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1.
Int J Mol Sci ; 25(11)2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38892324

RESUMO

SARS-CoV-2 infection ranges from mild to severe presentations, according to the intensity of the aberrant inflammatory response. Purinergic receptors dually control the inflammatory response: while adenosine A2A receptors (A2ARs) are anti-inflammatory, ATP P2X7 receptors (P2X7Rs) exert pro-inflammatory effects. The aim of this study was to assess if there were differences in allelic and genotypic frequencies of a loss-of-function SNP of ADORA2A (rs2298383) and a gain-of-function single nucleotide polymorphism (SNP) of P2RX7 (rs208294) in the severity of SARS-CoV-2-associated infection. Fifty-five individuals were enrolled and categorized according to the severity of the infection. Endpoint genotyping was performed in blood cells to screen for both SNPs. The TT genotype (vs. CT + CC) and the T allele (vs. C allele) of P2RX7 SNP were found to be associated with more severe forms of COVID-19, whereas the association between ADORA2A SNP and the severity of infection was not significantly different. The T allele of P2RX7 SNP was more frequent in people with more than one comorbidity and with cardiovascular conditions and was associated with colorectal cancer. Our findings suggest a more prominent role of P2X7R rather than of A2AR polymorphisms in SARS-CoV-2 infection, although larger population-based studies should be performed to validate our conclusions.


Assuntos
COVID-19 , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2X7 , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Receptor A2A de Adenosina/genética , Gravidade do Paciente , COVID-19/complicações , COVID-19/genética , COVID-19/patologia , Genótipo , Frequência do Gene , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/genética , Neoplasias do Colo/complicações , Neoplasias do Colo/genética
2.
Int J Mol Sci ; 25(1)2023 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-38203682

RESUMO

In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.


Assuntos
Demência Frontotemporal , Doença de Pick , Humanos , Demência Frontotemporal/genética , Mutação , Portugal , Progranulinas/genética
3.
Neurogenetics ; 23(1): 1-9, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851492

RESUMO

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease. It is caused by mutations in the NOTCH3 gene, which encodes a membranebound receptor protein with three main distinct functional domains. Thus far, several different NOTCH3 mutations, most of them cysteine altering variants, have been described and although they tend to cluster in certain exons, their distribution varies in different geographically populations. Therefore, in this study, we describe the mutation analysis of NOTCH3 gene in 24 Portuguese families with small vessel disease suspected to have CADASIL from the central region of Portugal. The genetic analysis revealed 15 different heterozygous variants, eight pathogenic cysteine altering variants, six cysteine sparing variants and one nonsense variant, located mainly in the exons 4, 8 and 11. Thus, in our population, the genetic testing should initially be focused on these exons. In addition, the genetic findings broaden the mutational and clinical spectrum of CADASIL related phenotype and provide additional evidences for genetic counseling and clinical management.


Assuntos
CADASIL , Receptor Notch3 , CADASIL/genética , CADASIL/patologia , Humanos , Imageamento por Ressonância Magnética , Mutação , Fenótipo , Portugal , Receptor Notch3/genética
4.
Neurogenetics ; 23(4): 279-283, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36114914

RESUMO

Dementia with Lewy bodies is a neurodegenerative disease, sharing features with Parkinson's and Alzheimer's diseases. We report a case of a patient dementia with Lewy bodies carrying combined PSEN1 and ATP7B mutations. A man developed dementia with Lewy bodies starting at the age of 60 years. CSF biomarkers were of Alzheimer's disease and DaTSCAN was abnormal. Whole-exome sequencing revealed a heterozygous p.Ile408Thr PSEN1 variant and a homozygous p.Arg616Trp ATP7B variant. This case reinstates the need of considering ATP7B mutations when evaluating a patient with parkinsonism and supports p.Ile408Thr as a pathogenic PSEN1 variant.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doenças Neurodegenerativas , Humanos , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/genética , Sequenciamento do Exoma , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Estudos de Associação Genética , Presenilina-1/genética
5.
Eur J Neurol ; 29(5): 1524-1528, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35020242

RESUMO

BACKGROUND AND PURPOSE: TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. METHODS: We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). RESULTS: Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. CONCLUSION: We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.


Assuntos
Esclerose Lateral Amiotrófica , Afasia Primária Progressiva , Demência Frontotemporal , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Afasia Primária Progressiva/genética , Proteína C9orf72/genética , Estudos de Coortes , Demência Frontotemporal/genética , Humanos , Fenótipo , Proteína Supressora de Tumor p53
6.
Eur J Neurol ; 29(1): 36-46, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34375485

RESUMO

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD). We investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL with detailed neuropsychological data and cognitive decline in a cohort of sporadic and familial FTD. METHODS: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD) biomarkers (Aß42, t-Tau, p-Tau181), were determined in 63 FTD patients (30 sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome 9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and 31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals. Correlations between baseline CSF and serum NfL levels, standardized neuropsychological tests, and the rate of cognitive decline in FTD patients were assessed. RESULTS: CSF and serum NfL presented with significantly higher levels in FTD than in AD patients and both control groups. Within FTD subtypes, genetic cases, and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant correlations between NfL levels and overall cognitive function, abstract reasoning (CSF and serum), executive functions, memory, and language (serum) were found. A relationship between increased baseline CSF and serum NfL and a decay in cognitive performance over time was also observed. CONCLUSIONS: Our findings highlight the potential of serum NfL as a useful surrogate end point of disease severity in upcoming targeted treatments.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Demência Frontotemporal , Doença de Alzheimer/líquido cefalorraquidiano , Disfunção Cognitiva/genética , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/genética , Humanos , Filamentos Intermediários , Proteínas tau/líquido cefalorraquidiano
7.
Exp Cell Res ; 395(2): 112217, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768500

RESUMO

Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum TTR, achieved via silencing oligonucleotides, was introduced as therapy of ATTR amyloidosis. We explored the impact of Serpin Family A Member 1 (SERPINA1) on TTR mRNA and protein expression. Oncostatin M (OSM) induced SERPINA1 in hepatoma cells and mice, while concomitantly TTR expression was significantly reduced. SERPINA1 knockdown resulted in specific elevated TTR expression in hepatoma cells; however other genes belonging to the group of acute phase proteins were unaffected. In mice, serum TTR was elevated after mSERPINA1 knockdown throughout antisense treatment. Following SERPINA1 knockdown, TTR deposition in several tissues, including dorsal root ganglia and intestine, was found to be increased, however numbers did not exceed significance levels. The data suggest that SERPINA1 is a co-factor of TTR expression. Our findings provide novel insight in the regulation of TTR and reveal a role of SERPINA1 in the pathogenesis of ATTR amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/metabolismo , Pré-Albumina/metabolismo , alfa 1-Antitripsina/metabolismo , Animais , Humanos , Camundongos , RNA Mensageiro/genética , alfa 1-Antitripsina/genética
8.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502397

RESUMO

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.


Assuntos
Pré-Albumina/metabolismo , alfa 1-Antitripsina/metabolismo , Fatores Etários , Amiloide/metabolismo , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/fisiopatologia , Amiloidose/genética , Amiloidose/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Fibrinolisina , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pré-Albumina/genética , Pré-Albumina/fisiologia , Proteólise , alfa 1-Antitripsina/fisiologia
9.
Muscle Nerve ; 59(3): 362-365, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30447080

RESUMO

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are considered part of the same pathological spectrum. There is an increased risk of ALS in patients who have had melanoma. The risk of FTLD in melanoma (or cancer) patients is unknown. We aimed to study if C9ORF72 expansion is linked to a higher prevalence of melanoma. METHODS: We selected patients with a diagnosis in the ALS-FTLD spectrum who were tested for pathogenic mutations. Medical history was reviewed, to identify those with pathologically documented melanomas. RESULTS: We included 189 patients. Sixty-two had identified pathogenic mutations (39 C9ORF72). C9ORF72 carriers had a significantly higher risk of melanoma (odds ratio = 24.709; P < 0.007). There was no association with phenotype. CONCLUSIONS: These findings suggest that patients with a history of melanoma may have an increased probability of carrying a C9ORF72 repeat expansion. ALS or FTLD carriers of C9ORF72 should undergo surveillance for skin changes. Muscle Nerve 59:362-365, 2019.


Assuntos
Proteína C9orf72/genética , Melanoma/epidemiologia , Melanoma/genética , Idoso , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Estudos de Casos e Controles , Expansão das Repetições de DNA/genética , Feminino , Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Risco
10.
Epilepsy Behav ; 98(Pt A): 207-209, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31382178

RESUMO

INTRODUCTION: Neurofibrillary tangles and tau protein, the neuropathological hallmarks of Alzheimer's disease (AD), have been identified in patients with epilepsy. Tau protein was also associated with the modulation of neuronal excitability in animal models of AD. MATERIALS AND METHODS: We evaluated in 292 patients with AD the association between the risk of seizure development and AD cerebrospinal fluid (CSF) biomarkers, demographic characteristics, baseline Mini-Mental State Examination (MMSE) score, comorbidities, and apolipoprotein E status. RESULTS: The development of seizures was associated with younger age at dementia's onset, lower baseline MMSE, and higher CSF total tau protein levels, but only MMSE (hazard ratio [HR] = 0.935; 95% confidence interval [CI] = [0.903, 0.968]; p < 0.001) and CSF tau (HR = 1.001; 95%CI = [1.001, 1.002]; p = 0.001) were independent predictors on multivariate analysis. DISCUSSION: While CSF tau and lower baseline MMSE association with seizure development could in part be explained by a greater degree of cortical damage, the role of tau in the modulation of neuronal excitability may also play a role and should be further investigated.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Convulsões/líquido cefalorraquidiano , Convulsões/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Convulsões/epidemiologia
11.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875761

RESUMO

Transthyretin (TTR) amyloidoses (ATTR amyloidosis) are diseases associated with transthyretin (TTR) misfolding, aggregation and extracellular deposition in tissues as amyloid. Clinical manifestations of the disease are variable and include mainly polyneuropathy and/or cardiomyopathy. The reasons why TTR forms aggregates and amyloid are related with amino acid substitutions in the protein due to mutations, or with environmental alterations associated with aging, that make the protein more unstable and prone to aggregation. According to this model, several therapeutic approaches have been proposed for the diseases that range from stabilization of TTR, using chemical chaperones, to clearance of the aggregated protein deposited in tissues in the form of oligomers or small aggregates, by the action of disruptors or by activation of the immune system. Interestingly, different studies revealed that curcumin presents anti-amyloid properties, targeting multiple steps in the ATTR amyloidogenic cascade. The effects of curcumin on ATTR amyloidosis will be reviewed and discussed in the current work in order to contribute to knowledge of the molecular mechanisms involved in TTR amyloidosis and propose more efficient drugs for therapy.


Assuntos
Neuropatias Amiloides Familiares/genética , Curcumina/farmacologia , Fármacos Neuroprotetores/farmacologia , Pré-Albumina/química , Substituição de Aminoácidos , Neuropatias Amiloides Familiares/tratamento farmacológico , Animais , Curcumina/uso terapêutico , Humanos , Fármacos Neuroprotetores/uso terapêutico , Pré-Albumina/genética , Dobramento de Proteína/efeitos dos fármacos
12.
Acta Neuropathol ; 134(3): 475-487, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28447221

RESUMO

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença , Mutação , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Idoso , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade
13.
Hum Mutat ; 36(12): 1226-35, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26411346

RESUMO

Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Variação Genética , Fosfolipase D/genética , Adulto , Idade de Início , Idoso , Alelos , Processamento Alternativo , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente)/epidemiologia , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metanálise como Assunto , Pessoa de Meia-Idade , Razão de Chances , Risco
14.
Biochim Biophys Acta ; 1832(1): 39-45, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23069388

RESUMO

The transthyretin amyloidoses (ATTR) are devastating diseases characterized by progressive neuropathy and/or cardiomyopathy for which novel therapeutic strategies are needed. We have recently shown that curcumin (diferuloylmethane), the major bioactive polyphenol of turmeric, strongly suppresses TTR fibril formation in vitro, either by stabilization of TTR tetramer or by generating nonfibrillar small intermediates that are innocuous to cultured neuronal cells. In the present study, we aim to assess the effect of curcumin on TTR amyloidogenesis in vivo, using a well characterized mouse model for familial amyloidotic polyneuropathy (FAP). Mice were given 2% (w/w) dietary curcumin or control diet for a six week period. Curcumin supplementation resulted in micromolar steady-state levels in plasma as determined by LC/MS/MS. We show that curcumin binds selectively to the TTR thyroxine-binding sites of the tetramer over all the other plasma proteins. The effect on plasma TTR stability was determined by isoelectric focusing (IEF) and curcumin was found to significantly increase TTR tetramer resistance to dissociation. Most importantly, immunohistochemistry (IHC) analysis of mice tissues demonstrated that curcumin reduced TTR load in as much as 70% and lowered cytotoxicity associated with TTR aggregation by decreasing activation of death receptor Fas/CD95, endoplasmic reticulum (ER) chaperone BiP and 3-nitrotyrosine in tissues. Taken together, our results highlight the potential use of curcumin as a lead molecule for the prevention and treatment of TTR amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/metabolismo , Amiloide/metabolismo , Curcumina/administração & dosagem , Pré-Albumina/metabolismo , Animais , Humanos , Camundongos , Camundongos Transgênicos
15.
Neurodegener Dis ; 13(4): 214-23, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24022032

RESUMO

BACKGROUND: Progranulin (PGRN) mutations are associated with different clinical phenotypes, including frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS) and Alzheimer's disease (AD). As all pathogenic PGRN mutations identified so far cause disease through haploinsufficiency, determination of PGRN levels has been proposed as a reliable method to identify mutation carriers. OBJECTIVE: To evaluate the accuracy of peripheral PGRN levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort. METHODS: Serum PGRN levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendants of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit. RESULTS: Low PGRN levels were detected in 7 individuals (5 behavioral variant frontotemporal dementia, 1 CBS, and 1 still clinically unaffected) that constituted the group of the null PGRN mutation carriers previously identified in our molecular diagnostic laboratory. The pathogenic mutations found consisted of 4 insertion-deletions, causing frameshifts resulting in premature stop codons, 3 of which were novel. In addition, a normal PGRN level was found in a patient harboring a novel missense variant. For this novel ELISA kit, we established a PGRN cut-off level that identified with 100% accuracy the pathogenic mutation carriers. CONCLUSION: This study supports the use of a novel assay for the determination of PGRN levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload and should be extended to other clinical phenotypes than behavioral variant frontotemporal dementia and to apparently sporadic cases.


Assuntos
Doença de Alzheimer/diagnóstico , Demência Frontotemporal/diagnóstico , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Estudos de Coortes , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/genética , Humanos , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologia , Progranulinas
16.
Acta Neurol Belg ; 124(1): 49-54, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37392320

RESUMO

BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central , Masculino , Humanos , Pessoa de Meia-Idade , Adulto , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Proteína KRIT1/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Linhagem , Imageamento por Ressonância Magnética , Cefaleia
17.
Amyloid ; : 1-7, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38946492

RESUMO

BACKGROUND: Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable TTR homotetramers prone to dissociation into non-native monomers, which rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Thus, the initial event of the amyloid cascade produces the smallest transthyretin species: the monomers. This creates engineering opportunities for diagnosis that remain unexplored. METHODS: We hypothesise that molecular sieving represents a promising method for isolating and concentrating trace TTR monomers from the tetramers present in plasma samples. Subsequently, immunodetection can be utilised to distinguish monomeric TTR from other low molecular weight proteins within the adsorbed fraction. A two-step assay was devised (ImmunoSieve assay), combining molecular sieving and immunodetection for sensing monomeric transthyretin. This assay was employed to analyse plasma microsamples from 10 individuals, including 5 pre-symptomatic carriers of TTR-V30M, the most prevalent amyloidosis-associated TTR variant worldwide, and 5 healthy controls. RESULTS: The ImmunoSieve assay enable sensitive detection of monomeric transthyretin in plasma microsamples. Moreover, the circulating monomeric TTR levels were significantly higher in carriers of amyloidogenic TTR mutation. CONCLUSIONS: Monomeric TTR can function as a biomarker for evaluating disease progression and assessing responses to therapies targeted at stabilising native TTR.

18.
Parkinsonism Relat Disord ; 123: 106069, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38493523

RESUMO

Corticobasal syndrome is generally considered to be a sporadic condition. There are familial and isolated genetic cases, associated with GRN, MAPT, c9orf72 or PNRP variants. Some reports implicate other genes: LRRK2, CHMP2B, GBA, CYP27A1, PSEN1, APP, TARDBP and TBK1. Here, we report a case of a patient carrying a SQSTM1 Pro392Leu variant. We report a 57-year-old right-handed-woman with a history of progressive speech impairment, marked right side rigidity and bradykinesia, with rest tremor and stimulus sensitive myoclonus. She had predominantly right-sided apraxia. She had right side agraphestesia and astereognosis. MRI showed asymmetrical left frontotemporoparietal atrophy. DaTSCAN showed predominantly left involvement, PiB-PET was negative. CSF NfL was of 9356.5pg/mL. She carried a heterozygous variant P392L in SQSTM1. This case report expands the spectrum of phenotypes associated with SQSTM1 pathogenic variants. It also expands the list of genes associated with corticobasal syndrome, supporting the involvement of the ubiquitin-proteasome system in this condition.


Assuntos
Afasia Primária Progressiva não Fluente , Proteína Sequestossoma-1 , Humanos , Feminino , Pessoa de Meia-Idade , Proteína Sequestossoma-1/genética , Afasia Primária Progressiva não Fluente/genética , Degeneração Corticobasal/genética , Degeneração Corticobasal/complicações
19.
Alzheimers Res Ther ; 16(1): 66, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38539243

RESUMO

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.


Assuntos
Demência Frontotemporal , Masculino , Humanos , Feminino , Progranulinas/genética , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Virulência , Mutação/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética
20.
Hum Mutat ; 34(2): 363-73, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23111906

RESUMO

We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.


Assuntos
Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/genética , Instabilidade Genômica , Proteínas/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/genética , Sequência de Bases , Proteína C9orf72 , Cromossomos Humanos Par 9/genética , Estudos de Coortes , Expansão das Repetições de DNA , Europa (Continente)/epidemiologia , Finlândia/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Alemanha/epidemiologia , Haplótipos , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Prevalência , Espanha/epidemiologia , Suécia/epidemiologia
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