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

Formando profesionales sanitarios en tiempos difíciles: resiliencia vs resistencia

Proyecto realizado en colaboración con la Fac. CC Agropecuarias Medicina Veterinaria, Univ. Católica de Córdoba (Argentina).Cuando todo se derrumba porque un virus o un invasor desdibujan el equilibrio global, formarse en tiempo presente continuo es todo un desafío para el estudiante. Cuando la incertidumbre impera y enraiza en el tiempo, su proyecto de futuro se ve amenazado y se difumina. El agotamiento emocional y mental, la frustración y la hipervigilancia le empujan hacia la ira reactiva o hacia la angustia vital, el derrotismo y el desaliento. La comunicación en redes sociales cibernéticas, la inmediatez y la necesidad de estar en permanente conexión, lejos de dar apoyo, les aboca hacia la infoxicación y el doomscrolling. “Una adversidad es una herida que se escribe en nuestra historia, pero no es el destino” (Cyrulnik, 2001). La libertad de elección de acción y la capacidad de aceptación, están unidas a la información racional, a la formación y a la puesta en práctica de nuestros valores nucleares (perspectiva eudaimónica de la felicidad). Al conectar nuestras motivaciones con nuestros valores, podemos ayudarnos a desarrollar una mayor resiliencia cuando las circunstancias vitales son difíciles. El compromiso mantenido a largo plazo y en lucha contra las amenazas externas, unido a la presión social y la frustración, puede causar fatiga emocional y agotamiento psicológico en estudiantes y en personal de administración y servicios (PAS) docente e investigador (PDI). Con tres dimensiones: baja realización personal, agotamiento emocional y despersonalización. La OMS ha decidido introducir en la CIE-11 (en vigor 1/1/2022) el “síndrome del trabajador quemado” como un “fenómeno ocupacional”. La lucha frente a la pandemia ha demostrado los efectos de “cuidar de uno mismo y de los demás”, un aprendizaje inferencial permitiría a los estudiantes empoderase para cuidar de su propia salud mental y prestar apoyo a los demás. El escenario globalizante de crisis mundial, genera en sí mismo la posibilidad de transformar la amenaza en una oportunidad. La oportunidad de trabajar la ecuanimidad, la vulnerabilidad y la impermanencia, y de promover el cultivo de la compasión, la aceptación activa y el afrontamiento resiliente, como antídotos contra la desesperanza, la sobreidentificación, el distrés empático y la indolencia, y como fuente de bienestar y salud psicoemocional. Nos está tocando convivir con respuestas que atentan contra los derechos humanos. Ante ellas: compasión activa y resiliencia. “Si nada nos salva de la muerte, por lo menos que el amor nos salve de la vida” (Pablo Neruda). Intervención psicoeducativa en línea con ODS3 (Salud y bienestar), ODS5 (Igualdad de género) y ODS16 (Paz y justicia), de la ONU en su Agenda 2030.UCM- Vicerrectorado de CalidadDepto. de Farmacología y ToxicologíaFac. de VeterinariaFALSEsubmitte

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