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1.
Genes (Basel) ; 12(11)2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34828412

RESUMO

We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in ß-site APP-cleaving enzyme 1 (BACE1)-along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.

2.
Neurobiol Aging ; 72: 186.e9-186.e12, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30057241

RESUMO

Loss-of-function mutations in progranulin (PGRN) gene cause frontotemporal lobar degeneration. Here, we report a case of a 63-year-old woman with a 2-year history of speech impairment, diagnosed with a nonfluent variant of primary progressive aphasia, a subtype of frontotemporal lobar degeneration. In this patient, a novel heterozygous frameshift mutation, c.77delG, in exon 2 of PGRN gene, introducing premature stop codon, p.(C26SfsX28), has been identified. Cultured fibroblasts derived from the patient and her asymptomatic first-degree relative with c.77delG mutation had decreased levels of PGRN messenger RNA (mRNA) and protein. However, PGRN mRNA levels did not recover upon incubation with inhibitors of nonsense-mediated mRNA decay (cycloheximide or puromycin), suggesting involvement of other mRNA degradation pathways. In addition, we observed upregulated wingless-type mouse mammary tumor virus integration site (WNT) signaling pathway gene, WNT3A, in fibroblasts of the patient and her asymptomatic first-degree relative with c.77delG mutation. As reported previously, this is an early hallmark of PGRN deficiency.


Assuntos
Fibroblastos/metabolismo , Afasia Primária Progressiva não Fluente/genética , Progranulinas/genética , Proteína Wnt3/genética , Células Cultivadas , Feminino , Mutação da Fase de Leitura , Haploinsuficiência , Humanos , Pessoa de Meia-Idade , Linhagem , Progranulinas/deficiência , RNA Mensageiro/metabolismo
4.
PLoS One ; 11(11): e0165112, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27855167

RESUMO

Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the limitations of these tests used and the sample sizes, olfactory dysfunction appears to be associated with the inability to identify odors reliably and consistently, not with the loss of an ability to identify specific odors. Irreproducibility in odor identification appears to be a non-disease-specific, general feature of olfactory dysfunction that is accelerated or accentuated in neurodegenerative disease. It may reflect a fundamental organizational principle of the olfactory system, which is more "error-prone" than other sensory systems.


Assuntos
Mutação , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/genética , Transtornos do Olfato/etiologia , Transtornos do Olfato/fisiopatologia , Proteínas tau/genética , Adulto , Idade de Início , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Odorantes , Transtornos do Olfato/diagnóstico , Característica Quantitativa Herdável , Índice de Gravidade de Doença , Olfato
5.
Neurol Neurochir Pol ; 49(4): 217-22, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26188937

RESUMO

BACKGROUND: The overlap between progressive supranuclear palsy (PSP) and progressive non-fluent aphasia (PNFA) is being increasingly recognized. In this paper descriptive writing in patients with Richardson syndrome of progressive supranuclear palsy (PSP-RS) is compared to writing samples from patients with PNFA. METHODS: Twenty-seven patients participated in the study: 17 with the clinical diagnosis of PSP-RS and 10 with PNFA. Untimed written picture description was administered during neuropsychological assessment and subsequently scored by two raters blinded to the clinical diagnosis. Lexical and syntactic content, as well as writing errors (e.g. omission and perseverative errors) were analyzed. RESULTS: In patients with PSP-RS both letter and diacritic mark omission errors were very frequent. Micrographia was present in 8 cases (47%) in PSP-RS group and in one case (10%) with PNFA. Perseverative errors did not differentiate between the groups. CONCLUSIONS: As omission errors predominate in writing of patients with PSP-RS, writing seems to be compromised mainly because of oculomotor deficits, that may alter visual feedback while writing.


Assuntos
Agrafia/fisiopatologia , Afasia Primária Progressiva não Fluente/fisiopatologia , Paralisia Supranuclear Progressiva/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Agrafia/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Afasia Primária Progressiva não Fluente/complicações , Paralisia Supranuclear Progressiva/complicações
6.
Pol J Radiol ; 79: 251-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25343001

RESUMO

BACKGROUND: Primary progressive aphasia (PPA) is a progressive language disorder associated with atrophy of the dominant language hemisphere, typically left. Current PPA criteria divide PPA into three variants: non-fluent (nfvPPA), semantic (svPPA) and logopenic (lvPPA). The classification of PPA into one of the three variants may be performed at 3 levels: I) clinical, II) imaging-supported, III) definite pathologic diagnosis. This paper aimed at assessing the feasibility of the imaging-supported diagnostics of PPA variants in the Polish clinical setting with access to magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) examinations. CASE REPORT: We present the clinical and neuroimaging data on 6 patients (4 women, 2 men) clinically diagnosed with PPA (3 with nfvPPA and 3 with lvPPA) in whom MRI and SPECT were performed in order to determine if imaging-supported diagnosis could be established in those cases. In 4 individuals (2 with nfvPPA and 2 with lvPPA) clinical diagnosis was supported by neuroimaging (SPECT, albeit not MRI), thus level II of PPA diagnosis could be established in those cases. MRI results were either inconsistent with the clinical diagnosis (Patients 1 and 2) or a mixed pattern of atrophy was observed (Patients 3-6). CONCLUSIONS: Imaging-supported diagnosis of PPA variant is more feasible with quantitative analysis of SPECT images than with purely qualitative visual analysis of MRI. Hypoperfusion abnormalities evidenced by SPECT are more variant-specific than patterns of atrophy.

7.
Clin Neuropharmacol ; 37(4): 96-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24992088

RESUMO

BACKGROUND: According to recent investigations, the eradication of Helicobacter pylori (H. pylori) may influence levodopa (LD) pharmacokinetics (PK) and improve the motor function of infected patients with Parkinson disease (PD). The aim of this study was to compare PK of LD and its metabolite 3-O-methyldopa (3-OMD), between H. pylori-positive (HP+) and -negative (HP-) patients with PD and motor fluctuations. MATERIALS AND METHODS: Patients with the clinical diagnosis of PD, under stable LD therapy, reporting daily motor fluctuations and who had no history of previous eradication treatment were screened for the H. pylori infection with an antigen stool test. Two groups of patients-bacteria-infected and noninfected-matched demographically and clinically, were selected for the examination of PK values. Blood samples were collected after morning oral LD dose. Noncompartmental PK parameters were computed from the LD and 3-OMD plasma concentration-time data. RESULTS: Interindividual variability was seen in LD absorption curve in both groups. There were no clinically significant differences in PK parameters of LD and 3-OMD. Changes of small magnitude but with possible clinical impact were found according to tmax and Cmax that tended to be lower in HP- patients and AUC0-t that was larger in the HP+ group. The Cmax value of 3-OMD was almost identical in both groups. The HP- group had smaller AUC0-∞t of 3-OMD. CONCLUSIONS: The H. pylori infection in PD patients with motor fluctuations, despite not significantly influencing PK parameters of LD and 3-OMD, may still have important clinical implications.


Assuntos
Antiparkinsonianos/farmacocinética , Infecções por Helicobacter/complicações , Helicobacter pylori/patogenicidade , Levodopa/farmacocinética , Atividade Motora/efeitos dos fármacos , Doença de Parkinson , Adulto , Idoso , Antiparkinsonianos/uso terapêutico , Benserazida/uso terapêutico , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/sangue , Jejum , Feminino , Infecções por Helicobacter/sangue , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Índice de Gravidade de Doença , Tirosina/análogos & derivados
8.
Neurocase ; 20(1): 69-86, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23121543

RESUMO

OBJECTIVES: Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation. METHODS: Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits. RESULTS: All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair. CONCLUSION: Agraphia associated with FTDP-17 is very heterogeneous.


Assuntos
Agrafia/diagnóstico , Agrafia/genética , Cromossomos Humanos Par 17 , Demência Frontotemporal/genética , Transtornos Parkinsonianos/genética , Proteínas tau/genética , Encéfalo/patologia , Progressão da Doença , Feminino , Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/psicologia
9.
PLoS One ; 8(4): e61074, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593396

RESUMO

Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum.


Assuntos
Córtex Cerebral/patologia , Mutação/genética , Presenilina-1/genética , Idoso , Atrofia , Córtex Cerebral/fisiopatologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Presenilina-1/química , Presenilina-1/metabolismo , Presenilina-2/metabolismo , Ligação Proteica , Tomografia Computadorizada de Emissão de Fóton Único , Visão Ocular
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