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INTRODUCTION: Huntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. OBJECTIVE: To compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset). METHOD: A sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance. RESULTS: Significant differences were observed between groups in performance on the Mini-Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms. CONCLUSIONS: Members of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD.
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Transtornos Cognitivos , Disfunção Cognitiva , Doença de Huntington , Humanos , Doença de Huntington/genética , Cognição , Efeitos Psicossociais da DoençaRESUMO
INTRODUCTION: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; Pâ¯=⯠.015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; Pâ¯=⯠.025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; Pâ¯=⯠.010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; Pâ¯=⯠.010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; Pâ¯=⯠.001). TTTTTT carriers presented the earliest age of onset (23.0⯱â¯7.7 years, vs 31.6⯱â¯10.7; Pâ¯=⯠.0001). CONCLUSIONS: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Doenças Desmielinizantes , Feminino , Humanos , Idade de Início , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Doenças Desmielinizantes/epidemiologia , Doenças Desmielinizantes/genética , Genótipo , Fatores de RiscoRESUMO
INTRODUCTION: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI: 1.12-2.86; P=.015), as were the genotypes GG2677 (OR: 2.72; 95% CI: 1.11-6.68; P=.025) and CC3435 (OR: 1.82; 95% CI: 1.15-2.90; P=.010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P=.010), and the CAT haplotype (OR: 0.21; 95% CI: 0.05-0.66; P=.001). TTTTTT carriers presented the earliest age of onset (23.0±7.7 years, vs. 31.6±10.7; P=.0001). CONCLUSIONS: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
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AIMS: The pathogenesis of spontaneous cervical artery dissection remains unknown. We examined the association between different polymorphisms frequently found in young patients with cryptogenic stroke [methylenetetrahydrofolate reductase (MTHFR) C677T, factor II (prothrombin) G20210A, factor V G1691A (Leiden), nitric oxide synthase 3 (NOS3) intron 4 VNTR, and apolipoprotein E (APOE) epsilon4 gene] in patients with a cerebral infarct caused by spontaneous cervical artery dissection. METHODS: Forty-eight patients (27 males) and 96 matching control subjects were recruited. Clinical history, including cardiovascular risk factors, was assessed in all subjects. Genotypes were determined by a polymerase chain reaction with and without a restriction fragment length polymorphism. The genotypes and allele frequencies of the five genetic variants studied were compared between spontaneous cervical artery dissection cases and controls. We also incorporated our data into a meta-analysis of the MTHFR/C677T variant. RESULTS: Of 48 patients with spontaneous cervical artery dissection (28 vertebral and 20 carotid), the mean age of the patients was 36.6 +/- SD 9.9 years. There were no significant associations between the alleles of the five genetic polymorphisms studied and spontaneous cervical artery dissection. In the meta-analysis of the MTHFR/C677T variant, a total of 564 individuals (231 cases and 333 controls) were analysed; no significant association was observed. CONCLUSIONS: The results from this exploratory case-control study show the lack of an association between MTHFR, factor II G20210A, factor V G1691A, NOS3, intron 4 VNTR, and APOE epsilon4 gene polymorphisms and the development of spontaneous cervical artery dissection. Our findings contribute towards a better understanding of the genetic risk factors associated with spontaneous cervical artery dissection.
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Apolipoproteínas E/genética , Fator V/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Dissecação da Artéria Vertebral/genética , Adulto , Demografia , Feminino , Genótipo , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Falha de Tratamento , Resultado do Tratamento , Dissecação da Artéria Vertebral/enzimologiaRESUMO
BACKGROUND: The nasal vaccine candidate (NASVAC), comprising hepatitis B virus (HBV) surface (HBsAg) and core antigens (HBcAg), has been shown to be highly immunogenic in animal models. METHODS: A phase I double-blinded, placebo-controlled randomized clinical trial was carried out in 19 healthy male adults with no serologic markers of immunity/infection to HBV. This study was aimed at exploring the safety and immunogenic profile of nasal co-administration of both HBV recombinant antigens. The trial was performed according to Good Clinical Practice guidelines. Participants ranged in age from 18 to 45 years and were randomly allocated to receive a mixture of 50 microg HBsAg and 50 microg HBcAg or 0.9% physiologic saline solution, as a placebo, via nasal spray in a five-dose schedule at 0, 7, 15, 30, and 60 days. A total volume of 0.5 ml was administered in two dosages of 125 microl per nostril. Adverse events were actively recorded 1 h, 6 h, 12 h, 24 h, 48 h, 72 h, 7 days and 30 days after each dose. Anti-HBs and anti-HBc titers were evaluated using corresponding ELISA kits at days 30 and 90. RESULTS: The vaccine candidate was safe and well tolerated. Adverse reactions included sneezing (34.1%), rhinorrhea (12.2%), nasal stuffiness (9.8%), palate itching (9.8%), headache (9.8%), and general malaise (7.3%). These reactions were all self-limiting and mild in intensity. No severe or unexpected events were recorded during the trial. The vaccine elicited anti-HBc seroconversion in 100% of subjects as early as day 30 of the immunization schedule, while a seroprotective anti-HBs titer (>or=10 IU/l) was at a maximum at day 90 (75%). All subjects in the placebo group remained seronegative during the trial. CONCLUSION: The HBsAg-HBcAg vaccine candidate was safe, well tolerated and immunogenic in this phase I study in healthy adults. To our knowledge, this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigens.
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Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/imunologia , Hepatite B/prevenção & controle , Administração Intranasal , Adolescente , Adulto , Método Duplo-Cego , Hepatite B/imunologia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/genética , Antígenos de Superfície da Hepatite B/genética , Vacinas contra Hepatite B/efeitos adversos , Vírus da Hepatite B/genética , Humanos , Imunidade nas Mucosas/imunologia , Masculino , Pessoa de Meia-Idade , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/efeitos adversos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversosRESUMO
OBJECTIVES: Human leukocyte antigen (HLA)-DRB1, DQA1, DQB1 allele typing was performed in Mexicans Mestizos with multiple sclerosis (MS) to define the HLA class II alleles associated with the disease in this population. METHODS: Patients (n = 51) diagnosed according to the Poser criteria and a group of 173 unrelated healthy subjects were studied. PCR-SSOP and PCR-SSP were used for genotyping. RESULTS: Fifty five percent of the patients were females. The mean age at disease onset was 27 years. A relapsing-remitting disease was the most frequent type of MS (67%). A significant association of DRB1*0403 (OR = 5.68) with MS was shown. DRB1*0802 was also involved in susceptibility (OR = 2.41). An excess of DRB1*0802 homozygotes was observed in patients (P = 0.005), this genotype being in genetic equilibrium in controls. CONCLUSIONS: Two novel class II associations are described in Mexicans with MS: DRB1*0403 and DRB1*0802. Both alleles share with DRB1*1501, valine-86 and negatively charged amino acids, in the DRB1-anchoring motif of pocket 4.
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Alelos , Etnicidade/genética , Antígenos de Histocompatibilidade Classe II/genética , Indígenas Centro-Americanos/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Adolescente , Adulto , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Homozigoto , Humanos , Masculino , Região do Mediterrâneo/etnologia , México , Pessoa de Meia-IdadeRESUMO
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by expansion of an unstable ATTCT repeat. SCA10 has been described as a pure cerebellar syndrome accompanied by seizures and has been recognized only in families of Mexican origin. We describe clinical and molecular findings of 18 patients in four Mexican families with SCA10. Affected individuals had an average age at onset of 26.7 years (range 14-44 years) and ATTCT repeats ranging from 920 to 4,140 repeats. We could not detect significant anticipation or correlation between repeat size and age at onset, probably due to the small sample size. In addition to pure cerebellar ataxia and seizures, patients often showed soft pyramidal signs, ocular dyskinesia, cognitive impairment, and/or behavioral disturbances. Brain magnetic resonance imaging showed predominant cerebellar atrophy, and nerve conduction studies indicated polyneuropathy in 66% of patients. One family showed hepatic, cardiac, and hematological abnormalities in affected members. These findings suggest that a wide range of tissues may be affected in SCA10, including those outside of the cerebellum and cerebral cortex.