RESUMEN
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.
RESUMEN
The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.
Asunto(s)
Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/fisiopatología , Adulto , Anciano , Ataxinas , Encéfalo/patología , Encéfalo/fisiopatología , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Cuba/epidemiología , Medidas del Movimiento Ocular , Femenino , Humanos , Entrevistas como Asunto , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/genética , Examen Neurológico , Pruebas Neuropsicológicas , Síntomas Prodrómicos , Movimientos Sacádicos , Índice de Severidad de la Enfermedad , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Adulto JovenRESUMEN
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.
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Proteínas del Tejido Nervioso/genética , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatología , Repeticiones de Trinucleótidos/genética , Adolescente , Adulto , Factores de Edad , Ataxinas , Estudios de Casos y Controles , Niño , Cuba , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Examen Neurológico , Estudios Retrospectivos , Riesgo , Índice de Severidad de la Enfermedad , Ataxias Espinocerebelosas/patología , Adulto JovenRESUMEN
Huntington disease is the most frequent polyglutamine disorder with variable worldwide prevalence. Although some Latin American populations have been studied, HD prevalence in Cuban population remains unknown. In order to characterize the disease in Cuba, the relative frequency of HD was determined by studying 130 patients with chorea and 63 unrelated healthy controls, emphasizing in the molecular epidemiology of the disease. Sixty-two patients with chorea belonging to 16 unrelated families carried a pathological CAG expansion in the HTT gene, ranging from 39 to 67 repeats. Eighty-three percent of them come from the eastern region of the country. A significant inverse correlation between age at onset and expanded CAG repeats was seen. Intermediate alleles in affected individuals and controls represented 4.8% and 3.97% respectively, which have been a putative source of de novo mutation. This study represents the largest molecular characterization of Huntington disease in the Cuban population. These results may have significant implications for an understanding of the disease, its diagnosis and prognosis in Cuban patients, giving health professionals the tools to implement confirmatory genetic testing, pre-symptomatic testing and clinical trials in this population.
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Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/genética , Proteínas del Tejido Nervioso/genética , Repeticiones de Trinucleótidos/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Cuba/epidemiología , Femenino , Frecuencia de los Genes , Humanos , Proteína Huntingtina , Masculino , Persona de Mediana Edad , Fenotipo , Estadísticas no Paramétricas , Adulto JovenRESUMEN
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)
Asunto(s)
Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Suplementos Dietéticos , Placebos , Ataxias Espinocerebelosas/sangre , Ataxias Espinocerebelosas/tratamiento farmacológico , Ataxias Espinocerebelosas/fisiopatología , Sulfato de Zinc/administración & dosificación , Sulfato de Zinc/uso terapéuticoRESUMEN
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.
RESUMEN
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia characterized by a progressive cerebellar syndrome associated to saccadic slowing, peripheral neuropathy, cognitive disorders, and other multisystem features. SCA2 is caused by the abnormal expansion of cytosine-adenine-guanine triplet repeats in the encoding region of the ATXN2 gene and therefore the expression of toxic polyglutamine expansions in the ataxin 2 protein, which cause progressive neuronal death of Purkinje cells in the cerebellum and several pontine, mesencephalic, and thalamic neurons among other cells. Worldwide, SCA2 is the second most frequent type of spinocerebellar ataxia, only surpassed by SCA3. Nevertheless, in Holguin, Cuba, the disease reaches the highest prevalence, resulting from a putative foundational effect. This review discusses the most important advances in the genotypical and phenotypical studies of SCA2, highlighting the comprehensive characterization reached in Cuba through clinical, neuroepidemiological, neurochemical, and neurophysiological evaluation of SCA2 patients and pre-symptomatic subjects, which has allowed the identification of new disease biomarkers and therapeutical opportunities. These findings provide guidelines, from a Cuban viewpoint, for the clinical management of the disease, its diagnosis, genetic counseling, and therapeutical options through rehabilitative therapy and/or pharmacological options (AU)
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Humanos , Animales , Predisposición Genética a la Enfermedad , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatología , Ataxias Espinocerebelosas/terapia , Cuba/epidemiología , FenotipoRESUMEN
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.
Asunto(s)
Suplementos Dietéticos , Placebos , Ataxias Espinocerebelosas/tratamiento farmacológico , Sulfato de Zinc/administración & dosificación , Sulfato de Zinc/uso terapéutico , Adolescente , Adulto , Catalasa/sangre , Cuba , Método Doble Ciego , Humanos , Malondialdehído/sangre , Persona de Mediana Edad , Movimientos Sacádicos/fisiología , Ataxias Espinocerebelosas/fisiopatología , Ataxias Espinocerebelosas/rehabilitación , Superóxido Dismutasa/sangre , Resultado del Tratamiento , Adulto Joven , Zinc/sangreRESUMEN
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)
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Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Trastornos del Sueño-Vigilia/etiología , Ataxias Espinocerebelosas/complicacionesRESUMEN
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.
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Trastornos del Sueño-Vigilia/etiología , Ataxias Espinocerebelosas/complicaciones , Adolescente , Adulto , Biomarcadores , ADN/genética , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Fenotipo , Polisomnografía , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sueño REM/fisiología , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido , Adulto JovenRESUMEN
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.
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Proteínas del Tejido Nervioso/genética , Sueño REM/genética , Ataxias Espinocerebelosas/fisiopatología , Adolescente , Adulto , Ataxinas , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Ataxias Espinocerebelosas/genética , Encuestas y CuestionariosRESUMEN
Las enfermedades poliglutamínicas constituyen un grupo de patologías humanas causadas por la expansión de secuencias repetitivas de CAG En las familias afectadas, la edad de inicio de la enfermedad es altamente variable, lo cual se debe en su mayor parte al número de repeticiones de CAG en los alelos patológicos Ha sido sugerida la existencia de otros factores genéticos con efecto modificador sobre la edad inicio, entre los que se encuentra la dosis genética Aquí fue realizada una revisión de toda la evidencia disponible acerca del efecto fenotípico de la homocigosis para alelos patológicos en enfermedades poliglutamínicas A pesar de la muy baja frecuencia de casos homocigóticos para estas enfermedades en la población humana, la evidencia apoya un modelo según el cual en los homocigóticos los alelos patológicos tienen un efecto aditivo que agrava la presentación clínica Los estudios realizados en animales modelos para estas enfermedades corroboran esta afirmación...(AU)
Polyglutamine disorders constitute a group of human diseases caused by the expansion of repetitive sequences of the CAG. In affected families, the age at onset of the disease is highly variable, and most of it is due to the CAG repeat number in the pathological alleles Genetic factors with modifiable effect on the age at onset was suggested one of those is the genetic dose A review of the whole available evidence on the phenotype effect of the homozygosis state for pathologic alleles in polyglutamine disorders was analyzed. In spite of the very low frequency of homozygous cases for these disorders in human population, the results showed that in the homozygous individuals the pathologic alleles have an additive effect that increases the severity of the clinical presentation, these results were obtained through the studies that were carried out in a sample of animals...(AU)