutura , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/patologia , Doenças Musculares/patologia , Miofibrilas/genética , Fenótipo , Deleção de Sequência , TransfecçãoRESUMO
BACKGROUND: The APOE genotype has been shown to influence the risk of developing sporadic and familial AD. This effect is isoform-dependent, the APOE epsilon4 allele increasing susceptibility and the APOE epsilon2 allele providing protection. Amyloid formation is an important part of the pathogenesis in AD as well as in spongiform encephalopathies; apoE deposition in amyloid plaques has been documented in both conditions. METHODS: We examined the frequency of the APOE alleles in patients with various forms of transmissible spongiform encephalopathies, or prion diseases, including sporadic and iatrogenic Creutzfeldt-Jakob disease; familial Creutzfeldt-Jakob disease associated with PRNP 178N/129V and 200K/129M point mutations and a 24-nucleotide repeat expansion; fatal familial insomnia caused by the 178N/129M mutation; Gerstmann-Sträussler-Scheinker disease associated with 102L/129M mutation; and kuru. RESULTS: None of the groups we studied had a significant excess of APOE epsilon4 allele when compared with appropriate controls. CONCLUSION: Our results do not support the contention that the APOE epsilon4 allele is a risk factor for developing Creutzfeldt-Jakob disease or related disorders.
Assuntos
Amiloidose/genética , Apolipoproteínas E/genética , Doenças Priônicas/genética , Alelos , Síndrome de Creutzfeldt-Jakob/genética , Genótipo , Doença de Gerstmann-Straussler-Scheinker/genética , Humanos , Doença Iatrogênica , Kuru/genética , Mutação , Periodicidade , Fatores de RiscoRESUMO
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.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Éxons , Corpos de Inclusão , Doenças Musculares/genética , Adulto , Sequência de Bases , Feminino , Humanos , Dados de Sequência Molecular , MutaçãoRESUMO
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.
Assuntos
Doenças Priônicas/genética , Animais , Encéfalo/patologia , Angiopatia Amiloide Cerebral/diagnóstico , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/patologia , Cromossomos Humanos Par 20 , Humanos , Exame Neurológico , Testes Neuropsicológicos , Doenças Priônicas/diagnóstico , Doenças Priônicas/transmissão , Príons/genéticaRESUMO
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.
Assuntos
Doenças Priônicas/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Transplante de Tecido Encefálico , Callithrix , Carnívoros , Gatos , Cebidae , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/etiologia , Síndrome de Creutzfeldt-Jakob/transmissão , Família , Feminino , Doença de Gerstmann-Straussler-Scheinker/transmissão , Humanos , Kuru/transmissão , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Pan troglodytes , Aves Domésticas , Primatas , Roedores , Ruminantes , Saimiri , Estados UnidosRESUMO
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.
Assuntos
Precursor de Proteína beta-Amiloide/química , Síndrome de Creutzfeldt-Jakob/genética , Sequência de Aminoácidos , Precursor de Proteína beta-Amiloide/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Humanos , Substâncias Macromoleculares , Microscopia Eletrônica , Dados de Sequência Molecular , Mutação Puntual , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Química Encefálica , Demência/etiologia , Doenças Priônicas/etiologia , Príons/análise , Adulto , Idoso , Animais , Cebidae , Cercopithecidae , Síndrome de Creutzfeldt-Jakob/patologia , Síndrome de Creutzfeldt-Jakob/transmissão , Demência/genética , Demência/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pan troglodytes , Doenças Priônicas/genética , Doenças Priônicas/patologiaRESUMO
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.
Assuntos
Síndrome de Creutzfeldt-Jakob/epidemiologia , Adulto , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Códon , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Síndrome de Creutzfeldt-Jakob/fisiopatologia , DNA/análise , Eletroencefalografia , Finlândia/epidemiologia , Antígenos HLA/análise , Humanos , Pessoa de Meia-Idade , Biologia Molecular , Linhagem , Proteínas PrPSc , Príons/genéticaAssuntos
Amiloidose/genética , Doenças por Vírus Lento/genética , Adulto , Idoso , Amiloidose/etiologia , Cromossomos Humanos Par 20 , Códon/genética , Síndrome de Creutzfeldt-Jakob/etiologia , Síndrome de Creutzfeldt-Jakob/genética , Genes Dominantes/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , Proteínas PrPSc , Doenças por Vírus Lento/etiologia , Proteínas Virais/genéticaRESUMO
Human T-lymphotropic virus type I (HTLV-I), the etiological agent of adult T-cell leukemia/lymphoma, also appears to be the cause of tropical spastic paraparesis, a chronic myelopathy reported in several different regions of the world. The prevalence of antibodies to HTLV-I in patients with chronic neurodegenerative disorders other than tropical spastic paraparesis and in patients with some muscle inflammatory disorders has been investigated. IgG antibodies to HTLV-I were measured in the sera and/or cerebrospinal fluid from 82 Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia, 164 Guamanian normal controls, 10 patients with kuru from the Eastern Highlands of Papua New Guinea, 4 patients with Viliuisk encephalomyelitis from the Iakut region of eastern Siberia, 45 Italian patients with multiple sclerosis, and 56 patients with polymyositis (49 from the United States and 7 from Jamaica). As determined by enzyme-linked immunosorbent assay, Western immunoblot, and gelatin particle agglutination techniques, serological evidence of HTLV-I infection was found in 1 patient with amyotrophic lateral sclerosis and 1 control subject from Guam, and in 1 patient from the United States and all 7 Jamaican patients with polymyositis. Except for the high seropositivity rate among the group of Jamaican patients with polymyositis, our data indicate that HTLV-I is an unlikely causative agent in the spectrum of the neurological diseases examined. The seropositivity of the 7 Jamaican patients with polymyositis requires further study.