RESUMO
BACKGROUND: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called "prion", which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-ß protein plaques are associated with memory loss and cognitive impairment in patients. OBJECTIVE: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. METHODS: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. RESULTS: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers in the cerebellum. CONCLUSION: We conclude that phosphorylation of tau may be a response to a toxic and inflammatory environment generated by the pathological form of prion.
Assuntos
Cerebelo/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Doenças Priônicas/patologia , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Encefalopatias/metabolismo , Encefalopatias/patologia , Bovinos , Cerebelo/patologia , Síndrome de Creutzfeldt-Jakob/metabolismo , Encefalopatia Espongiforme Bovina/metabolismo , Encefalopatia Espongiforme Bovina/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Priônicas/metabolismo , Treonina/metabolismoRESUMO
BACKGROUND: Cognitive functions represent useful endophenotypes to identify the association between genetic variants and schizophrenia. In this sense, the NR4A2 gene has been implicated in schizophrenia and cognition in different animal models and clinical trials. We hypothesized that the NR4A2 gene is associated with working memory performance in schizophrenia. This study aimed to analyze two variants and the expression levels of the NR4A2 gene with susceptibility to schizophrenia, as well as to evaluate whether possession of NR4A2 variants influence the possible correlation between gene expression and working memory performance in schizophrenia. METHODS: The current study included 187 schizophrenia patients and 227 controls genotyped for two of the most studied NR4A2 genetic variants in neurological and neuropsychiatric diseases. Genotyping was performed using High Resolution Melt and sequencing techniques. In addition, mRNA expression of NR4A2 was performed in peripheral mononuclear cells of 112 patients and 118 controls. A group of these participants, 54 patients and 87 controls, performed the working memory index of the WAIS III test. RESULTS: Both genotypic frequencies of the two variants and expression levels of the NR4A2 gene showed no significant difference when in patients versus controls. However, patients homozygous for the rs34884856 promoter variant showed a positive correlation between expression levels and auditory working memory. CONCLUSIONS: Our finding suggested that changes in expression levels of the NR4A2 gene could be associated with working memory in schizophrenia depending on patients' genotype in a sample from a Mexican population.
Assuntos
Esquizofrenia , Estudos de Casos e Controles , Humanos , Transtornos da Memória , Memória de Curto Prazo , México , Testes Neuropsicológicos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Esquizofrenia/complicações , Esquizofrenia/genéticaRESUMO
Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.
Assuntos
Variação Genética , Genética Populacional , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Desequilíbrio de Ligação , Adolescente , Adulto , África , Alelos , Feminino , Frequência do Gene , Genótipo , Geografia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Homozigoto , Humanos , Masculino , México/etnologia , Pessoa de Meia-Idade , Análise de Componente Principal , Adulto Jovem , Indígena Americano ou Nativo do AlascaRESUMO
BACKGROUND: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. OBJECTIVE: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. METHODS: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. RESULTS: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. CONCLUSION: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.
INTRODUCCIÓN: La paraoxonasa-1 (PON1) sérica asociada a las HDL presenta dos polimorfismos comunes en las posiciones 192 y 55. Estos polimorfismos se consideran determinantes para la capacidad de las HDL de proteger a las LDL de su modificación oxidativa. En este contexto, el genotipo de PON1 se ha asociado con enfermedades cerebrovasculares, que incluyen el infarto cerebral. OBJETIVO: Determinar las frecuencias alélicas y genotípicas de PON1-L55M y PON1- Q192R, así como las actividades enzimáticas de PON1 en sujetos con y sin infarto cerebral aterotrombótico. MÉTODOS: Se incluyeron 28 personas con infarto cerebral aterotrombótico y 29 sin infarto. Las genotipificaciones se realizaron mediante PCR-RFLP y las fenotipificaciones mediante la medición de las actividades paraoxonasa y arilesterasa en suero. RESULTADOS: Para el polimorfismo Q192R, las frecuencias alélicas (Q/R) fueron 0.46/0.54 y 0.48/0.52 (p= 0.843) para el grupo control y el grupo con infarto, respectivamente. Mientras que para el polimorfismo L55M, las frecuencias alélicas (L/M) fueron 0.81/0.19 para el grupo control y 0.78/0.22 para el grupo con infarto (p= 0.610). Los niveles de actividad paraoxonasa no fueron significativamente diferentes entre los grupos control y con infarto (450 vs. 348 Ul/mL, p= 0.093). Mientras que los niveles de actividad arilesterasa fueron significativamente diferentes entre los grupos estudiados (90 vs. 70 Ul/mL, p= 0.001), sin embargo, al ajustarla por regresión lineal múltiple, dejo de ser significativa. CONCLUSIÓN: Los polimorfismos Q192R y L55M, y la actividad paraoxonasa de la PON1 no son factores de riesgo para el infarto cerebral aterotrombótico en este estudio.
Assuntos
Arildialquilfosfatase/genética , Isquemia Encefálica/genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Adulto , Idoso , Alelos , Isquemia Encefálica/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Lineares , Masculino , México , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Acidente Vascular Cerebral/patologiaRESUMO
Abstract Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.
Resumen Introducción: La paraoxonasa-1 (PON1) sérica asociada a las HDL presenta dos polimorfismos comunes en las posiciones 192 y 55. Estos polimorfismos se consideran determinantes para la capacidad de las HDL de proteger a las LDL de su modificación oxidativa. En este contexto, el genotipo de PON1 se ha asociado con enfermedades cerebrovasculares, que incluyen el infarto cerebral. Objetivo: Determinar las frecuencias alélicas y genotípicas de PON1-L55M y PON1- Q192R, así como las actividades enzimáticas de PON1 en sujetos con y sin infarto cerebral aterotrombótico. Métodos: Se incluyeron 28 personas con infarto cerebral aterotrombótico y 29 sin infarto. Las genotipificaciones se realizaron mediante PCR-RFLP y las fenotipificaciones mediante la medición de las actividades paraoxonasa y arilesterasa en suero. Resultados: Para el polimorfismo Q192R, las frecuencias alélicas (Q/R) fueron 0.46/0.54 y 0.48/0.52 (p= 0.843) para el grupo control y el grupo con infarto, respectivamente. Mientras que para el polimorfismo L55M, las frecuencias alélicas (L/M) fueron 0.81/0.19 para el grupo control y 0.78/0.22 para el grupo con infarto (p= 0.610). Los niveles de actividad paraoxonasa no fueron significativamente diferentes entre los grupos control y con infarto (450 vs. 348 Ul/mL, p= 0.093). Mientras que los niveles de actividad arilesterasa fueron significativamente diferentes entre los grupos estudiados (90 vs. 70 Ul/mL, p= 0.001), sin embargo, al ajustarla por regresión lineal múltiple, dejo de ser significativa. Conclusión: Los polimorfismos Q192R y L55M, y la actividad paraoxonasa de la PON1 no son factores de riesgo para el infarto cerebral aterotrombótico en este estudio.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Encefálica/genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Arildialquilfosfatase/genética , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Estudos de Casos e Controles , Modelos Lineares , Isquemia Encefálica/patologia , Projetos Piloto , Reação em Cadeia da Polimerase , Fatores de Risco , Acidente Vascular Cerebral/patologia , Alelos , Frequência do Gene , Genótipo , MéxicoRESUMO
INTRODUCTION: The NR4A2 transcription factor is important in the development, survival and phenotype of dopaminergic neurons and it is postulated as a possible biomarker for Parkinson's disease (PD). Therefore, our aim was to analyze in a sample of a Mexican population with idiopathic PD, mutations (in two hotspot mutation regions) and two polymorphisms (rs34884856 in promotor and rs35479735 intronic regions) of the NR4A2 gene. We also evaluate the levels of NR4A2 gene expression in peripheral blood for a Mexican population, and identify whether they are associated with NR4A2 gene polymorphisms. METHODS: We conducted a case-control study, which included 227 idiopathic PD cases and 454 unrelated controls. Genetic variants of the NR4A2 gene were genotyped by high-resolution melting (HRM) and validated by an automated sequencing method. The gene expression was performed in peripheral blood using a real-time polymerase chain reaction. RESULTS: The rs35479735 polymorphism was associated with a higher risk of developing PD. In addition, NR4A2 gene expression was significantly decreased in patients with PD. Linkage disequilibrium analysis showed a haplotype H4 (3C-3G) that showed lower levels of expression, and contained the risk alleles for both polymorphisms. CONCLUSIONS: In summary, this is the first study in a Mexican population that considers the analysis of NR4A2 in patients with PD. An association was identified between genotype and mRNA expression levels of NR4A2 in patients with PD. These results suggest that polymorphisms and expression of the NR4A2 gene could play an important role in the risk of developing PD in Mexican populations.
Assuntos
Estudos de Associação Genética/métodos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Polimorfismo Genético/genética , Vigilância da População , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Expressão Gênica , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Doença de Parkinson/diagnóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Several neuropathological studies in spinocerebellar ataxia type 2 (SCA2) have revealed significant atrophy of the cerebellum, brainstem, sensorimotor cortex, and several regions in the frontal lobe. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is unknown. To analyze the clinical impact of these functional changes, we correlated the abnormal functional connectivity found in SCA2 patients with their scores in clinical scales. To obtain the functional connectivity changes, we followed two approaches. In one we used areas with significant cerebellar gray matter atrophy as anchor seeds, and in the other we performed a whole-brain data-driven analysis. METHODS: Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Voxel-based morphometry and resting-state functional magnetic resonance imaging (fMRI) were done to analyze structural and functional brain changes. Independent component analysis and dual regression were used for intrinsic network comparison. Significant functional connectivity differences were correlated with the behavioral scores. RESULTS: Seed-based analysis found reduced functional connectivity within the cerebellum and between the cerebellum and frontal/parietal cortices. Cerebellar functional connectivity increases were found with parietal, frontal, and temporal areas. Intrinsic network analysis found a functional decrease in the cerebellar network, and increase in the default-mode and fronto-parietal networks. Further analysis showed significant correlations between clinical scores and the abnormal functional connectivity strength. CONCLUSION: Our findings show significant correlations between functional connectivity changes in key areas affected in SCA2 and these patients' motor and neuropsychological impairments, adding an important insight to our understanding of the pathophysiology of SCA2.
Assuntos
Cerebelo/fisiopatologia , Córtex Cerebral/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/fisiopatologia , Desempenho Psicomotor/fisiologia , Ataxias Espinocerebelares/fisiopatologia , Adulto , Transtornos Cognitivos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/complicaçõesRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dementia is a frequent complication of idiopathic Parkinsonism or PD, usually occurring later in the protracted course of the illness. Some risk factors to develop dementia in PD are aging, severe Parkinson´s symptoms, rigid-akinetic form, hallucinations, and mild cognitive impairment documented at the first examinations. It is not yet clear if some genetic factors are either risk or protector for progression to dementia. In a review of the literature, we found that mutations in the alpha-synuclein gene are the most responsible for developing dementia, either from PARK1 or 4 mutations. GBA (glucocerebrosidase) is another accountable factor. However, the vast majority of patients suffer from non-Mendelian or complex forms of PD, which are likely caused by the combined effects of genetic and environmental factors. There is not until now a clear relation between some polymorphisms in candidate genes and cognitive deterioration, as many studies have not clearly identified this phenotype.
Assuntos
Demência/etiologia , Predisposição Genética para Doença , Doença de Parkinson/complicações , Demência/genética , Glucosilceramidase/genética , Humanos , Doença por Corpos de Lewy/genética , Mutação , Doença de Parkinson/genética , Fenótipo , Fatores de Risco , alfa-Sinucleína/deficiência , alfa-Sinucleína/genéticaRESUMO
O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) is a racemic organophosphate compound (OP) that induces delayed neuropathy in vivo. The O-hexyl 2,5-dichlorophenyl phosphoramidate R (R-HDCP) isomer inhibits and ages neuropathic target esterase (NTE) in hen brain. Moreover, human serum paraoxonase-1 (PON1) is a Ca(2+)-dependent enzyme capable of hydrolyzing OPs. The enzymatic activity of PON1 against OPs depends on the genetic polymorphisms present at position 192 (glutamine or arginine). The catalytic efficiency of PON1 is an important factor that determines neurotoxic susceptibility to some OPs. In the present study, we characterized the stereospecific hydrolysis of HDCP by alloforms PON1 Q192R human serum by chiral chromatography. Forty-seven human samples were characterized for the PON1 192 polymorphism. The hydrolysis data demonstrate that the three alloforms of PON1 show an exclusive and significant stereospecific Ca(2+)-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate S isomer (S-HDCP) at 19-127 µM at the concentrations that remain in all the samples. This stereoselective Ca(2+)-dependent hydrolysis of S-HDCP is inhibited by EDTA and is independent of the PON1 Q192R alloform. The present research reinforces the hypothesis that R-HDCP (an isomer that inhibits and causes NTE aging) is the enantiomer that induces delayed neuropathy by this chiral phosphoramidate due to the low hydrolysis level of the R-HDCP observed in this study.
Assuntos
Arildialquilfosfatase/genética , Síndromes Neurotóxicas/etiologia , Compostos Organofosforados/toxicidade , Polineuropatias/induzido quimicamente , Adulto , Cálcio/metabolismo , Feminino , Humanos , Hidrólise , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/química , Polimorfismo Genético , EstereoisomerismoRESUMO
AIM: In previous CYP2D6 genotyping studies in Mexican-Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. MATERIALS & METHODS: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican-Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. RESULTS: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. CONCLUSION: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican-Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations.
Assuntos
Citocromo P-450 CYP2D6/genética , Variações do Número de Cópias de DNA/genética , Indígenas Norte-Americanos/genética , Adulto , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , MéxicoRESUMO
BACKGROUND: The expression of apolipoprotein E (apoE) polymorphisms has been proposed as a risk factor for early development of psychotic symptoms in patients with Parkinson's disease. The association between apoE polymorphisms and motor complications is controversial. The aim was to determine the association between apoE polymorphisms and its allele frequency with the development of complications secondary to dopaminergic replacement therapy. METHODS: We evaluated 231 patients with the diagnosis of Parkinson's disease. The presence of motor complications secondary to treatment was determined by a neurologist, and the genotypification of apoE polymorphisms was performed. Descriptive statistics and chi-squared test were used. RESULTS: Genotype ?3/?3 was expressed in 80.5 % of the sample; there was no association between genotype or allele frequency of apoE polymorphisms and the development of psychosis or dyskinesia. Patients who expressed the ?2 allele showed a tendency to develop motor fluctuations, but without reaching statistical significance (p = 0.08). CONCLUSIONS: ApoE polymorphisms are not associated with the development of complications from dopaminergic replacement therapy.
INTRODUCCIÓN: se ha propuesto que la expresión de los polimorfismos de la apolipoproteína E (apoE) es un factor predisponente para el desarrollo temprano de psicosis en los pacientes con enfermedad de Parkinson. La relación entre el genotipo de la apoE y el desarrollo de complicaciones motoras es controvertida. El objetivo de esta investigación fue determinar la relación entre los polimorfismos de la apoE y su frecuencia alélica y el desarrollo de complicaciones secundarias al reemplazo dopaminérgico. MÉTODOS: se evaluaron 231 pacientes con diagnóstico de enfermedad de Parkinson. La presencia de complicaciones fue determinada por un neurólogo y se realizó la genotipificación de los polimorfismos de la apoE. Se utilizó la chi cuadrada para determinar la relación entre la presencia o ausencia de las complicaciones estudiadas y el genotipo de la apoE. RESULTADOS: se identificó el genotipe ?3/?3 en 80.5 % de la muestra. No existió relación entre el genotipo o la frecuencia alélica de los polimorfismos de la apoE y el desarrollo de psicosis o discinesias. Los pacientes que expresaron el alelo ?2 mostraron una tendencia al desarrollo de fluctuaciones, pero sin significación estadística (p = 0.08). CONCLUSIONES: los polimorfismos de la apoE no se relacionaron con el desarrollo de complicaciones derivadas del reemplazo dopaminérgico. El tratamiento de la enfermedad de Parkinson se basa principalmente en la administración de precursores de la dopamina (como la levodopa) o de agonistas dopaminérgicos.
Assuntos
Antiparkinsonianos/efeitos adversos , Apolipoproteínas E/genética , Dopaminérgicos/efeitos adversos , Discinesias/etiologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Transtornos Psicóticos/etiologia , Adulto , Antiparkinsonianos/uso terapêutico , Estudos Transversais , Dopaminérgicos/uso terapêutico , Feminino , Frequência do Gene , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Polimorfismo Genético , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Vasovagal syncope is a common clinical condition, consequential to reduced cerebral blood flow resulting from a failure in cardiovascular homeostasis during orthostasis. Blood pressure regulation is the basis for syncope development. In this regulation, the α1a-adrenergic receptor plays a major role. Some studies have found a positive correlation between the Arg347Cys polymorphism of the α1a-adrenergic receptor to hypertension and heart autonomic control. The goal of this study is to evaluate the possible association between the Arg347Cys α1a-adrenergic receptor polymorphism and vasovagal syncope in a Mexican population. METHODS/MAJOR FINDINGS: A sample of 89 vasovagal syncope patients and 40 healthy controls were studied. Arg347Cys α1a-adrenergic receptor polymorphism was determined by the PCR-RFLP method. We found an increased frequency of genotype ArgArg in vasovagal syncope patients. In a logistic regression model significant associations were found in two genetic models, in codominant model (OR=13.21: CI 95% 3.69-54.99, p<0.001) and in additive model (OR=12.68: CI 95% 3.5-53.07, p<0.001) for ArgArg genotype with CysCys as reference. CONCLUSIONS: Our data suggests an important participation of Arg347Cys polymorphism as susceptibility factor in patients with vasovagal syncope. ArgArg genotype could be a marker for vasovagal syncope susceptibility in the Mexican population.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos alfa 1/genética , Síncope Vasovagal/genética , Adolescente , Adulto , Fatores Etários , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética , Genótipo , Técnicas de Genotipagem , Humanos , Modelos Logísticos , Masculino , México , Pessoa de Meia-Idade , Modelos Genéticos , Fatores Sexuais , Adulto JovemRESUMO
Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder characterized by progressive ataxia and retinal dystrophy. It is caused by a CAG trinucleotide expansion in the ataxin7 gene. Anatomical studies have shown severe cerebellar degeneration and region-specific neocortical atrophy in SCA7 patients. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is still unknown. The aim of this study was to examine functional connectivity abnormalities in areas with significant gray matter atrophy in SCA7 patients and their relationship with number of CAG repeats. Using a combination of voxel-based morphometry and resting-state fMRI, we studied 26 genetically confirmed SCA7 patients and aged-matched healthy controls. In SCA7 patients we found reduced functional interaction between the cerebellum and the middle and superior frontal gyri, disrupted functional connectivity between the visual and motor cortices, and increased functional coordination between atrophied areas of the cerebellum and a range of visual cortical areas compared with healthy controls. The degree of mutation expansion showed a negative effect on both the functional interaction between the right anterior cerebellum and the left superior frontal gyrus and the connectivity between the right anterior cerebellum and left parahippocampal gyrus. We found abnormal functional connectivity patterns, including both hypo- and hyperconnectivity, compared with controls. These abnormal patterns show reasonable association with the severity of gene mutation. Our findings suggest that aberrant changes are prevalent in both motor and visual systems, adding significantly to our understanding of the pathophysiology of SCA7.
Assuntos
Cerebelo/fisiopatologia , Vias Eferentes/fisiopatologia , Lobo Frontal/fisiopatologia , Rede Nervosa/fisiopatologia , Ataxias Espinocerebelares/fisiopatologia , Vias Visuais/fisiopatologia , Adulto , Atrofia/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurônios/fisiologiaRESUMO
UNLABELLED: BACKGROUND. Levodopa-induced dyskinesia is one of the main complications and limitations of the treatment of patients with Parkinson's disease. OBJECTIVE: To determine the incidence and risk factors involved in the development of dyskinesias in a retrospective cohort of Mexican patients with Parkinson's disease. MATERIAL AND METHODS: We reviewed a total of 601 cases of Parkinson's disease patients treated at the National Institute of Neurology and Neurosurgery in the period between January 1990 and June 2010; 482 of them had history of exposure to levodopa. RESULTS: The follow-up was equivalent to 4,392 person-years. 154 patients had dyskinesias at some point in the evolution of the disease. The person-time incidence was 35 cases per 1,000 person-years. The onset of motor symptoms before 50 years of age and levodopa doses > or = 600 mg of levodopa were the main risk factors for early development of dyskinesia (HR of 1.01 [95% CI 1.0 to 1.01, p = 0.001] and HR 1.10 [95% CI 1.04 to 1.23, p = 0.04], respectively]. CONCLUSION: The main determinants of dyskinesias were present early age of onset of motor symptoms and the dose of levodopa. Knowledge of these factors will improve the management planning.
Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/epidemiologia , Levodopa/efeitos adversos , Feminino , Humanos , Incidência , Masculino , México , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants.
RESUMO
BACKGROUND: motor fluctuations induced by dopamine replacement therapy are among the main complications of the treatment of patients with Parkinson's disease. Our objective was to determine the incidence of motor fluctuations in a retrospective cohort of Mexican patients with Parkinson's disease. METHODS: we reviewed the files of 584 cases of Parkinson's disease patients treated at the National Institute of Neurology and Neurosurgery between 1990 and 2010. We registered the demographic and clinical data to analyze the disease course. RESULTS: the follow-up was of 4736 person-years. 33.9 % of patients (n = 198) had motor fluctuations at some point in the evolution of the disease. The rate of person-time incidence was 43 cases per 1000 person-years. The daily dose of levodopa equivalents greater than 600 mg/d and the use of levodopa were the main risk factors for early development of motor fluctuations (HR 1.40 [95 % CI = 1.07 to 1.83, p < 0.001] and HR 1.61 [95 % CI = 1.17 to 2.23, p = 0.004], respectively). CONCLUSIONS: the main determinants of early development of motor fluctuations are the levodopa equivalent daily dose and the quantity and early use of levodopa.
Assuntos
Dopamina/efeitos adversos , Discinesia Induzida por Medicamentos/epidemiologia , Discinesia Induzida por Medicamentos/etiologia , Doença de Parkinson/tratamento farmacológico , Estudos de Coortes , Dopamina/uso terapêutico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Increased area of the substantia nigra (SN) associated to iron deposition has been proposed as a specific marker for Parkinson's disease (PD). Echogenicity, assessed by transcranial sonography (TCS), has been used to measure such an iron deposition. On the other hand, ferroxidase activity is known to play a role in brain iron metabolism and thus could be involved in increased SN echogenicity of PD patients. The present study was conducted to search for a possible correlation between both markers: TCS of SN and plasma ferroxidase activity. Twenty-one PD patients and 13 healthy volunteers (HV) were included. Mean SN sonographic areas were 0.31 cm² for PD patients and 0.12 cm² for HV (P < 0.001), while plasma ferroxidase activity was reduced in PD patients (P < 0.001). Interestingly, plasma ferroxidase activity was inversely correlated with the SN size by TCS (R² = 0.31), suggesting a relationship between the two markers.
Assuntos
Ceruloplasmina/metabolismo , Doença de Parkinson/diagnóstico por imagem , Substância Negra/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/metabolismo , Projetos Piloto , Substância Negra/metabolismo , Ultrassonografia Doppler TranscranianaRESUMO
Mutations in leucine-rich repeat kinase 2 gene (LRRK2) account for as much as 5-6% of familial Parkinson's disease (PD) and 1-2% of sporadic PD. These mutations represent the most frequent cause of autosomal dominant PD, particularly in certain ethnic groups. In this first report concerning LRRK2 mutations in Mexican-mestizos, we screened 319 consecutive PD patients (186 males; 133 females; mean age at onset: 52.4 years) for LRRK2 mutations in exons 31 and 41 and for the mutation in exon 35, which produces the Y1699C substitution. Three (0.94%) patients, two with sporadic PD and one with familial PD (disease mean age at onset, 53.3 years), were heterozygous for LRRK2 mutations. Of these three, two patients had one of two different mutations in exon 31 (R1441G and R1441H, respectively); the other patient carried the G2019S mutation in exon 41. The Y1699C mutation was absent from this PD sample. Four additional subjects, unaffected relatives of one PD patient with a mutation in LRRK2, were subsequently genetically tested. None of the three LRRK2 mutations identified was present in 200 neurologically healthy Mexican control individuals. These findings have important implications for molecular testing of LRRK2 mutations in Mexican PD patients.
Assuntos
Frequência do Gene , Predisposição Genética para Doença/genética , Mutação/genética , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Doença de Parkinson/etnologia , Doença de Parkinson/metabolismo , Linhagem , Adulto JovemRESUMO
BACKGROUND: von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children. METHODS: We tested 17 families (n = 109 individuals) for VHL mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the VHL gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. RESULTS: Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02). Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01). CONCLUSIONS: The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening procedures in non mutation-carriers. However, mutation-carriers showed poor adherence to long-term tumor surveillance. Therefore, many of them did not obtain the full benefit of early detection and treatment, which is central to the reduction of morbidity and mortality in VHL disease. Studies designed to improve adherence to vigilance protocols will be necessary to improve treatment and quality of life in patients with hereditary cancer syndromes.
Assuntos
Testes Genéticos/métodos , Neoplasias/diagnóstico , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Ansiedade , Criança , Pré-Escolar , Cromossomos Humanos Par 3 , Depressão , Feminino , Seguimentos , Aconselhamento Genético , Genótipo , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores Socioeconômicos , Ubiquitina-Proteína Ligases/genética , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/psicologiaRESUMO
Huntington's disease (HD) is an autosomal dominant progressive, disabling neurodegenerative disorder, for which there is no effective treatment. Predictive testing (PT) for this illness began in 1986 and by 1993 it became more precise after cloning of the gene and the discovery of a CAG repeat expansion as the underlying cause. The objective of this paper is to illustrate the implementation and results of a PT program in a group of at-risk Mexican individuals with 12 years of follow-up. Our PT program conforms to the guidelines proposed by the International Huntington Association and the HD Working group of the World Federation of Neurology. Seventy-five individuals requested the testing, four of them did not fulfill the inclusion criteria, and five abandoned the program voluntarily before receiving the test results. Therefore, 66 results were delivered to 41 noncarriers and 25 mutation carriers. We did not have any catastrophic event, but 4 individuals with normal results and 11 mutation carriers were depressed. Even if this is a small sample, it is the first report of PT in a Latin-American population in which we have been faced with the same problems referred to in larger series.
