Genetic analysis of age at onset variation in spinocerebellar ataxia type 2.

OBJECTIVE: To examine heritability of the residual variability of spinocerebellar ataxia type 2 (SCA2) age at onset (AO) after controlling for CAG repeat length. METHODS: From 1955 to 2001, dates of birth, CAG repeat lengths, AO, sex, familial inheritances, and clinical manifestations were collected for a large Cuban SCA2 cohort of 382 affected individuals, including 129 parent-child pairs and 69 sibships. Analyses were performed with log-transformed AO in the GENMOD procedure to predict AO using repeat length, taking into account family structure. Because all relationships were first degree, the model was implemented with an exchangeable correlation matrix. Familial correlations were estimated using the Pedigree Analysis Package to control for similarity due to genetic relatedness. RESULTS: For the entire sample, the mutant CAG repeat allele explained 69% of AO variance. When adjusted for pedigree structure, this decreased to 50%. Evidence for imprinting or sex-specific effects of the CAG repeat on AO was not found. For the entire sample, we determined an upper bound for heritability of the residual variance of 33% (p = 0.008). Heritability was higher in sib-sib pairs, especially in female sib-sib pairs, than in parent-child pairs. CONCLUSIONS: We established that a large proportion of AO variance in SCA2 was determined by genetic modifiers in addition to CAG repeat length. The genetic structure of heritability of the residual AO variance was surprisingly similar to Huntington disease, suggesting the presence of recessive modifying alleles and possibly X-chromosome-linked modifiers.

Caracterización de las principales variables clínicas del glaucoma en pacientes con retinosis pigmentaria / Main clinical variables in characterization of patients with retinitis pigmentosa and glaucoma

Se realizó un estudio epidemiológico, descriptivo y transversal de 85 pacientes con alguna de las formas clínicas de glaucoma, dispensarizados en el Centro Nacional de Referencia de Retinosis Pigmentaria durante el primer semestre del 2010. Entre las variables analizadas de acuerdo con la clasificación de la Escuela Cubana de Retinosis Pigmentaria, figuraron: agudeza visual, alteraciones campimétricas, herencia de retinosis y consanguinidad, hipertensión ocular y espesor corneal, según los tipos de dichas afecciones. En la serie, 32,9 % tenía visión entre 0,1 y 0,3; 47,05 %, reducción concéntrica del campo visual (5 y 10 °) y patrón autosómico recesivo; 17,64 %, antecedentes de consanguinidad y 38,8 %, comienzo juvenil. Se halló hipertensión ocular en 82,35 %, con predominio en la retinosis típica de grado IV (40,0 %), así como disminución del espesor corneal en 34,1% de la casuística. La letalidad visual por la asociación de ambas oftalmopatías exige que sea investigada detenidamente. Hasta el momento, la medición adecuada de la presión intraocular (aplanación con ajuste a los valores del espesor corneal) constituye la herramienta más útil para diagnosticar la enfermedad y evaluar su evolución en estos pacientes.

An epidemiological, descriptive and cross-sectional study was carried out in 85 patients with some clinical forms of glaucoma, attended and monitored at the National Reference Center of Retinitis Pigmentosa during the first semester of 2010. Among the analyzed variables according to the classification of the Cuban School of Retinitis Pigmentosa were visual acuity, visual field defects, retinitis inheritance and consanguinity, ocular hypertension and corneal thickness according to the types of these conditions. In the series 32,9 % had vision between 0,1 and 0,3; concentric reduction of vision field (5 and 10 °) and autosomal recessive pattern in 47,05 %; history of consanguinity in 17,4 % and juvenile onset in 38.8%. Ocular hypertension was found in 82,35 % with predominance in grade IV typical retinitis (40,0 %), as well as reduction of corneal thickness in 34,1 % of all cases. The visual letality caused by association of both eye diseases requires to be studied carefully. So far, proper measurement of intraocular pressure (applanation adjusted to the values of corneal thickness) is the most useful tool to diagnose disease and to evaluate its progress in these patients.

Effectiveness of an intervention in groups of family caregivers of dependent patients for their application in primary health centers. Study protocol.

BACKGROUND: Although Primary Health Care (PHC) Teams are used to deal with prevention and treatment of sanitary problems in adults with chronic diseases, they usually have a lack of experience in development of psychotherapeutic interventions. However, these interventions are the ones that achieve better results to reduce symptomatology and improve emotional state of caregivers.The study aims to evaluate the effectiveness of an intervention of psychotherapy in improving the mental health and Quality of life of caregivers. This intervention is based on theoretical approaches to care adjusted to cognitive theory, in order to be applied in primary health care centres. METHODS/DESIGN: This is multicentre clinical trials study, randomized in two parallel groups, carry out in two PHC, Study population: 150 caregivers will be included by consecutive sampling and they will be randomized the half to experimental group and the other half to control group. They provide mostly all the assistance to care-dependent familiars receiving attention in PHC Centers. MEASUREMENTS: Each caregiver will be evaluated on a personal interview. The caregivers' assessment protocol: 1) Assessment of different socio-demographic related to care, and caregiver's personal situation. 2)Care-dependent individuals will also be assessed by Barthel Index and Pfeiffer Questionnaire (SPMSQ). 3)Change in caregivers will be the principal measure: family function (Family APGAR Questionnaire), burden short questionnaire (Short Zarit Burden Interview), quality of life (Ruiz & Baca: 1993 Questionnaire), the Duke-UNK Functional Social Support Questionnaire, the General Health Questionnaire-12, and changes in Dysfunctional Thoughts about caring. 4) Intervention implementation measures will also be assessed. INTERVENTION: A psychotherapeutic intervention will be 8 sessions of 90 minutes in groups. This intervention has been initially developed for family caregivers of patients with dementia. DISCUSSION: Psychotherapeutic interventions have been proved to obtain better results to reduce symptomatology and improve emotional state of caregivers. Moreover, this intervention has been proved to be effective in a different setting other than PHC, and was developed by professionals of Mental Health. If we found that this intervention is effective in PHC and with our professionals, it would be an important instrument to offer to caregivers of care-dependent patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01177696.

[Analysis of placement in public nursing homes after hospital admission in the fragile elderly]. / Análisis del índice de consecución de residencia pública asistida tras ingreso hospitalario en ancianos frágiles.

INTRODUCTION: To analyze placement in public nursing homes in elderly inpatients referred by the social work unit. MATERIAL AND METHODS: We performed a cohort study in an acute geriatric unit of a tertiary hospital. The sociodemographic, clinical, functional and socioeconomic data registered on admission (inclusion period: 4 years) were analyzed. The patients were followed-up for 6 months after discharge. The percentage gaining places in public nursing homes, the waiting time (monthly incidence rate) and the reasons for not gaining a place were evaluated. The variables associated with gaining a place were introduced into a multivariate logistic regression model. RESULTS: A total of 415 elders were referred to public nursing homes. The mean age was 85.1 years (SD=6.7), and 61.9% were women. During the follow-up period, 72 elders were granted a place (17.3%; monthly incidence rate 3.14%). In the multivariate analysis, the factors independently associated with gaining a place at a public nursing home were living alone (OR 2.788; p=0.005), having a lower income (OR 0.807; p=0.018), having a social work report from the hospital (OR 2.132; p=0.037), having previously requested a place at a public nursing home (OR 3.298; p=0.002) and discharge destination other than the home (OR 5.792; p<0.001). The main causes associated with not gaining a place were death while on the waiting list (41.4%) and not completing the paperwork (32.9%). CONCLUSIONS: Hospitalization in the frail elderly frequently leads to requests for public nursing home admission, although few places are granted in the short term to patients in the acute unit. Certain socioeconomic factors and referral by social workers were positively associated with gaining a place. However, the waiting time leads to a substantial proportion of deaths and incomplete paperwork, largely due to the complexity of the process.

[Family function and the mental health of the caregiver of dependent relatives]. / Función familiar y salud mental del cuidador de familiares con dependencia.

OBJECTIVE: To analyse the influence of family function on the caregiver's perceived mental health. DESIGN: Cross-sectional study. SETTING: Two primary care urban health centres. PARTICIPANTS: 153 caregivers of dependent people. MEASUREMENT: Sociodemographic variables of caregiver and dependent relative and psychoactive drugs prescribed to caregiver. Caregiver questionnaires: mental health evaluated with General Health Questionnaire (GHQ-12), family function with adaptation, partnership, growth, affection and resolve (APGAR), and Duke University-University of North Carolina functional social support questionnaire. Care-recipient questionnaires: cognitive disorders with Pfeiffer and functional dependence level with Barthel. RESULTS: Caregiver's mean age was 63.8 years; 72.5% (n=111) were female; 57.5% have only primary school studies; and 37.1% take psychoactive drugs. More than 40% of the care-receivers have cognitive disorders and 49.7% have total functional impairment. According to the GHQ-12, 27% of the caregivers had mental health disorders; 31.3% of the families were dysfunctional and 32.7% had poor social support. The variables that significantly contributed to the explanation of caregiver's mental health have been: psychoactive drug intake, family function, social support and educational level. CONCLUSION: Family function is an important predictor of caregiver's mental health.

The safety and efficacy of robotic image-guided radiosurgery system treatment for intra- and extracranial lesions: a systematic review of the literature.

BACKGROUND: The CyberKnife is a new, frameless stereotactic radiosurgery system. This work reviews its safety and efficacy in the treatment of intra- and extracranial lesions. METHODS: A literature search was made of the Medline, Embase, Pascal Biomed, CINAHL and Cancerlit databases. Health technology assessment reports on stereotactic radiosurgery systems were also consulted. All searches were made in June 2007. Data on efficacy and safety were extracted and then synthesized into the present review. RESULTS: Thirty five clinical studies were identified, the majority of which included no patient comparison group. These studies assessed the use of the CyberKnife mainly in the treatment of primary and metastatic intracranial and spinal tumours. CONCLUSIONS: The CyberKnife system allows to carry out standard radiosurgical and fractionated stereotactic radiotherapy procedures. The use of this system offers an alternative for the treatment of inoperable tumours, and of lesions located close to critical structures that cannot be treated using other types of stereotactic radiosurgery system. Unfortunately, the quality of the reviewed papers still does not allow definite conclusions to be drawn regarding the safety and efficacy of these treatments.

Mitochondrial complex I gene variant associated with early age at onset in spinocerebellar ataxia type 2.

BACKGROUND: A common mitochondrial complex I gene polymorphism (10398G) is reported to be inversely associated with the risk of Parkinson disease. We hypothesized that this variant might have a protective effect on the central nervous system and therefore might delay the onset of symptoms in spinocerebellar ataxia type 2 (SCA2). OBJECTIVE: To assess the association of the 10398G polymorphism with age at onset in Cuban patients with SCA2. DESIGN: Genetic association study. SETTING: Holguin, Cuba. PATIENTS: Forty-six Cuban patients with SCA2. MAIN OUTCOME MEASURES: Presence or absence of the 10398G polymorphism was determined in 46 Cuban patients with SCA2 and early or late onset of symptoms, defined as at least 2 SDs lower than or higher than the mean age at onset for patients with a similarly sized triplet repeat expansion. RESULTS: The polymorphism was present in 11 of 27 Cuban patients with SCA2 and early onset (41%) vs 2 of 19 with late onset (11%) (Fisher exact test; P = .04). CONCLUSION: Contrary to our prediction of a later onset of SCA2 in patients with the 10398G polymorphism, we find that this variant is associated with an earlier age at onset in Cuban patients with SCA2.

Psychological follow-up of presymptomatic genetic testing for spinocerebellar ataxia type 2 (SCA2) in Cuba.

Presymptomatic testing for spinocerebellar ataxia type 2 (SCA2) in Cuba started five years ago. We have now investigated the psychological impact of test results on 150 individuals at 50% risk for SCA2. In a prospective study, psychological instruments were used to evaluate depression, anxiety and family functioning (1) before testing and (2) one year after disclosure of the test result. One year after, anxiety and depression levels decreased both in carriers and non-carriers, but anxiety decreased significantly more in carriers. Pathological levels of anxiety were seen mostly in members of dysfunctional families, but decreased more in them than in other consultands. Presymptomatic testing thus seems to have been especially beneficial for these testees, possibly due to a greater gain from the psychosocial support received. It would be pertinent to evaluate now the impact of other psychosocial variables and perform longer-term longitudinal studies.

Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice.

The objective of this work was the generation of an animal model of the SCA2 disease for future studies on the benefits of therapeutic molecules and neuropathological mechanisms that underline this human disorder. The transgenic fragment was microinjected into pronuclei of B6D2F1 X OF1 mouse hybrid strain. For Northern blots, RNAs were hybridized with a human cDNA fragment from the SCA2 gene and a mouse beta-actin cDNA fragment. Monoclonal antibody directed to the N-terminal of the ataxin 2 protein with 22Q was used for Western blot analysis. A rotating rod apparatus was utilized to measure motor coordination of mice. Immunohistochemical detection of Purkinje neurons was performed with anti-calbindin 28K as primary antibody. Ubiquitous expression of the SCA2 transgene with 75 CAG repeats regulated by the SCA2 self promoter was obtained after generation of our transgenic mice. Analysis of transgenic mice revealed significant differences of motor coordination compared with the wild type littermates. Specific degeneration of Purkinje neurons and transgene over-expression in the brain, liver and skeletal muscle, rather than in lungs and kidneys was also observed, resembling the expression pattern of the ataxin 2 in humans.

Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset.

Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.