Epidemiological, clinical, and molecular characterization of Cuban families with spinocerebellar ataxia type 3/Machado-Joseph disease.

BACKGROUND: Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD) is a hereditary neurodegenerative disorder resulting from the expansion of CAG repeats in the ATXN3 gene. It is the most common autosomal dominant ataxia in the world, but its frequency prevalence in Cuba remains uncertain. We undertook a national study in order to characterize the ATXN3 gene and to determine the prevalence of SCA3/MJD in Cuba. RESULTS: Twenty-two individuals belonging to 8 non-related families were identified as carriers of an expanded ATXN3 allele. The affected families come from the central and western region of the country. Ataxia of gait was the initial symptom in all of the cases. The normal alleles ranged between 14 and 33 CAG repeats while the expanded ones ranged from 63 to 77 repeats. The mean age at onset was 40 ± 9 years and significantly correlated with the number of CAG repeats in the expanded alleles. CONCLUSIONS: This disorder was identified as the second most common form of spinocerebellar ataxia (SCA) in Cuba based on molecular testing, and showing a different geographical distribution from that of SCA2. This research constitutes the first clinical and molecular characterization of Cuban SCA3 families, opening the way for the implementation of predictive diagnosis for at risk family members.

[Therapeutic potential of bone marrow stem cells in cerebral infarction]. / Potencial terapéutico de las células madre derivadas de la médula ósea en el infarto cerebral.

INTRODUCTION: Stem cells are an alternative therapy for cerebral infarction that is still in the experimental phase. AIMS: To report on the existing scientific evidence on the therapeutic potential of bone marrow stem cells in this disease. DEVELOPMENT: Cerebral infarction accounts for 80% of cerebrovascular diseases. Thrombolysis is the only approved therapy, but, owing to its narrow therapeutic window, it is only applied to a low percentage of patients. Conversely, neurorestorative treatments, such as stem cells, can be applied over longer periods of time. For this reason a literature search was conducted on PubMed using the key words 'stem cells', 'bone marrow derived mononuclear cells' and 'stroke'. Evidence was found of the safety and effectiveness of such cells at different points in the development of the completed stroke. Results included studies that, in the clinical and preclinical period, collected them by spinal puncture and in peripheral blood, and transplanted them either directly into the infarcted area or intravenously. The therapeutic effect is related with their cell plasticity and trophic-factor releasing properties. CONCLUSIONS: Autologous mononuclear cell concentrate, obtained from peripheral blood or by puncturing the bone marrow and transplanted intravenously, is a feasible methodological option that will make it possible to quickly increase the number of clinical trials conducted at different stages of the development of a completed stroke. This therapy has proved itself to be safe and effective; nevertheless, further evidence is needed to endorse its generalised use in humans.

TITLE: Potencial terapeutico de las celulas madre derivadas de la medula osea en el infarto cerebral.Introduccion. Las celulas madre constituyen una alternativa terapeutica que se encuentra en fase de experimentacion para el infarto cerebral. Objetivo. Mostrar la evidencia cientifica existente sobre el potencial terapeutico de las celulas madre de la medula osea en esta enfermedad. Desarrollo. El infarto cerebral representa el 80% de las enfermedades cerebrovasculares. La trombolisis constituye la unica terapia aprobada, pero, por su estrecha ventana terapeutica, solo se aplica a un bajo porcentaje de los pacientes. De manera alternativa, los tratamientos neurorrestauradores, como el de celulas madre, pueden aplicarse en periodos mas prolongados. Por esta razon se efectuo una busqueda bibliografica en PubMed con el empleo de las palabras clave 'stem cells', 'bone marrow derived mononuclear cells' y 'stroke'. Se encontraron evidencias de seguridad y eficacia de dichas celulas en diferentes momentos evolutivos del infarto cerebral. Se identificaron estudios que en clinica y preclinica las recolectaron por puncion medular y en sangre periferica, y las trasplantaron directamente en el area infartada o por via intravascular. El efecto terapeutico se relaciona con sus propiedades de plasticidad celular y liberacion de factores troficos. Conclusiones. El concentrado de celulas mononucleares autologas, obtenido en sangre periferica o por puncion de la medula osea, y trasplantado por via intravenosa, es una factible opcion metodologica que permitira rapidamente incrementar el numero de ensayos clinicos en diferentes etapas evolutivas del infarto cerebral. Esta terapia muestra seguridad y eficacia; sin embargo, deben ampliarse las evidencias que avalen su generalizacion en humanos.

Potencial terapéutico de las células madre derivadas de la médula ósea en el infarto cerebral / Therapeutic potential of bone marrow stem cells in cerebral infarction

Introducción. Las células madre constituyen una alternativa terapéutica que se encuentra en fase de experimentación para el infarto cerebral. Objetivo. Mostrar la evidencia científica existente sobre el potencial terapéutico de las células madre de la médula ósea en esta enfermedad. Desarrollo. El infarto cerebral representa el 80% de las enfermedades cerebrovasculares. La trombólisis constituye la única terapia aprobada, pero, por su estrecha ventana terapéutica, sólo se aplica a un bajo porcentaje de los pacientes. De manera alternativa, los tratamientos neurorrestauradores, como el de células madre, pueden aplicarse en períodos más prolongados. Por esta razón se efectuó una búsqueda bibliográfica en PubMed con el empleo de las palabras clave ‘stem cells’, ‘bone marrow derived mononuclear cells’ y ‘stroke’. Se encontraron evidencias de seguridad y eficacia de dichas cé- lulas en diferentes momentos evolutivos del infarto cerebral. Se identificaron estudios que en clínica y preclínica las recolectaron por punción medular y en sangre periférica, y las trasplantaron directamente en el área infartada o por vía intravascular. El efecto terapéutico se relaciona con sus propiedades de plasticidad celular y liberación de factores tróficos. Conclusiones. El concentrado de células mononucleares autólogas, obtenido en sangre periférica o por punción de la médula ósea, y trasplantado por vía intravenosa, es una factible opción metodológica que permitirá rápidamente incrementar el número de ensayos clínicos en diferentes etapas evolutivas del infarto cerebral. Esta terapia muestra seguridad y eficacia; sin embargo, deben ampliarse las evidencias que avalen su generalización en humanos (AU)

Introduction. Stem cells are an alternative therapy for cerebral infarction that is still in the experimental phase. Aims. To report on the existing scientific evidence on the therapeutic potential of bone marrow stem cells in this disease. Development. Cerebral infarction accounts for 80% of cerebrovascular diseases. Thrombolysis is the only approved therapy, but, owing to its narrow therapeutic window, it is only applied to a low percentage of patients. Conversely, neurorestorative treatments, such as stem cells, can be applied over longer periods of time. For this reason a literature search was conducted on PubMed using the key words ‘stem cells’, ‘bone marrow derived mononuclear cells’ and ‘stroke’. Evidence was found of the safety and effectiveness of such cells at different points in the development of the completed stroke. Results included studies that, in the clinical and preclinical period, collected them by spinal puncture and in peripheral blood, and transplanted them either directly into the infarcted area or intravenously. The therapeutic effect is related with their cell plasticity and trophic-factor releasing properties. Conclusions. Autologous mononuclear cell concentrate, obtained from peripheral blood or by puncturing the bone marrow and transplanted intravenously, is a feasible methodological option that will make it possible to quickly increase the number of clinical trials conducted at different stages of the development of a completed stroke. This therapy has proved itself to be safe and effective; nevertheless, further evidence is needed to endorse its generalised use in humans (AU)

Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study.

BACKGROUND: The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2). METHODS: We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments. FINDINGS: We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively). INTERPRETATION: Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease. FUNDING: Cuban Ministry of Public Health.

Síndrome Metabólico: un problema de salud con múltiples definiciones / Metabolic syndrome: a health problem with many definitions

El síndrome metabólico comprende un conjunto de factores de riesgo cardiovascular representado por obesidad central, dislipidemias, anormalidades en el metabolismo de la glucosa e hipertensión arterial, estrechamente asociado a resistencia a la insulina; actualmente no existe un criterio único para definirlo. La presente revisión se propuso mostrar los diferentes grupos de criterios diagnósticos que más se utilizan para definir a este síndrome, y las variaciones que existen en su prevalencia en dependencia del criterio utilizado, con posicionamiento de los autores. Se exponen diferentes valoraciones relacionadas con los criterios propuestos por cinco organismos internacionales o locales de expertos, y los resultados de investigaciones internacionales que los utilizan. Se concluyó que a pesar de existir diferentes grupos de criterios para diagnosticar este síndrome, el más utilizado en estudios poblacionales es el del Tercer Reporte del Programa de Educación sobre el colesterol, actualizado en el año 2005; que la prevalencia del síndrome varía en dependencia del criterio que se utiliza, aún en una misma población, y de la población objeto de estudio; que la importancia clínica de su diagnóstico se relaciona con el potencial impacto que tiene en la morbilidad y mortalidad al constituir un indicador de elevado riesgo cardiovascular; y que se necesita un consenso internacional sobre el uso de un mismo criterio para diagnosticar este síndrome de manera uniforme(AU)

The metabolic syndrome comprises a group of cardiovascular risk facts represented by central obesity, dyslipidemias, anomalies in the glucose metabolism and arterial hypertension, tightly associated to the insulin resistance; at the present there is not a unique criteria to define it. The current review was aimed to show the different groups of diagnostic criteria that are used the most to define this syndrome, and the existent variation in its prevalence in dependence of the used criteria, with authors positioning. We expose different valuations related with the criteria proposed by five international or local experts organisms, and the results of the international investigations that use them. We concluded that in spite of that there are different groups of criteria to diagnose this syndrome, the most used one in population studies is the Third Report of the Educational Program on cholesterol, updated in 2005; that the syndrome prevalence changes in dependence of the used criteria; that the clinical importance of the research is related with the potential impact it has in the morbidity and mortality because it is an indicator of high cardiovascular weight; and that we need an international consensus on the usage of a same criteria to diagnose this syndrome in a uniformed way(AU)

Síndrome Metabólico: un problema de salud con múltiples definiciones / Metabolic syndrome: a health problem with many definitions

El síndrome metabólico comprende un conjunto de factores de riesgo cardiovascular representado por obesidad central, dislipidemias, anormalidades en el metabolismo de la glucosa e hipertensión arterial, estrechamente asociado a resistencia a la insulina; actualmente no existe un criterio único para definirlo. La presente revisión se propuso mostrar los diferentes grupos de criterios diagnósticos que más se utilizan para definir a este síndrome, y las variaciones que existen en su prevalencia en dependencia del criterio utilizado, con posicionamiento de los autores. Se exponen diferentes valoraciones relacionadas con los criterios propuestos por cinco organismos internacionales o locales de expertos, y los resultados de investigaciones internacionales que los utilizan. Se concluyó que a pesar de existir diferentes grupos de criterios para diagnosticar este síndrome, el más utilizado en estudios poblacionales es el del Tercer Reporte del Programa de Educación sobre el colesterol, actualizado en el año 2005; que la prevalencia del síndrome varía en dependencia del criterio que se utiliza, aún en una misma población, y de la población objeto de estudio; que la importancia clínica de su diagnóstico se relaciona con el potencial impacto que tiene en la morbilidad y mortalidad al constituir un indicador de elevado riesgo cardiovascular; y que se necesita un consenso internacional sobre el uso de un mismo criterio para diagnosticar este síndrome de manera uniforme.

The metabolic syndrome comprises a group of cardiovascular risk facts represented by central obesity, dyslipidemias, anomalies in the glucose metabolism and arterial hypertension, tightly associated to the insulin resistance; at the present there is not a unique criteria to define it. The current review was aimed to show the different groups of diagnostic criteria that are used the most to define this syndrome, and the existent variation in its prevalence in dependence of the used criteria, with author’s positioning. We expose different valuations related with the criteria proposed by five international or local experts organisms, and the results of the international investigations that use them. We concluded that in spite of that there are different groups of criteria to diagnose this syndrome, the most used one in population studies is the Third Report of the Educational Program on cholesterol, updated in 2005; that the syndrome prevalence changes in dependence of the used criteria; that the clinical importance of the research is related with the potential impact it has in the morbidity and mortality because it is an indicator of high cardiovascular weight; and that we need an international consensus on the usage of a same criteria to diagnose this syndrome in a uniformed way.

La concepción integral de la salud: principio de la educación en ciencias de la salud / The integral health conception: principle of the education in the medical sciences

La educación médica se considera como un proceso continuo de aprendizaje que empieza con la admisión en la escuela de Medicina y que termina con el retiro de la práctica activa. Su objetivo es formar profesionales que fomenten la salud de todas las personas. Es por esto que durante todo el proceso formativo se contempla la concepción integral de la salud como principio incuestionable de la educación en Ciencias de la Salud. En este artículo se pretendió fundamentar el principio y los elementos que el mismo contempla a través de la revisión de documentos de trascendencia y el criterio de los autores, lo que hace evidente cómo el principio de la concepción integral de la salud está concebido en todo el proceso de formación de los profesionales de la salud y también como premisa del profesional que se desempeña en el Sistema Nacional de Salud en Cuba. Se consideran aspectos relacionados con la dimensión bio-psico-social del hombre, el enfoque de las acciones de promoción, prevención, curación y rehabilitación de la salud, lo clínico epidemiológico y ambiental, todos estos constituyen elementos del principio de la concepción integral de la salud, el cual se concreta en la educación en el trabajo, contribuyendo a garantizar una formación integral de los futuros profesionales que tribute a un fin común: contribuir al mejoramiento del estado de salud de la población(AU)

The medical education is considered a continuous learning process that begins with the admission at the medicine school and finishes when the professional retires from the active practice. Its objective is forming professionals who foment all the people's health. That is why throughout the formation process, the integral health conception is seeing as an incontestable principle of the education in the Health Sciences. In this article we pretended to fundament the principle and its elements reviewing the transcendent documents and the authors' criteria, making it evident how the principle of the integral health conception is conceived in all the formation process of the health professionals, and also as the premise of the professional working in the Health National System in Cuba. We consider aspects related with bio-psycho-social dimension of the man, the approach of the promotional actions, the health prevention, healing and rehabilitation, the clinic-epidemiologic and environmental aspect. All of them are elements of the integral health conception principle, taking form in the education at work, guarantying an integral formation of the future professionals contributing to a common purpose: the improvement of the population health(AU)

La concepción integral de la salud: principio de la educación en ciencias de la salud / The integral health conception: principle of the education in the medical sciences

La educación médica se considera como un proceso continuo de aprendizaje que empieza con la admisión en la escuela de Medicina y que termina con el retiro de la práctica activa. Su objetivo es formar profesionales que fomenten la salud de todas las personas. Es por esto que durante todo el proceso formativo se contempla la concepción integral de la salud como principio incuestionable de la educación en Ciencias de la Salud. En este artículo se pretendió fundamentar el principio y los elementos que el mismo contempla a través de la revisión de documentos de trascendencia y el criterio de los autores, lo que hace evidente cómo el principio de la concepción integral de la salud está concebido en todo el proceso de formación de los profesionales de la salud y también como premisa del profesional que se desempeña en el Sistema Nacional de Salud en Cuba. Se consideran aspectos relacionados con la dimensión bio-psico-social del hombre, el enfoque de las acciones de promoción, prevención, curación y rehabilitación de la salud, lo clínico epidemiológico y ambiental, todos estos constituyen elementos del principio de la concepción integral de la salud, el cual se concreta en la educación en el trabajo, contribuyendo a garantizar una formación integral de los futuros profesionales que tribute a un fin común: contribuir al mejoramiento del estado de salud de la población.

The medical education is considered a continuous learning process that begins with the admission at the medicine school and finishes when the professional retires from the active practice. Its objective is forming professionals who foment all the people's health. That is why throughout the formation process, the integral health conception is seeing as an incontestable principle of the education in the Health Sciences. In this article we pretended to fundament the principle and its elements reviewing the transcendent documents and the authors' criteria, making it evident how the principle of the integral health conception is conceived in all the formation process of the health professionals, and also as the premise of the professional working in the Health National System in Cuba. We consider aspects related with bio-psycho-social dimension of the man, the approach of the promotional actions, the health prevention, healing and rehabilitation, the clinic-epidemiologic and environmental aspect. All of them are elements of the integral health conception principle, taking form in the education at work, guarantying an integral formation of the future professionals contributing to a common purpose: the improvement of the population health.

Oral Zinc Sulphate Supplementation for Six Months in SCA2 Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

Cuban patients with Spinocerebellar Ataxia type 2 (SCA2) have reduced concentrations of zinc in serum and cerebrospinal fluid (CSF). To assess the effect and safety of zinc supplementation, 36 Cuban SCA2 patients were randomly assigned to receive daily either 50 mg ZnSO4 or placebo, together with neurorehabilitation therapy in a randomized, double-blind, placebo-controlled clinical trial during 6 months. Outcome measures included the changes of zinc levels in CSF and serum, ataxia score, oxidative stress and saccadic eye movements. At the end of the study, the Zinc-treated group showed: (i) a significant increase of the Zn levels in the CSF, (ii) mild decrease in the ataxia scale subscores for gait, posture, stance and dysdiadochocinesia (iii) reduction of lipids oxidative damage, and (iv) reduction of saccadic latency when compared with the placebo group. The treatment was safe and well tolerated by all subjects. This study demonstrated the efficacy and safety of Zn supplementation, combined with neurorehabilitation for SCA2 patients and therefore it may encourage further studies on the clinical effect of zinc supplementation in SCA2 based in the conduction of future clinical trials with higher number of subjects(AU)

Caracterización integral de la ataxia espinocerebelosa 2 en Cuba y su aplicación en proyectos de intervención / Comprehensive characterization of spinocerebellar ataxia type 2 in Cuba and its application in intervention projects

Introducción Cuba es el país con mayores tasas de prevalencia e incidencia para las ataxias hereditarias, lo que constituye un problema de salud que motivó la creación del Centro para la Investigación y Rehabilitación de Ataxias Hereditarias en Holguín. Objetivos Describir los principales resultados, aportes científicos, estrategias de intervención e impactos que durante más de 10 años se han obtenido por el citado centro, como modelo para el abordaje integral de las ataxias hereditarias en Cuba. Fuente de datos Se realizó una revisión en las bases de datos Pubmed-Medline y Scopus, analizando todos los artículos relevantes, comprendidos en el periodo 1978-2011. Se utilizó el descriptor «ataxia espinocerebelar¼, de elevada especificidad y sensibilidad para el tema en análisis. Síntesis de los datos La prevalencia de la enfermedad se ha mantenido constante durante 40 años, extendiéndose a toda la isla. La mutación ataxia espinocerebelosa tipo 2 es responsable del 60 % de la variabilidad fenotípica mientras que el 40 % restante se debe a factores modificadores genéticos y/o ambientales. Se ha descrito la existencia de un daño oxidativo severo, disminución de neuroprotectores y oligoelementos. Los estudios neurofisiológicos permitieron definir etapas evolutivas desde estadios preclínicos de la enfermedad así como biomarcadores de progresión y daño genético. Estos resultados proiciaron el diseño y ejecución de varios ensayos clínicos controlados en busca de un protocolo de tratamiento contra la enfermedad. Adicionalmente se brinda un servicio de diagnostico prenatal y presintomático 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 identificación de biomarcadores, los ensayos clínicos, el diagnóstico prenatal y presintomático permitieron conformar un nuevo modelo cubano para el abordaje de las ataxias hereditarias y el estudio de otras enfermedades neurodegenerativas.

Introduction Cuba is one of the countries with high rates of prevalence and incidence of hereditary ataxias, which is a health problem that encouraged the foundation of the Center for Research and Rehabilitation of Hereditary Ataxias in Holguín province. Objectives To describe the main results, scientific achievements, intervention strategies and impacts of this institution for more than 10 years, as a sort of pattern to be followed to approach hereditary ataxias in Cuba in a more comprehensive way. Data source Pubmed-Medline and Scopus database were reviewed in which all the relevant articles published from 1978 to 2011 were analyzed. Spinocerebelar ataxia, highly specific and sensitive subject headings, were used for the topic under analysis. Data synthesis The prevalence of this disease has remained unchanged for 40 years, being extended to the whole island. Spinocerebelar ataxia type 2 mutation accounts for 60% of the phenotypical variability whereas the remaining 40% is caused by genetic and/or environmental modifying factors. Severe oxidative damage, reduction of neuroprotectors and of oligoelements have been described. The neurophysiological studies allowed defining evolutionary phases from the preclinical stagings as well as progression and genetic damage biomarkers. These results allowed designing several controlled clinical assays in search of one treatment protocol for the disease. Additionally, prenatal and pre-symptomatic diagnosis service is rendered, with positive impact on affected families. Conclusions The research studies on spinocerebelar ataxia type 2 in Cuba as a health problem have had comprehensive approach. The new breakthroughs on pathogeny, identification of biomarkers, clinical assays, prenatal and presymptomatic diagnosis allowed making a new Cuban model to approach hereditary ataxias and the study of other neurodegenerative diseases.

Saccadic latency is prolonged in Spinocerebellar Ataxia type 2 and correlates with the frontal-executive dysfunctions

Data on saccadic latency in patients with Spinocerebellar Ataxia 2 (SCA2) are sparse and contradictory. In order to determine whether saccadic latency is definitely prolonged, identify its possible determinants and evaluate it as disease biomarker we assessed the saccadic latency by electronystagmography in 110 SCA2 patients and their paired controls. Mean saccadic latencies were significantly longer in patients when compared to controls for all tested target displacements. Forty-six percent of SCA2 patients had saccadic latencies above the normal range. Reciprobit plots of saccadic latency demonstrated a skewed distribution in the direction of longer latencies for the patients compared to controls. As saccadic latency increased, the velocity and amplitude of saccades significantly decreased in SCA2 subjects but not in controls. Saccadic latency was not influenced by any demographical, clinical or molecular SCA2 variables, but it showed a significant correlation with the performance of the Stroop test, the verbal fluency test and the Wisconsin Card Sorting Test in SCA2 patients. This paper demonstrated that saccadic latency is prolonged in SCA2 patients and it significantly correlates with the performance of frontal-executive functions, thus this parameter could be a useful biomarker to evaluate the efficiency of future therapeutical options on these dysfunctions(AU)

Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial.

Cuban patients with Spinocerebellar Ataxia type 2 (SCA2) have reduced concentrations of zinc in serum and cerebrospinal fluid (CSF). To assess the effect and safety of zinc supplementation, 36 Cuban SCA2 patients were randomly assigned to receive daily either 50 mg ZnSO(4) or placebo, together with neurorehabilitation therapy in a randomized, double-blind, placebo-controlled clinical trial during 6 months. Outcome measures included the changes of zinc levels in CSF and serum, ataxia score, oxidative stress and saccadic eye movements. At the end of the study, the Zinc-treated group showed: (i) a significant increase of the Zn levels in the CSF, (ii) mild decrease in the ataxia scale subscores for gait, posture, stance and dysdiadochocinesia (iii) reduction of lipid's oxidative damage, and (iv) reduction of saccadic latency when compared with the placebo group. The treatment was safe and well tolerated by all subjects. This study demonstrated the efficacy and safety of Zn supplementation, combined with neurorehabilitation for SCA2 patients and therefore it may encourage further studies on the clinical effect of zinc supplementation in SCA2 based in the conduction of future clinical trials with higher number of subjects.

Saccadic latency is prolonged in Spinocerebellar Ataxia type 2 and correlates with the frontal-executive dysfunctions.

Data on saccadic latency in patients with Spinocerebellar Ataxia 2 (SCA2) are sparse and contradictory. In order to determine whether saccadic latency is definitely prolonged, identify its possible determinants and evaluate it as disease biomarker we assessed the saccadic latency by electronystagmography in 110 SCA2 patients and their paired controls. Mean saccadic latencies were significantly longer in patients when compared to controls for all tested target displacements. Forty-six percent of SCA2 patients had saccadic latencies above the normal range. Reciprobit plots of saccadic latency demonstrated a skewed distribution in the direction of longer latencies for the patients compared to controls. As saccadic latency increased, the velocity and amplitude of saccades significantly decreased in SCA2 subjects but not in controls. Saccadic latency was not influenced by any demographical, clinical or molecular SCA2 variables, but it showed a significant correlation with the performance of the Stroop test, the verbal fluency test and the Wisconsin Card Sorting Test in SCA2 patients. This paper demonstrated that saccadic latency is prolonged in SCA2 patients and it significantly correlates with the performance of frontal-executive functions, thus this parameter could be a useful biomarker to evaluate the efficiency of future therapeutical options on these dysfunctions.

Sleep disorders in spinocerebellar ataxia type 2 patients.

BACKGROUND: Sleep disturbances are common features in spinocerebellar ataxias (SCAs). Nevertheless, sleep data on SCA2 come from scarce studies including few patients, limiting the evaluation of the prevalence and determinants of sleep disorders. OBJECTIVE: To assess the frequency and possible determinants of sleep disorders in the large and homogeneous SCA2 Cuban population. METHODS: Thirty-two SCA2 patients and their age- and sex-matched controls were studied by video-polysomnography and sleep interviews. RESULTS: The most striking video-polysomnography features were rapid eye movement (REM) sleep pathology and periodic leg movements (PLMs). REM sleep abnormalities included a consistent reduction of the REM sleep percentage and REM density as well as an increase in REM sleep without atonia (RWA). REM sleep and REM density decreases were closely related to the increase in ataxia scores, whereas the RWA percentage was influenced by the cytosine-adenine-guanine (CAG) repeats. PLMs were observed in 37.5% of cases. The PLM index showed a significant association with the ataxia score and disease duration but not with CAG repeats. CONCLUSIONS: REM sleep pathology and PLMs are closely related to SCA2 severity, suggesting their usefulness as disease progression markers. The RWA percentage is influenced by the CAG repeats and might thus be a sensitive parameter for reflecting polyglutamine toxicity. Finally, as PLMs are sensible to drug treatment, they represents a new therapeutic target for the symptomatic treatment of SCA2.

Sleep disorders in spinocerebellar ataxia type 2 patients

Background: Sleep disturbances are common features in spinocerebellar ataxias (SCAs). Nevertheless, sleep data on SCA2 come from scarce studies including few patients, limiting the evaluation of the prevalence and determinants of sleep disorders. Objective: To assess the frequency and possible determinants of sleep disorders in the large and homogeneous SCA2 Cuban population. Methods: Thirty-two SCA2 patients and their age- and sex-matched controls were studied by video-polysomnography and sleep interviews. Results: The most striking video-polysomnography features were rapid eye movement (REM) sleep pathology and periodic leg movements (PLMs). REM sleep abnormalities included a consistent reduction of the REM sleep percentage and REM density as well as an increase in REM sleep without atonia (RWA). REM sleep and REM density decreases were closely related to the increase in ataxia scores, whereas the RWA percentage was influenced by the cytosine-adenine-guanine (CAG) repeats. PLMs were observed in 37.5% of cases. The PLM index showed a significant association with the ataxia score and disease duration but not with CAG repeats. Conclusions: REM sleep pathology and PLMs are closely related to SCA2 severity, suggesting their usefulness as disease progression markers. The RWA percentage is influenced by the CAG repeats and might thus be a sensitive parameter for reflecting polyglutamine toxicity. Finally, as PLMs are sensible to drug treatment, they represents a new therapeutic target for the symptomatic treatment of SCA2(AU)

Progression markers of Spinocerebellar Ataxia 2: A twenty years neurophysiological follow up study

Nerve conduction is profoundly affected in Spinocerebellar ataxia 2 (SCA2) even before the onset of the disease, but there is no information regarding its progression to the final stage of SCA2. In order to study the progression patterns of nerve conduction abnormalities in SCA2 we performed a prospective follow up evaluation of sensory and motor conduction in 21 SCA2 mutation carriers-initially presymptomatics- and 19 non-SCA2 mutation carriers during 20 years. The earliest electrophysiological alterations were the reduction of sensory amplitudes in median and sural nerves, which could be found 8 to 5 years prior disease onset and in the last 4 years of the preclinical stage respectively. These abnormalities were followed by the increase of sensory latencies and decrease of conduction velocities. Sensory amplitudes progressively decreased during the follow-up clinical stage, rendering almost all patients with abnormal amplitudes and lack of sensory potentials, with faster progression rates in patients with larger CAG repeat lengths. Peripheral motor nerves showed the later involvement. These findings were used to define three distinct stages that describe the progression of the peripheral neuropathy. We suggest that sensory amplitudes could be useful biomarkers to assess the progression of peripheral nerve involvement and therefore to evaluate future clinical trials of therapeutic agents(AU)