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1.
J Alzheimers Dis ; 40(3): 679-85, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24503614

RESUMO

BACKGROUND: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer's disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. OBJECTIVE: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. METHODS: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. RESULTS: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. CONCLUSION: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD.


Assuntos
Arginina/genética , Cisteína/genética , Degeneração Lobar Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Saúde da Família , Feminino , Degeneração Lobar Frontotemporal/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Progranulinas
2.
Neurobiol Aging ; 33(12): 2948.e1-2948.e10, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22819134

RESUMO

The objectives of this study were to estimate frontotemporal dementia (FTD) prevalence, identify FTD-related mutations, and correlate FTD phenotype with mutations in a southern Italian population. The study population consisted of subjects ≥ 50 years of age residing in the Community of Biv. on January 1, 2004, and a door-to-door 2-phase design was used. Genetic and biochemical analyses were done on samples collected from 32 patients. Prevalence rates were 0.6 for Alzheimer's disease, 0.4 for vascular dementia (VD), 3.5 for FTD, 0.2 for Parkinson dementia, and 1.2 for unspecified dementia. Three GRN (1 known and 2 novel) mutations with reduced plasma protein levels were found associated to 3 distinct phenotypes (behavioral, affective, and delirious type). We report an unusually high FTD prevalence in the investigated population, but a low prevalence of Alzheimer's disease. We confirm the heterogeneity of FTD phenotype associated with different GRN mutations.


Assuntos
Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Proteína C9orf72 , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Demência Vascular/epidemiologia , Demência Vascular/genética , Feminino , Demência Frontotemporal/sangue , Testes Genéticos , Inquéritos Epidemiológicos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Progranulinas , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteínas tau/metabolismo
3.
Neurobiol Aging ; 30(11): 1825-33, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18314228

RESUMO

BACKGROUND: Frontotemporal dementia is a clinically and genetically heterogeneous syndrome. Mutations in two genes, Microtubule Associated Protein Tau (MAPT) and Progranulin (PGRN), and rarely Presenilin mutations, have been causally linked to this disorder. OBJECTIVE: To investigate the presence of PGRN, PSEN1, PSEN2 and APP mutations in a group of familial early-onset frontotemporal dementia (f-EOFTD) patients negative for MAPT gene mutations. SUBJECTS AND METHODS: We prospectively studied 17 unrelated subjects diagnosed with f-EOFTD (one case neuropathologically confirmed as FTD-Ub+). Among these subjects eight belonged to eight autosomal dominant families unrelated to each other, and nine had at least one first degree relative affected by dementia. RESULTS: We identified two novel heterozygous mutations in two unrelated patients, Cys139Arg in the PGRN gene and Val412Ile in the PSEN1 gene. CONCLUSIONS: Early-onset f-FTD remains a heterogeneous disorder from a genetic point of view. PGRN mutation frequency was low in our sample. The presence of a novel PSEN1 mutation suggests that presenilin molecular studies should be performed when screening for MAPT and PGRN genes is negative.


Assuntos
Saúde da Família , Demência Frontotemporal/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Presenilina-1/genética , Adulto , Arginina/genética , Cisteína/genética , Análise Mutacional de DNA , Feminino , Fluordesoxiglucose F18 , Demência Frontotemporal/diagnóstico por imagem , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Progranulinas , Cintilografia
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