Patients' and caregivers' perspectives: assessing an intensive rehabilitation programme and outcomes in Huntington's disease

Aim: To investigate the subjective evaluation of an intensive rehabilitation programme and outcomes by people with Huntington’s disease (HD) and their caregivers. Subjects and methods: A written questionnaire was mailed to people with mild-moderate HD (n = 40) who had completed at least one course of the intensive, inpatient rehabilitation protocol carried out at a facility of the Italian National Welfare System in the previous 3 years (on average 8.6 months before). Descriptive and inferential statistics were used. Thematic analyses were also conducted on written texts. Results: The response rate was 93%. A general improvement after discharge was perceived by all of the respondents. Improvements were reported on gait, balance, motor control, and fall reduction. Duration of benefits was estimated to last from 1 to 3 months by 71% of informants with no carry over to the next admission, which occurred on average 5.7 months later. Ameliorations were also reported in speech and swallowing, and several psychosocial aspects: mood, apathy, familiar and social relationships (binomial test, p < 0.05). As far as organisational aspects of structure and programme are concerned, all respondents expressed a positive evaluation (binomial test, p < 0.05). The mean vote given to the whole rehabilitation experience by patients on a 10-point scale was 7.3, confirmed by caregivers’ mean vote of 7.4. Additional free comments were added by the majority of respondents (n = 35). From caregivers’ and patient’s perspectives, relevant themes emerged. Conclusion: An intensive rehabilitation programme in people with HD is perceived to produce relevant improvements beyond bodily motor and functional performance. Patients’ and caregivers’ evaluations are relevant in health-care research in order to assess the worth of a programme and to define new ones

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

Affrontare il rischio genetico e preservare la speranza. Storia e risultati di un modello di collaborazione tra ricercatori, medici e famiglie con Malattia di Huntington

E' nella natura umana spaventarsi di più di ciò che si conosce meno. Ma non sempre è sufficiente dare un nome alle cose per poterle capire e “controllare”. Spesso è necessario uno sforzo ulteriore per permettere a chi ci ascolta di arrivare a una comprensione piena di ciò che si vuole trasmettere. Ci sono situazioni in cui questo sforzo diventa indispensabile.Da oltre vent’anni nel nostro laboratorio, all’Università Statale di Milano studiamo una malattia ereditaria neurodegenerativa, la Còrea di Huntington. Anche nel mio caso, la responsabilità cui mi sento ogni giorno chiamata è aprire le porte del laboratorio e raccontare la storia di questa malattia, per accrescere la consapevolezza su cosa e perché si fa ricerca e mettere ogni informazione a disposizione del cittadino, dei familiari dei malati e di chi è a rischio di svilupparla. Una responsabilità che è ben rappresentata dall’esperienza culturale di incontro e scambio tra mondo della scienza e società raccontata in questo libro, esperienza che dimostra come un’alleanza tra ricercatori, medici e famiglie sia non solo possibile, quanto auspicabile. L’Huntington è una malattia che provoca la morte dei nostri neuroni nelle aree cerebrali che controllano il movimento e alcune funzioni cognitive. Questa degenerazione dipende dalla mutazione di un singolo gene, chi ne è portatore svilupperà la malattia (in media intorno ai 40-50 anni) ed ogni figlio di una persona malata presenta il 50 per cento di possibilità di ereditare quella stessa mutazione. La diagnosi di Malattia, quindi, porta con sé una serie di implicazioni che vanno oltre il presente e legano il destino di chi la riceve alle generazioni passate e, ciò che è più doloroso, a quelle future. Il momento della diagnosi cattura ogni pensiero e, a volte, ribalta ogni prospettiva. Dopo tanti anni di ricerca su questa malattia, ancora non riesco a comprendere l’insieme della fatica quotidiana, del coraggio e della voglia di futuro che ricadono e crescono sulle spalle di questi malati e dei loro familiari, molti dei quali – a caro prezzo – costruiscono intorno a sé una vita serena e piena. Anche se, mi spiegano, i tratti della malattia restano sempre lì. In questa altalena di vita, un grande contributo arriva dai medici che accompagnano scelte e momenti critici. La diagnosi si caratterizza certamente come uno snodo fondamentale nell’esistenza dell’individuo che finisce per coinvolgere anche il medico che la comunica. Le pagine che seguono spiegano quanto il ruolo di uno psicologo, di un genetista, dell’assistenza delle associazioni possa essere d’aiuto nel vigilare sulle ricadute che una tale diagnosi può avere nella vita di ciascun individuo. Non esiste ancora una cura per l’Huntington ma, ogni giorno, emerge l’intensità del lavoro di ricerca nei tanti laboratori e ospedali del mondo interamente dedicati a questa malattia. Non c’è altro tempo, se non quello necessario per consegnare un risultato scientificamente solido e medicalmente significativo. Ogni strada scientificamente fondata può rivelarsi quella giusta, perciò deve essere perseguita. La speranza di riuscire ad aiutare non deve mai venir meno né in chi fa ricerca, né in chi quelle cure le aspetta per sé o per chi verrà dopo di lui. Ma accanto alla speranza sono necessarie strutture di sostegno e di accompagnamento, anche economico. L’esperienza raccontata nel libro ci aiuta a comprendere quanto l’assistenza sia oggi minima e frammentata, quando non superficiale, nonostante viviamo nella parte più avanzata e fortunata del mondo. Mentre si seguono i risultati della ricerca scientifica, c’è un dovere sociale che ci vede coinvolti e che Gioia Jacopini, Marina Frontali e le altre autrici di questo volume ci invitano a ricordare: il dovere di riconoscere chi ci sta di fronte non come “portatore di una mutazione genetica”, ma come individuo che ha il diritto di comprendere, decidere e conservare dignità e speranza. Un sociologo francese, tempo fa, rimase stupito del rapporto diretto che, in laboratorio, abbiamo sviluppato con i malati e le famiglie. Non ci siamo mai domandati se fosse una cosa giusta o meno, perché ne sentiamo la responsabilità. Sono parte del lavoro che facciamo, la nostra motivazione, il nostro obiettivo. E a loro, al loro incitamento e alla loro paziente comprensione dei nostri tempi e della nostra fatica dobbiamo tutto. Procediamo insieme, affinché possa arrivare il giorno in cui al nome della malattia possa immediatamente corrispondere una valida proposta terapeutica

Effects of an intensive rehabilitation programme on patients with Huntington's disease: a pilot study

To investigate the effects of an intensive, inpatient rehabilitation programme on individuals affected by Huntington's disease

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;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 &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.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 &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.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

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