Luis Enrique Almaguer Mederos

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.

Spinocerebellar ataxia type 2 olfactory impairment shows a pattern similar to other major neurodegenerative diseases

Olfactory function is affected in different neurodegenerative diseases. Recently, it has been found that some hereditary ataxias are also associated with significant olfactory impairment. However, the initial findings did not examine the nature of the olfactory impairment associated with these ataxias. In the present article the effect of spinocerebellar ataxia type 2 (SCA2) on olfactory function was studied in 53 SCA2 patients and 53 healthy control subjects from Holguín, Cuba. Several tests were applied to evaluate olfactory threshold, description, identification and discrimination. The results show significant impairment in SCA2 patients on all olfactory measurements, and the pattern of olfactory deficits found suggests that they have much in common with those reported for other neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.

Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications

Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.

Subtle rapid eye movement sleep abnormalities in presymptomatic spinocerebellar ataxia type 2 gene carriers.

Rapid eye movement (REM) sleep disorders are commonly associated to patients with spinocerebellar ataxia type 2 (SCA2); however, these abnormalities have not been studied in presymptomatic gene carriers. To determine whether the REM sleep pathology is detectable before clinical manifestation of SCA2 and evaluate it as a preclinical biomarker, we studied 36 presymptomatic SCA2 individuals and 36 controls by video‐polysomnography (VPSG) and sleep questionnaires. Presymptomatic subjects showed significant decrease of REM sleep percentage, REMs density, total sleep time, and sleep efficiency. Aging effect on REM sleep percentage was significant in both groups. There was no correlation between cytosine‐adenine‐guanine (CAG) repeat length and REM sleep. Our findings identified the REM sleep pathology as a prominent herald sign of SCA2, conferring a special importance to VPSG as a sensitive neurophysiological tool to detect early changes associated with SCA2, which contributes to the understanding of disease pathophysiology and the development of therapeutic trials focused on the preclinical disease stage.

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (∼3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs.

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.