10 research outputs found
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation
Violencia de género en mujeres con consumo de sustancias ingresadas en el hospital general: cribado y prevalencia
La violencia de género (VG) es un problema de salud pública a escala mundial. Existen determinados factores asociados a un aumento de la prevalencia, como el consumo de sustancias. Se realizó un estudio transversal con el objetivo de determinar la prevalencia de VG en las mujeres que ingresaron en el Hospital del Mar (Barcelona) por cualquier motivo médico/quirúrgico y con el diagnóstico de trastorno por consumo de sustancias. Secundariamente, se pretendió validar la versión en español del cuestionario Hurt, Insulted, Threatened with Harm, Screamed (HITS). Se evaluaron a todas las pacientes mediante dos cuestionarios de detección de VG, el Composite Abuse Scale (CAS) y el HITS. De las 52 pacientes entrevistadas durante el período de estudio, 46 respondieron ambos cuestionarios. Según el cuestionario CAS, 23 pacientes (50%) presentaron VG alguna vez en la vida y 11 (23,9%) en el último año. El consumo de cannabis se asoció a una mayor gravedad de la VG (IC95% 3,5-28,9, p = .013). La prevalencia de VG, según el HITS, fue de 39,1% (18 pacientes) en los últimos 12 meses. El HITS mostró en relación al CAS una especificidad del 100% y una sensibilidad del 78%. Un punto de corte x∈ [6,7], obtenido mediante el análisis ROC, fue el que mejor discriminó al 91% de las víctimas y al 100% de las no-víctimas. Los resultados obtenidos demostraron una elevada prevalencia de VG entre las mujeres consumidoras de más de una sustancia de abuso. Por ese motivo, se recomienda incorporar el cribado sistemático mediante el cuestionario HITS.Intimate partner violence (IPV) is a public health problem worldwide. Several factors have been found to be associated with an increased prevalence of IPV, such as substance use. A cross-sectional study was conducted with the aim of determining the prevalence of IPV among women entering Hospital del Mar (Barcelona) for any medical/surgical reason, and who had a diagnosis of substance use disorder. Secondly, it was intended to psychometrically validate the Spanish version of the Hurt, Insulted, Threatened with Harm, Screamed (HITS) questionnaire. All patients were assessed by two IPV questionnaires, the Composite Abuse Scale (CAS) and HITS. Out of 52 patients interviewed, 46 answered both questionnaires. According to the CAS questionnaire, 23 patients (50%) experienced IPV at some point in their lives and 11 (23.9%) in the last year. Cannabis consumption was also associated with an increased severity of IPV (95% CI 3.5-28.9, p = .013).According to the HITS questionnaire, there was a prevalence of 39.1% (18 patients) in the last 12 months. HITS had a specificity of 100% and a sensitivity of 78% relative to the CAS questionnaire. A cut-off score x∈ [6.7], derived through ROC analysis, correctly discriminated 91% of the victims and 100% of the non-victims. The results obtained showed that the prevalence of IPV was very high among women who suffered from more than one substance use disorder. Therefore, it is highly recommended to systematically screen for IPV victimization by putting the HITS questionnaire into practice.Este trabajo fue parcialmente financiado por el proyecto: RD12/0028/009 del Fondo de Investigaciones Sanitarias, Instituto Carlos III-FEDER y la AGAUR (2014 SGR790
Terapia grupal basada en mindfulness en pacientes con alucinaciones auditivas crónicas. estudio de tres casos .
Este estudio tiene como objetivo principal evaluar la eficacia de un programa piloto de intervención grupal basada en atención plena (mindfulness) en un grupo reducido de pacientes que presentan alucinaciones auditivas crónicas y resistentes a la medicación, independientemente de su diagnóstico principal. Se trata de un estudio empírico de intervención psicológica basado en un diseño pre-post con un solo grupo (de cohorte). La intervención consistió en una propuesta de terapia basada en mindfulness adaptado a la psicosis en base a la literatura disponible, con una duración de 8 sesiones de 90 minutos cada una, incluyendo meditaciones guiadas y trabajo de introspección metacognitiva. Se realizó una evaluación pre y post intervención con la Psychotic Symptom Rating Scale (PSYRATS), separadas por 10 semanas. Un total de 9 pacientes ambulatorios fueron reclutados, de los cuales 3 completaron el estudio. Los resultados muestran un cambio clínicamente significativo en la relación de los pacientes con sus voces, que se refleja en una reducción de la cantidad de angustia, la duración, la intensidad, la cantidad de contenido negativo y la interferencia que provocan en su vida cotidiana. Asimismo, aumentó la percepción de control sobre las voces. Los resultados apoyan el mindfulness como herramienta terapéutica prometedora en pacientes con alucinaciones auditivas crónicas, y apuntan a la necesidad de trabajos con grupos más amplios y diseños de investigación más complejos
Violencia de género en mujeres con consumo de sustancias ingresadas en el hospital general: cribado y prevalencia
La violencia de género (VG) es un problema de salud pública a escala mundial. Existen determinados factores asociados a un aumento de la prevalencia, como el consumo de sustancias. Se realizó un estudio transversal con el objetivo de determinar la prevalencia de VG en las mujeres que ingresaron en el Hospital del Mar (Barcelona) por cualquier motivo médico/quirúrgico y con el diagnóstico de trastorno por consumo de sustancias. Secundariamente, se pretendió validar la versión en español del cuestionario Hurt, Insulted, Threatened with Harm, Screamed (HITS). Se evaluaron a todas las pacientes mediante dos cuestionarios de detección de VG, el Composite Abuse Scale (CAS) y el HITS. De las 52 pacientes entrevistadas durante el período de estudio, 46 respondieron ambos cuestionarios. Según el cuestionario CAS, 23 pacientes (50%) presentaron VG alguna vez en la vida y 11 (23,9%) en el último año. El consumo de cannabis se asoció a una mayor gravedad de la VG (IC95% 3,5-28,9, p = .013). La prevalencia de VG, según el HITS, fue de 39,1% (18 pacientes) en los últimos 12 meses. El HITS mostró en relación al CAS una especificidad del 100% y una sensibilidad del 78%. Un punto de corte x∈ [6,7], obtenido mediante el análisis ROC, fue el que mejor discriminó al 91% de las víctimas y al 100% de las no-víctimas. Los resultados obtenidos demostraron una elevada prevalencia de VG entre las mujeres consumidoras de más de una sustancia de abuso. Por ese motivo, se recomienda incorporar el cribado sistemático mediante el cuestionario HITS.Intimate partner violence (IPV) is a public health problem worldwide. Several factors have been found to be associated with an increased prevalence of IPV, such as substance use. A cross-sectional study was conducted with the aim of determining the prevalence of IPV among women entering Hospital del Mar (Barcelona) for any medical/surgical reason, and who had a diagnosis of substance use disorder. Secondly, it was intended to psychometrically validate the Spanish version of the Hurt, Insulted, Threatened with Harm, Screamed (HITS) questionnaire. All patients were assessed by two IPV questionnaires, the Composite Abuse Scale (CAS) and HITS. Out of 52 patients interviewed, 46 answered both questionnaires. According to the CAS questionnaire, 23 patients (50%) experienced IPV at some point in their lives and 11 (23.9%) in the last year. Cannabis consumption was also associated with an increased severity of IPV (95% CI 3.5-28.9, p = .013).According to the HITS questionnaire, there was a prevalence of 39.1% (18 patients) in the last 12 months. HITS had a specificity of 100% and a sensitivity of 78% relative to the CAS questionnaire. A cut-off score x∈ [6.7], derived through ROC analysis, correctly discriminated 91% of the victims and 100% of the non-victims. The results obtained showed that the prevalence of IPV was very high among women who suffered from more than one substance use disorder. Therefore, it is highly recommended to systematically screen for IPV victimization by putting the HITS questionnaire into practice.Este trabajo fue parcialmente financiado por el proyecto: RD12/0028/009 del Fondo de Investigaciones Sanitarias, Instituto Carlos III-FEDER y la AGAUR (2014 SGR790
Clinical manifestations of intermediate allele carriers in Huntington disease
Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589
Clinical and genetic characteristics of late-onset Huntington's disease
Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients
Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study
Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis