European Huntington's Disease Network Research Articles

Quinn L, Khalil H, Dawes H, et al; for the Outcome Measures Subgroup of the European Huntington's Disease Network. Reliability and minimal detectable change of physical performance measures in individuals with pre-manifest and manifest Huntington disease. Phys Ther. 2013;93:942–956.

Quinn L, Khalil H, Dawes H, et al; for the Outcome Measures Subgroup of the European Huntington's Disease Network. Reliability and minimal detectable change of physical performance measures in individuals with pre-manifest and manifest Huntington disease. Phys Ther. 2013;93:942–956.

The V471A Polymorphism in Autophagy-Related Gene ATG7 Modifies Age at Onset Specifically in Italian Huntington Disease Patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

Suicidal ideation in a European Huntington's disease population

BackgroundPrevious studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. MethodsThe study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. ResultsAt baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9–1.0), anxiety (OR=2.14; 95%CI: 1.4–3.3), aggression (OR=2.41; 95%CI: 1.5–3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4–6.6), and a depressed mood (OR=13.71; 95%CI: 6.7–28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1–4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2–5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LimitationsAs suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. ConclusionsSuicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.

Better global and cognitive functioning in choreatic versus hypokinetic‐rigid Huntington's disease

Understanding the relation between predominantly choreatic and hypokinetic-rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntington's disease. In the European Huntington's Disease Network Registry study, 1882 subjects were classified as being predominantly choreatic (n=528) or hypokinetic-rigid (n=432), according to their scores on items of the total motor score a priori labeled as choreatic or hypokinetic-rigid; the other 922 patients were of a mixed type. The relationship between motor type and cognitive (verbal fluency, symbol digit modalities, Stroop color, word and interference tests) and functional (total functional capacity) capacity was investigated using multiple linear regression. Motor subtype contributed significantly to the total functional capacity score (partial r(2) : 7.8%; P<.001) and to the 5 cognitive scores (partial r(2) ranged from 2.0% to 8.4%; all P<.001). Patients with a predominantly choreatic motor phenotype performing better in all areas than patients with a hypokinetic-rigid motor phenotype.

M04 European huntington's disease network registry: current status

BackgroundThe European Huntington's disease Network's (EHDN) REGISTRY is an observational, prospective, longitudinal, multi-national, multi-centre cohort study of Huntington's disease (HD). It is the largest study of HD to date, and...

K05 Suicidality in a European huntington's disease population

BackgroundThe suicide risk in Huntington's disease (HD) is 4–8 times higher compared to the general population, and the prevalence of suicidality (suicidal thoughts and attempts) in HD is also increased....

Current Pharmacological Management in Juvenile Huntington's Disease.

Background: The clinical presentation of Juvenile Huntington’s Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management.Aim: To survey the current use of pharmacological treatments for JHD.Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington’s Disease Network REGISTRY study.Results: The most commonly prescribed agents were anti-psychotics (24/45), anti-depressants (17/45) and anti-parkinsonian medications (15/45). 5 patients were taking more than 8 medications.Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple therapies, highlighting the need to rationalise medications.

NMDA receptor gene variations as modifiers in Huntington disease: a replication study

Several candidate modifier genes which, in addition to the pathogenic CAG repeat expansion, influence the age at onset (AO) in Huntington disease (HD) have already been described. The aim of this study was to replicate association of variations in the N-methyl D-aspartate receptor subtype genes GRIN2A and GRIN2B in the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). The analyses did replicate the association reported between the GRIN2A rs2650427 variation and AO in the entire cohort. Yet, when subjects were stratified by AO subtypes, we found nominally significant evidence for an association of the GRIN2A rs1969060 variation and the GRIN2B rs1806201 variation. These findings further implicate the N-methyl D-aspartate receptor subtype genes as loci containing variation associated with AO in HD.

Discrepancies in reporting the CAG repeat lengths for Huntington's disease.

Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.

Age-at-onset in Huntington disease.

Background: In Huntington disease, the accurate determination of age-at-onset is critical to identify modifiers and therapies that aim to delay it. Methods: Retrospective data from the European Huntington’s Disease Network’s REGISTRY and PREDICT-HD, a longitudinal study in prodromal huntingtin gene expansion mutation carriers. Data (age, gender, CAG repeat length, parent affected, and Unified Huntington’s Disease Rating Scale motor score, total functional capacity) from at least three visits in 423 REGISTRY and 124 PREDICT-HD participants were included. Data based extrapolations of individual age-at-onset using generalized linear mixed models based on individual slopes of motor score or total functional capacity, and predictions using the Langbehn, or Ranen formula, were compared with clinicians’ estimates. Results: Concordance was best for the observed age-at-onset in PREDICT-HD and the calculated onset using the PREDICT-HD UHDRS longitudinal motor scores. This was superior to the REGISTRY data. For total functional capacity, the investigator’s estimate was 4 years before the data derived age-at-onset. The concordance of predictions of probability of age-at-onset is better with the observed age-at-onset in the PREDICT-HD data (difference in 25%tile -5 to 10 years) than the REGISTRY data (±20 years). Conclusions: Estimating or predicting age-at-onset in Huntington disease may be inaccurate. It can be useful to 1) add in the manifest population motor score regression derived age-at-onset as additional motor onset and 2) add total functional capacity regression derived age-at-onset for the onset of functional impact of Huntington disease when patients are in mid- to late-stage.

Utilisation of Healthcare and Associated Services in Huntington’s disease: a data mining study

Background: People with Huntington’s disease (HD) often require tailored healthcare and support packages that develop as the disease progresses. The Client Service Receipt Inventory (CSRI) gathers retrospective information on service utilization. This study investigated the use of formal services and informal care as measured by the CSRI and explored associations between informal care, disease severity and functional ability as measured by the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS) and functional scales. Methods: All monitored longitudinal data from annual clinical assessments of UHDRS-TMS and functional assessments and CSRI collected under the auspices of the European Huntington’s Disease Network (EHDN) REGISTRY study between the years 2004 and 2009 were utilised in the analyses. Disease severity was reflected by UHDRS-TMS. Functional ability was measured using the UHDRS functional scales. CSRI data were analysed according to percentage use of individual formal services and total estimated hours per week of informal care. Regression analyses were conducted to identify any associations between disease severity, functional ability and hours of informal care.Results: 451 HD patients (212 female; 239 male) completed one visit; 105 patients (54 females; 51 males) completed two visits and 47 patients (20 females; 27 males) completed three visits in total over the 5 year period. The mean time between visits was 1.2 years. At visit one, 74% of the participants reported being in receipt of at least one formal hospital-based service in the previous six months, and 89% reported receipt of formal primary and community care services. In contrast, at the third visit, 62% of people had used hospital based services and 94% formal community based services in the previous six months. Fifty % of individuals required some form of informal care in the home at visit 1; this increased to 68% at visits 2 and 3. The mean (SD) estimated weekly total informal care hours at visits 1, 2 and 3 were 32.8 (49.4); 21.6 (53.6) and 21.3 (62.4) respectively. Only the scores on the Functional Assessment Scale (FAS) accounted for the variance in the weekly total informal care hours at each visit. Conclusions: Although it must be acknowledged that service use is supply driven, most HD patients across Europe surveyed as part of this study were in receipt of formal primary and community care services and to a lesser extent formal hospital based services. There was however a large reliance on informal care in the home. The FAS appear to have predictive value on informal care requirements and may have utility in facilitating pro-active service provision and in particular when managing carer burden in this population.

F02 Observing Huntington's disease (HD): the European Huntington's Disease Network's REGISTRY

BackgroundHD is relatively rare. Thus we need advanced, multi-centre, multi-national research frameworks to study simultaneously multiple complementary aspects of HD.Methods/techniquesFirst cross-sectional data cut of the first 1766 participants from 13...

J10 Speech and language therapy guidelines for Huntington's disease patients

BackgroundSpeech and Language Therapy (SLT) has an important role in the management of Huntington's disease (HD). During the progression of the disease, HD patients will experience communication problems, language difficulties,...

J01 EHDN standards of care occupational therapy guidelines

BackgroundOccupational Therapy is an essential component of the management of patients with Huntington's disease throughout the progression of the disease. Occupational therapists aim to enable individuals to maximise function in...

F01 The European HD Network REGISTRY: Current status and future directions

BackgroundThe European Huntington's Disease Network's (EHDN) REGISTRY is an observational, prospective, longitudinal, multi-national, multi-centre cohort study of Huntington's disease (HD). It is the largest study of HD to date, and...

D02 Discrepancies in reporting the upper CAG repeat allele between a central EHDN and local laboratories for centres participating in the REGISTRY project

AimThe European Huntington's Disease Network REGISTRY project analyses CAG repeat length measurements centrally which can be compared with the original laboratory result held at the local study site from 15...

J07 Guidelines for the oral health of adults with Huntington's disease

BackgroundA small group of dental professionals interested in the Oral Health Care of people with Huntington's disease were invited by the European Huntington's Disease Network to provide guidelines for Oral...

F06 Late-stage huntington's disease (HD): a cohort from the European HD network

BackgroundFew data is available regarding most advanced stages of HD.AimsTo describe clinical manifestations, medication use and caregivers’ burden in late-stage HD (LS-HD).Patients and methodsLS-HD patients were extracted from the database...

L01 Global site and investigator database (GSID-HD): a new tool to promote research collaboration and manage efficient clinical trials in Huntington's disease

BackgroundA global comprehensive database of sites and investigators does not exist. The Huntington Study Group (HSG) has a database of member sites and the European HD Network (EHDN) maintains site...

Poster 28: Delphi Process for the Development of Treatment Guidelines for Behavioral Symptoms and Chorea in Huntington's Disease

Background Despite large gaps in evidence-based knowledge, clinical experience supports the use of pharmacologic treatments for many symptoms of Huntington's disease (HD). The project goal is to develop consensus guidelines based on expert clinical experience that will improve the quality of HD care. Methods/Techniques The Delphi process, which provides an iterative formal strategy to gather expert opinion and form a consensus, was utilized. First steps of this process explored expert prescribing patterns. Step 1: Nine experts from Huntington's Study Group and European HD Network created initial statements for irritability, obsessive/compulsive behaviors (O/Cs), and chorea. Step 2: Statements were submitted via a web survey to a panel of 40 additional experts. Results Thirty expert neurologists and psychiatrists from Europe and North America responded. For irritability there was lack of consensus in first choice and in sequence of drugs used in combination therapy. For O/Cs there was high agreement (>80%) on SSRI as first choice; however, there was lack of consensus on adjuvant drug therapy. For chorea there was agreement that it should be treated when quality of life or ADL is affected, but there was lack of consensus on drug of first choice. The next round of the Delphi consensus process will begin in November of 2009. Conclusions Many areas of variability in the treatment for irritability, O/Cs, and chorea in HD, even among expert clinicians, have been identified. Results will guide future rounds of the Delphi process to elicit rational causes for the differences identified. Collection of further data on consensus will begin in November of 2009. When complete, this process will clarify useful treatment paradigms that will improve patient care and identify areas in which clinical trials would be most useful.