Luis Velázquez Pérez

Molecular epidemiology of spinocerebellar ataxias in Cuba: Insights into SCA2 founder effect in Holguin

The objective of this study was to determine the prevalence of hereditary ataxias in Cuba, with a special focus on the clinical and molecular features of SCA2. Clinical assessments were performed by neurological examinations and application of the SARA scale. Molecular analyses of genes SCA1-3, SCA6, SCA17 and DRPLA identified 753 patients with SCA and 7173 asymptomatic relatives, belonging to 200 unrelated families. 86.79% of all SCA patients were affected with SCA2. In the Holguin province, the average population prevalence of SCA2 is 40.18x10(5) inhabitants, with the remarkable figure of 141.66x10(5) in the Baguanos municipality. The high prevalence of the SCA2 mutation in Holguin reflects most likely a founder effect. The stabilization of the prevalence along time suggests the existence of premutated chromosomes with pure CAG, acting as reservoir for further expansions. CAG repeat length correlated inversely with age at onset, accounting for 80% of the variability. Genetic anticipation was observed in the 80% of transmissions. Repeat instability was greater in paternal transmissions whereas CAG expansions without anticipation was observed in 10.97% suggesting the effect of CAA interruptions in the CAG segment, which decrease the toxicity of the abnormal ataxin-2, and/or other protective factors.

Electrophysiological features in patients and presymptomatic relatives with spinocerebellar ataxia type 2

Abstract Motor and sensitive nerve conduction studies, visual (VEP), brainstem auditory (BAEP) and somatosensory (SSEP) evoked potentials in 82 patients with spinocerebellar ataxia type 2 (SCA2), 62 presymptomatics relatives and 80 controls, correlating it with CAG repeat, disease duration and ataxia score were assessed. All the groups showed differences in the amplitude of sensory action potentials in median and sural nerves. Sural amplitude was negatively correlated with disease duration and ataxia score. Differences among patients and controls in the mean latency and conduction velocity of sensory action potentials were found. Abnormal morphology and replicability of SSEPs and BSAEPs were found in patients and presymptomatics. Moreover, consistent increase in latencies of P40 component of SSEPs, III and V peaks and I–III interpeak of BSAEPs was found in patients. A positive correlation was found between latency of III and V waves, I–III and III–V interpeak latencies of BSAEPs and disease duration. CAG repeat and electrophysiological markers assessed were not correlative. Electrophysiological alterations in the SCA2 appeared in presymptomatic stages. These alterations are consistent markers which could be used to evaluate the progression of the disease.

De Novo Mutations in Ataxin-2 Gene and ALS Risk

Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal ATXN2 alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The de novo mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the ATXN2. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis.

Ethical Dilemmas in Genetic Testing: Examples from the Cuban Program for Predictive Diagnosis of Hereditary Ataxias

Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities.

Caracterización integral de la ataxia espinocerebelosa 2 en Cuba y su aplicación en proyectos de intervención

Introduccion Cuba es el pais con mayores tasas de prevalencia e incidencia para las ataxias hereditarias, lo que constituye un problema de salud que motivo la creacion del Centro para la Investigacion y Rehabilitacion de Ataxias Hereditarias en Holguin. Objetivos Describir los principales resultados, aportes cientificos, estrategias de intervencion e impactos que durante mas de 10 anos se han obtenido por el citado centro, como modelo para el abordaje integral de las ataxias hereditarias en Cuba. Fuente de datos Se realizo una revision en las bases de datos Pubmed-Medline y Scopus, analizando todos los articulos relevantes, comprendidos en el periodo 1978-2011. Se utilizo el descriptor «ataxia espinocerebelar», de elevada especificidad y sensibilidad para el tema en analisis. Sintesis de los datos La prevalencia de la enfermedad se ha mantenido constante durante 40 anos, extendiendose a toda la isla. La mutacion ataxia espinocerebelosa tipo 2 es responsable del 60 % de la variabilidad fenotipica mientras que el 40 % restante se debe a factores modificadores geneticos y/o ambientales. Se ha descrito la existencia de un dano oxidativo severo, disminucion de neuroprotectores y oligoelementos. Los estudios neurofisiologicos permitieron definir etapas evolutivas desde estadios preclinicos de la enfermedad asi como biomarcadores de progresion y dano genetico. Estos resultados proiciaron el diseno y ejecucion de varios ensayos clinicos controlados en busca de un protocolo de tratamiento contra la enfermedad. Adicionalmente se brinda un servicio de diagnostico prenatal y presintomatico con un impacto positivo sobre las familias afectadas. Conclusiones Las investigaciones sobre la ataxia espinocerebelosa tipo 2 cubana, como problema de salud, han tenido un enfoque integral. Los nuevos descubrimientos sobre la patogenia, la identificacion de biomarcadores, los ensayos clinicos, el diagnostico prenatal y presintomatico permitieron conformar un nuevo modelo cubano para el abordaje de las ataxias hereditarias y el estudio de otras enfermedades neurodegenerativas.