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3.
Eur J Pharmacol ; 817: 7-19, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28987272

RESUMO

Individuals with Down syndrome are at increased risk of developing Alzheimer's disease due to increase gene dosage resulting from chromosome 21 triplication. Although virtually all adults with Down syndrome will exhibit the major neuropathological hallmarks that define Alzheimer's disease, not all of them will develop the clinical symptoms associated with this disorder (i.e. dementia). Therefore, a good understanding of the pathophysiology of Alzheimer's disease in Down syndrome will be crucial for the identification of novel pharmacological targets to develop disease-modifying therapies for the benefit of Down syndrome individuals and for Alzheimer's sufferers alike. The study of biomarkers will also be essential for the development of better screening tools to identify dementia at its incipient stages. This review discusses the best-validated pharmacological targets for the treatment of cognitive impairment and Alzheimer's disease in Down syndrome. We further examine the relevance of newly discovered biological markers for earlier dementia diagnosis in this population.


Assuntos
Doença de Alzheimer/metabolismo , Síndrome de Down/metabolismo , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Síndrome de Down/tratamento farmacológico , Humanos
4.
J Matern Fetal Neonatal Med ; 30(22): 2752-2754, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27852141

RESUMO

OBJECTIVE: Trisomy 21 is the most frequent genetic cause of intellectual disability. Tumor Protein 53 (TP53) gene down-regulation triggers chromosomal instability. A TP53 gene polymorphism c.215G > C (rs1042522) is associated with accumulation of aneuploid cells. We analyzed the TP53 c.215G > C (rs1042522) polymorphism in Sicilian mothers of subjects with Down Syndrome (DS) within a case-control study. METHODS: Nucleotide polymorphism was detected by pyrosequencing technology. RESULTS: The distribution of TP53 c.215G > C polymorphism showed significant difference between mothers of subjects with DS and controls. CONCLUSIONS: Our data show that TP53 c.215G > C polymorphism is a risk factor for DS in Sicilian mothers.


Assuntos
Síndrome de Down/genética , Mães , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Estudos de Casos e Controles , Síndrome de Down/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Gravidez , Fatores de Risco , Sicília/epidemiologia
5.
Alzheimers Dement ; 12(11): 1132-1148, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27452424

RESUMO

INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aß, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aß40 and Aß42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aß correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aß42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aß and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.


Assuntos
Síndrome de Down/sangue , Síndrome de Down/imunologia , Adolescente , Adulto , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Citocinas/sangue , Progressão da Doença , Síndrome de Down/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Fator de Crescimento Neural/sangue , Neuropeptídeos/sangue , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Precursores de Proteínas/sangue , Serpinas/sangue , Ativador de Plasminogênio Tecidual/sangue , Adulto Jovem
6.
Menopause ; 23(11): 1247-1251, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27465716

RESUMO

OBJECTIVE: Women with Down's syndrome (DS) experience menopause earlier than healthy women and are twice as likely to undergo premature ovarian insufficiency. Menopause accelerates cognitive decline and is associated with a twofold increased mortality risk in DS women. Nonetheless, no previous studies investigated the ovarian reserve in this population. The aim of the present study was to evaluate the circulating antimullerian hormone (AMH) levels in DS women with regular menstrual cycles, in comparison with those observed in an age-matched group of healthy women. METHODS: Fourteen women with DS and 20 normo-ovulatory volunteers were enrolled in this study. A general physical examination was performed. Hormonal assays, including AMH, fasting insulin levels, and homeostatic model assessment-insulin resistance, were investigated in all participants. RESULTS: AMH levels were significantly lower in DS women compared with controls (1.34 ±â€Š1.11 vs 3.01 ±â€Š1.65 ng/mL, P < 0.01). Prolactin concentrations were in the normal range, although higher in DS women compared with controls (P < 0.01). After dividing the participants according to age, AMH was significantly lower in the DS group compared with controls, both below and above 30 years of age (1.77 vs 3.73 ng/mL, P < 0.01; 0.28 vs 2.20 ng/mL, P < 0.01, respectively). AMH was inversely correlated with age in both groups, and directly correlated with testosterone and dehydroepiandrosterone sulfate only in DS women. In the same participants, AMH showed a tendency toward a direct correlation with insulin levels (P = 0.055). CONCLUSIONS: AMH levels were significantly lower in DS women compared with age-matched controls. A subanalysis of data in DS participants under 30 years of age suggested an early follicular depletion related to trisomy 21.


Assuntos
Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Síndrome de Down/fisiopatologia , Reserva Ovariana/fisiologia , Adolescente , Adulto , Feminino , Humanos , Adulto Jovem
7.
Neurol Sci ; 37(5): 793-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27032399

RESUMO

Down syndrome is characterized by dysmorphic features, mental retardation and problems of immune deficiency. Chronic infection by Epstein-Barr virus is frequently present in subjects with Down syndrome. Ksp37 gene is commonly expressed by NK, CD8(+) T, γδ T and CD4(+) T cells; these data suggest that Ksp37 have cytotoxic properties. An increase of Ksp37 protein serum levels it has been showed during the acute phase of Epstein-Barr virus. In this study, we evaluated the expression of Ksp37 mRNA, in fibroblasts and leukocytes of DS subjects and in normal subjects with realtime reverse transcription-PCR. This analysis shows that in fibroblasts and leukocytes of Down syndrome subjects the KSP37 gene expression was increased compared with control subjects. The results of this study suggest that the expression of Ksp37 gene might be associated with increased susceptibility of individuals with Down syndrome to EBV infections and autoimmune problems.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Síndrome de Down/genética , Síndrome de Down/patologia , Leucócitos/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Adulto Jovem
8.
Eur J Hum Genet ; 24(5): 652-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26306646

RESUMO

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/diagnóstico , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade
10.
Mol Biol Rep ; 41(9): 5571-83, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24965145

RESUMO

We performed a large case-control study and a meta-analysis of the literature to address the role of the methionine synthase reductase (MTRR) c.66A>G polymorphism as a maternal risk factor for the birth of a child with Down Syndrome (DS) among Caucasian women. A total of 253 mothers of a DS child (MDS) and 298 control mothers of Italian origin were included in the case-control study. The meta-analysis of previous and present data involved a total of seven studies performed in Caucasian populations (971 MDS and 1,387 control mothers). Results from the meta-analysis indicated overall a positive significant association between MTRR c.66A>G genotype [OR 1.36 (95 % CI 1.10-1.68), dominant model] and allele frequencies [OR 1.26 (95 % CI 1.04-1.51), allele contrast model] and maternal risk of birth of a child with DS. A sensitivity analysis revealed some interesting differences between Europeans, Caucasians of European descent, and inhabitants of Mediterranean regions, suggesting the possibility of population-specific modifying factors. The case-control study revealed association of the polymorphism with increased folate levels, and a possible interaction with the methionine synthase (MTR) c.2756A>G one, that resulted in a borderline significant maternal risk of birth of a child with DS for the double heterozygous MTR 2756AG/MTRR 66AG genotype [OR 1.79 (95 % CI 1.00-3.18)]. Overall, present data suggest that the MTRR c.66A>G polymorphism represents a risk factor for the birth of a child with DS among white Caucasian women. However, the combined presence of other genetic factors and interactions with geographic and environmental ones, can modify the effect of the single polymorphism alone, leading to population specific effect sizes.


Assuntos
Síndrome de Down/genética , Grupo com Ancestrais do Continente Europeu/genética , Ferredoxina-NADP Redutase/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Ácido Fólico/sangue , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Técnicas de Genotipagem , Heterozigoto , Homocisteína/sangue , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Mães , Fatores de Risco , Vitamina B 12/sangue
11.
Autism ; 18(6): 638-50, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24113340

RESUMO

This report, based on four studies with children with low-functioning autism, aimed at evaluating the effects of repetitive transcranial magnetic stimulation delivered on the left and right premotor cortices on eye-hand integration tasks; defining the long-lasting effects of high-frequency repetitive transcranial magnetic stimulation; and investigating the real efficacy of high-frequency repetitive transcranial magnetic stimulation by comparing three kinds of treatments (high-frequency repetitive transcranial magnetic stimulation, a traditional eye-hand integration training, and both treatments combined). Results showed a significant increase in eye-hand performances only when high-frequency repetitive transcranial magnetic stimulation was delivered on the left premotor cortex; a persistent improvement up to 1 h after the end of the stimulation; better outcomes in the treatment combining high-frequency repetitive transcranial magnetic stimulation and eye-hand integration training. Based on these preliminary findings, further evaluations on the usefulness of high-frequency repetitive transcranial magnetic stimulation in rehabilitation of children with autism are strongly recommended.


Assuntos
Transtorno Autístico/reabilitação , Deficiência Intelectual/reabilitação , Córtex Motor , Desempenho Psicomotor , Estimulação Magnética Transcraniana/métodos , Adolescente , Transtorno Autístico/complicações , Criança , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Transtornos das Habilidades Motoras/complicações , Transtornos das Habilidades Motoras/reabilitação , Terapia Ocupacional , Adulto Jovem
12.
Am J Med Genet A ; 161A(12): 3018-22, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24214349

RESUMO

The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS-R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.


Assuntos
Cromossomos Humanos Par 3/genética , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos Mentais/genética , Adolescente , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Criança , Deleção Cromossômica , Cognição , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/psicologia , Feminino , Humanos , Deficiência Intelectual/psicologia , Masculino , Transtornos Mentais/fisiopatologia , Fenótipo , Deleção de Sequência
13.
Mol Biol Rep ; 40(12): 6913-25, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24150725

RESUMO

Methionine synthase (MTR) is required for the conversion of homocysteine (hcy) to methionine in the one-carbon metabolic pathway. Previous studies investigating a common MTR 2756A>G polymorphism as a maternal risk factor for the birth of a child with Down syndrome (DS) are conflicting and limited by small case-control cohorts, and its contribution to circulating hcy levels is still debated. We performed a large case-control study and a meta-analysis of the literature to further address the role of MTR 2756A>G as a maternal risk factor for the birth of a child with DS. 286 mothers of a DS child (MDS) and 305 control mothers of Italian origin were included in the case-control study. Genotyping was performed by means of PCR/RFLP technique. Data on circulating levels of hcy, folates, and vitamin B12 were available for 189 MDS and 194 control mothers. The meta analysis of previous and present data involved a total of 8 studies (1,171 MDS and 1,402 control mothers). Both the case-control study and the meta-analysis showed no association of MTR 2756A>G with the maternal risk of birth of a child with DS (OR = 1.15; 95 % CI 0.85-1.55, and OR = 1.08; 95 % CI 0.93-1.25, respectively), even after stratification of the overall data available for the meta-analysis into ethnic groups. No association of the studied polymorphism with circulating levels of hcy, folates, and vitamin B12 was observed. Present data do not support a role for MTR 2756A>G as independent maternal risk factor for a DS birth.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Síndrome de Down/enzimologia , Síndrome de Down/genética , Predisposição Genética para Doença , Parto/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estudos de Casos e Controles , Intervalos de Confiança , Demografia , Feminino , Ácido Fólico/metabolismo , Frequência do Gene/genética , Humanos , Itália , Redes e Vias Metabólicas/genética , Razão de Chances , Fatores de Risco
14.
Neurol Sci ; 34(11): 2023-5, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23979692

RESUMO

Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.


Assuntos
Antígenos/genética , Síndrome de Down/genética , Adulto , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Adulto Jovem
15.
Neurol Sci ; 34(4): 569-71, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22968744

RESUMO

Down syndrome (DS) is a chromosomal disorder caused by chromosome 21 trisomy and is the most frequent genetic cause of intellectual disability. The gene for the kinesin family member 21A (KIF21A), is a member of the kinesin superfamily involved in the anterograde fast axonal transport. In this study, we have evaluated the possible differential expression of KIF21A mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects and it compared with the normal population. In the assumption that changes in KIF21A gene expression levels may affect the axonal transport and the development of the nervous system of subjects with DS. In the present case-control study, KIF21A gene expression was increased in 72.72 % of DS samples compared with normal subjects. This finding suggests that changes in the expression levels of KIF21A in DS subjects may affect the axonal transport and the development of the nervous system.


Assuntos
Síndrome de Down , Cinesina/genética , RNA Mensageiro/metabolismo , Adulto , Estudos de Casos e Controles , Síndrome de Down/genética , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatologia , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Am J Med Genet A ; 121A(3): 219-24, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12923861

RESUMO

Contradictory findings have been recently published on the evaluation of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C-->T) and methionine synthase reductase (MTRR 66 A-->G) as risk factors for having a child with Down syndrome (DS); however, the influence of polymorphisms of methionine synthase (MTR 2756 A-->G) and of MTHFR 1298 A-->C has never been evaluated. In this study, the risk of being a DS case or having a DS child (case mother) was studied by multiple logistic regression analysis of the independent and combined genotypes and of plasma homocysteine, folates, and vitamin B12 in 92 DS cases and 140 control subjects as well as in 63 case mothers and 72 age-matched control mothers from Sicily. (The MTHFR 677 T allele frequency was not different in DS cases and case mothers, compared to the respective control groups). After adjustment for age, total homocysteine (t-Hcys) and MTR 2756 AG/GG genotype were significant risk factors for having a DS child, with odds ratio (OR) of 6.7 (95% CI: 1.4-32.0, P = 0.016) and of 3.5 (95% CI: 1.2-10.9, P = 0.028), respectively. By comparison, MTR 2756 AG/GG genotype increased significantly the risk of being a DS case, with an OR of 3.8 (95% CI: 1.4-10.5, P = 0.009). The double heterozygosity MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a DS child, with an OR estimated at 5.0 (95% CI: 1.1-24.1), after adjustment for t-Hcys. In conclusion, our results provide evidences that homocysteine and MTR genetic polymorphism are two potent risk factors for mothers to have a DS child in Sicily.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Síndrome de Down/genética , Ferredoxina-NADP Redutase/genética , Heterozigoto , Hiper-Homocisteinemia/genética , Polimorfismo Genético , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Criança , Síndrome de Down/enzimologia , Feminino , Flavoproteínas , Ácido Fólico/sangue , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/enzimologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Fatores de Risco , Sicília/epidemiologia
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