RESUMEN
Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Despite clinical and experimental evidence indicating the relevance of the gonadotropic axis to the prognosis and therapeutics for several late-onset neurodegenerative disorders, its functioning and association with disease severity have not been previously explored in SCA2. To assess serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), and their clinical relevance in SCA2 patients. A case-control study involving 94 Cuban SCA2 patients and 101 gender- and age-matched healthy controls was conducted. Testosterone, LH, and FSH serum levels were determined by radioimmunoassay or immunoradiometric assay systems. Clinical outcomes included age at onset, disease duration, Scale for the Assessment and Rating of Ataxia (SARA) score, and progression rate. Univariate general linear models were generated. Testosterone, LH, and FSH serum levels were significantly reduced in male SCA2 patients relative to control individuals. On average, there was a 35% reduction in testosterone levels in male patients versus male control individuals. Testosterone levels were associated with disease duration (r = 0.383; p = 0.025) and age at onset (r = 0.414; p = 0.011) in male SCA2 patients, but no association was observed between testosterone and CAG expansion size, SARA score, or progression rate. Testosterone levels might be a biomarker of disease progression in male SCA2 patients. Further studies are needed to explore the effects of low testosterone levels on non-motor symptoms, and to assess the potential of testosterone replacement therapy in male SCA2 patients.
Asunto(s)
Ataxias Espinocerebelosas/sangre , Testosterona/sangre , Adulto , Edad de Inicio , Estudios de Casos y Controles , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Masculino , Persona de Mediana EdadRESUMEN
In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles ≥27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them.
Asunto(s)
Alelos , Proteínas del Tejido Nervioso/genética , Diagnóstico Prenatal , Ataxinas , Femenino , Humanos , Masculino , Linaje , EmbarazoRESUMEN
There are different types of visuomotor learning. Among the most studied is motor error-based learning where the sign and magnitude of the error are used to update motor commands. However, there are other instances where individuals show visuomotor learning even if the sign or magnitude of the error is precluded. Studies with patients suggest that the former learning is impaired after cerebellar lesions, while basal ganglia lesions disrupt the latter. Nevertheless, the cerebellar role is not restricted only to error-based learning, but it also contributes to several cognitive processes. Therefore, here, we tested if cerebellar ataxia patients are affected in two tasks, one that depends on error-based learning and the other that prevents the use of error-based learning. Our results showed that cerebellar patients have deficits in both visuomotor tasks; however, while error-based learning tasks deficits correlated with the motor impairments, the motor error-dependent task did not correlate with any motor measure.
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Discapacidades para el Aprendizaje/etiología , Actividad Motora/fisiología , Trastornos de la Percepción/etiología , Desempeño Psicomotor/fisiología , Ataxias Espinocerebelosas/complicaciones , Percepción Visual/fisiología , Adaptación Fisiológica , Adulto , Ganglios Basales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Campos Visuales/fisiologíaRESUMEN
BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder due to a CAG-repeat expansion. This work is intended to identify modifiers of the clinical phenotype in SCA2, following up on recent genome-wide association analyses that demonstrated the prominent role of DNA-damage repair and methylation for the severity and progression of polyglutamine diseases. In particular, we assessed the impact of MTHFR as rate-limiting enzyme in DNA methylation pathways, which modulates cerebellar neurotransmission and motor neuron atrophy. METHODS: A sample of 166 Cuban SCA2 patients and of 130 healthy subjects from the same geographical and ethnic background was selected. The ATXN2 CAG repeat length was determined by PCR followed by polyacrylamide gel electrophoresis. Two amino acid substitutions known to decrease the enzyme activity of MTHFR, encoded by C677T and A1298C polymorphisms, were assessed by PCR/RFLP. RESULTS: No significant differences were observed for C677T or A1298C alleles or genotype frequencies between cases and controls, confirming that disease risk in SCA2 does not depend on MTHFR activity. However, MTHFR A1298C genotypes showed a significant association with saccade latency. CONCLUSIONS: \MTHFR A1298C polymorphism is associated with saccade latency in SCA2 patients, but not with disease risk, age at onset or maximal saccade velocity. These results provide evidence that folate-mediated onecarbon metabolism might be important in the physiopathology of SCA2.
Asunto(s)
Variación Genética/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple/genética , Movimientos Sacádicos/fisiología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatología , Adulto , Carbono , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ataxias Espinocerebelosas/diagnósticoRESUMEN
BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an inherited and still incurable neurodegenerative disorder. Evidence suggests that pro-oxidant agents as well as factors involved in antioxidant cellular defenses are part of SCA2 physiopathology. AIM: To assess the influence of superoxide dismutase (SOD3) and catalase (CAT) enzymatic activities on the SCA2 syndrome. METHOD: Clinical, molecular, and electrophysiological variables, as well as SOD3 and CAT enzymatic activities were evaluated in 97 SCA2 patients and in 64 age- and sex-matched control individuals. RESULTS: Spinocerebellar ataxia type 2 patients had significantly lower SOD3 enzymatic activity than the control group. However, there were no differences between patients and controls for CAT enzymatic activity. The effect size for the loss of patients' SOD3 enzymatic activity was 0.342, corresponding to a moderate effect. SOD3 and CAT enzymatic activities were not associated with the CAG repeat number at the ATXN2 gene. SOD3 and CAT enzymatic activities did not show significant associations with the age at onset, severity score, or the studied electrophysiological markers. CONCLUSION: There is a reduced SOD3 enzymatic activity in SCA2 patients with no repercussion on the clinical phenotype.
RESUMEN
Spinocerebellar ataxia type 2 (SCA2) is part of a group of at least nine dominantly inherited disorders characterized by progressive degeneration of specific neuronal populations and a shared mutational mechanism involving the expansion of a CAG repeat tract in coding regions of novel genes. Efforts have been made to identify biomarkers of disease progression, which would allow timely preventive therapeutic interventions. In the present study was assessed the influence of several genome instability biomarkers on SCA2 clinical severity. A case-control design was applied on exfoliated epithelial buccal cells to determine micronuclei frequency and others nuclear anomalies, using 5% Giemsa stains. The slides were analyzed under 1000X magnification and nuclei morphological anomalies were identified according to Tolbert PE, et al. (1992) and Bolognesi C, et al. (2013) criteria. It was found a highly significant increase in micronuclei frequency in cases related to age and sex-matched healthy controls (p <0.001). There was a trend for karyolytic, pyknotic and condensed chromatin cells to be increased in SCA2 cases, and a significant association was found between binucleated cells and disease duration (r = 0.46; p = 0.027). Nor the CAG repeat length neither the age at onset correlated significantly with any of the studied markers (p >0.05). Our results are consistent with report previous in similar neurodegenerative diseases, and suggest that micronuclei and binucleated cells constitute potential peripheral biomarkers for SCA2. These results should be validated by other studies.
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Micronúcleos con Defecto Cromosómico , Mucosa Bucal/ultraestructura , Ataxias Espinocerebelosas/patología , Adulto , Edad de Inicio , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Inestabilidad Genómica , Humanos , Masculino , Pruebas de Micronúcleos , Persona de Mediana Edad , Mutación , Ataxias Espinocerebelosas/genética , Adulto JovenRESUMEN
BACKGROUND: Spinocerebellar ataxia type 2 is a neurodegenerative disorder caused by a CAG repeat expansion in ATXN2 gene. There is high clinical variability among affected patients suggesting the occurring of modifier genes influencing the clinical phenotype. OBJECTIVE: The objective is to assess the association of GSTO1 rs4925 and GSTO2 rs2297235 SNPs on the clinical phenotype in SCA2 patients. METHODS: A case-control study was performed in a sample of 120 SCA2 Cuban patients and 100 healthy subjects. Age at onset, 60° Maximal Saccade Velocity and SARA score were used as clinical markers. GSTO1 rs4925 and GSTO2 rs2297235 SNPs were determined by PCR/RFLP. RESULTS: Distribution of the GSTO1 alleles and genotypes was nearly equal between the control group and SCA2 patients. GSTO1 genotypes were not associated to clinical markers in SCA2 patients. Distribution of the GSTO2 "G" allele and "AG" genotype differed significantly between SCA2 patients and controls. Symptomatic SCA2 individuals had a 2.29-fold higher chance of carrying at least one "G" allele at GSTO2 rs2297235 than controls (OR=2.29, 95% CI: 1.29-4.04). GSTO2 genotypes were significantly associated to age at onset (p=0.037) but not to 60° Maximal Saccade Velocity or SARA score in SCA2 patients. CONCLUSION: The GSTO1 rs4925 polymorphism is not associated to SCA2. Meanwhile, the GSTO2 rs2297235 "AG" genotype is associated to SCA2 but failed to show any association with clinical markers, with the exception of a potential association with the age at disease onset.
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Predisposición Genética a la Enfermedad/genética , Glutatión Transferasa/genética , Polimorfismo de Nucleótido Simple/genética , Ataxias Espinocerebelosas/genética , Edad de Inicio , Ataxina-2/genética , Estudios de Casos y Controles , Biología Computacional , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Lineales , Masculino , Movimientos Sacádicos/genética , Índice de Severidad de la Enfermedad , Repeticiones de Trinucleótidos/genéticaRESUMEN
Cuba reports the highest worldwide prevalence of spinocerebellar ataxia type 2 (SCA2) and the greatest number of descendants at risk. A protocol for genetic counseling, presymptomatic testing, and prenatal diagnosis of hereditary ataxias has been under development since 2001. Considering that the revision of the experience with prenatal diagnosis for SCA2 in Cuba would enable comparison of ours with international findings, we designed a descriptive study, based on the retrospective revision of the medical records belonging to the 58 couples that requested their inclusion in the program, during an 11-year period (2001-2011). Most of the participants in the prenatal diagnosis program were known presymptomatic carriers, diagnosed through the presymptomatic testing in the same period of study, for an uptake among them of 22.87 % (51 out of 223). In 28 cases, the fetuses were carriers, 20 of these couples (71.43 %) decided to terminate the pregnancy; the rest continued the pregnancy to term, this resulting in a predictive test for their unborn children. A predominance of females as the at-risk progenitor was observed. Except for a slightly lower average age, the results attained in the Cuban SCA2 prenatal diagnosis program resulted similar to the ones reported for Huntington disease in other countries. It is necessary to have easy access to the Cuban program through its expansion to other genetic centers along the island. Future research is needed to evaluate the long-term impact of both the predictive testing in unborn children and the selection of other reproductive options by the at-risk couples.
RESUMEN
INTRODUCTION: The Center for Research and Rehabilitation of Hereditary Ataxias faces biological risks. Nevertheless a Biosafety system was not yet implemented. OBJECTIVE: To apply the methodology in order to evaluate these risks MATERIALS AND METHODS: Interview with the researchers of the center and the use of the methodology for evaluating biological risks designed for Cobos, 2009. RESULTS: Fifty-three biological risks were identified and evaluated, 32 as moderated, 18 as tolerable and 3 as trivial. Such classification are crucial to establish its management priorities and represent a way of surveillance in Biosafety field. CONCLUSION: The results of this research represent an essential factor for the Biosafety documentation development adapted to the Center and according to the legal basis in terms of biological safety in Cuba
INTRODUCCIÓN: El Centro para la Investigación y Rehabilitación de las Ataxias Hereditarias presenta riesgo biológico, sin embargo no tiene implementado un sistema de bioseguridad. OBJETIVO: Aplicar la metodología para evaluar este tipo de riesgo. Materiales y MÉTODOS: Entrevistas con los trabajadores del centro y el empleo de la metodología diseñada por Cobos, 2009. RESULTADOS: Cincuenta y tres riesgos biológicos fueron identificados y evaluados, de ellos 32 moderados, 18 tolerables y 3 triviales. Esta clasificación es muy importante para establecer prioridades para su gestión, además representa una manera de establecer vigilancia en bioseguridad. CONCLUSIÓN: Los resultados de esta investigación representan un factor esencial para el desarrollo de la documentación de bioseguridad ajustada a las características de la entidad de acuerdo a la base legal en materia de seguridad biológica en Cuba