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Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY
  1. Michael Orth,
  2. The European Huntington 's Disease Network
  1. Correspondence to M Orth, Department of Neurology, Universitätsklinikum Ulm, Oberer Eselsberg 45/1, 89081 Ulm, Germany; michael.orth{at}

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. HD usually manifests in adult life, causing motor impairments, cognitive decline and behavioural/psychiatric alterations. HD is devastating and inevitably fatal; currently, no disease modifying treatment is established.1

Historically, the study of HD has benefited strikingly from multicentre research initiatives, typified by the international collaborative effort that identified the causative CAG repeat expansion in the HTT gene in 1993.2 Much effort at present is focused on identifying therapeutic targets and developing treatments that may delay onset of the disease, or slow down or stop the progression of HD once it manifests. With a prevalence of 5–8/100 000, manifest HD is relatively rare. Thus we need advanced, multicenter, multinational research frameworks that allow us to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research. The European Huntington's Disease Network (EHDN;, established in 2004, is a collaborative network of HD researchers, HD clinicians, people affected by HD and their relatives. It strives to lay the foundations on which to advance knowledge about HD, how to optimally assess disease progression and factors that modify the phenotype. This initiative aims to develop new symptomatic therapies and provide the infrastructure to test rapidly putative disease modifying treatments in a multicentre, multinational setting with the ultimate goal of improving the quality of life of people affected by the disease.

REGISTRY is EHDN's core observational study. REGISTRY is a multicentre, prospective, observational study with annual follow-up visits that enrols manifest and pre-manifest HD expansion mutation carriers, individuals at risk of HD, non-mutation gene carriers and controls (no family history of HD) (figure 1). Participants give informed written consent according to the International Conference on Harmonisation–Good Clinical Practice (ICH-GCP) guidelines ( For participants who lack the capacity to consent, study sites adhere to country specific guidelines for obtaining consent. Minors assent with both parents consenting for them. Ethics approval was obtained from the local ethics committee for each study site contributing to REGISTRY. Data collection uses electronic case report forms available in Czech, Danish, Dutch, English, Finnish, French, German, Italian, Norwegian, Polish, Portuguese, Spanish, Swedish and Russian. At each study site, clinicians with longstanding experience in HD take a careful history and examine patients clinically; motor, psychiatric and cognitive signs are scored using the Unified Huntington's Disease Rating Scale (UHDRS).3 Assessments are complemented by self-rating scales that probe mood, quality of life and health economics (for an overview see figure 1). Disease stage is derived from the total functional capacity scores.4

Figure 1

Flowchart illustrating REGISTRY study design. SF-36, Short Form-36; TFC, total functional capacity; UHDRS, Unified Huntington's Disease Rating Scale.

All participants are assigned a nine digit pseudonym created using a secure one way hash algorithm. No identifying data are stored on the EHDN server. Data are entered online using an electronic web based data capture system ( where a username determines access rights within the web portal. Entries for medication are coded according to the Anatomical Therapeutic Chemical classification (, and co-morbidities are coded according to ICD-10. Data entry onto the web portal is subject to automatic plausibility checks. In addition, study site raters are annually trained, assessed and certified to reduce inter- and intra-rater variability. Following data entry, data are monitored online and on site by monitors fluent in the language of the contributing study site. Data monitoring adheres to the principles laid out in ICH-GCP.

Blood is collected and shipped to BioRep at room temperature for genetic analysis and lymphoblastoid cell line creation (BioRep, Milan, Italy). DNA is extracted, and HTT gene CAG repeat length analysed5 (PCR amplification followed by capillary electrophoresis using the MegaBace Fragment Profiler Software from General Electric, Buckinghamshire, UK). A second independent accredited laboratory in Tübingen, Germany, duplicated CAG repeat analyses (Applied Biosystems, California, USA) in 342 DNA samples for quality control. Comparisons between BioRep and Tübingen resulted in agreement of 99% with respect to CAG expansion size for the larger and smaller allele: only 3/342 size determinations for the larger allele differed by two or more repeats (κ=0.98). Mid stream urine samples are collected. DNA and urine are stored at −80°C.

To date (August 2010), REGISTRY includes 6476 participants from 136 study sites in 16 countries. Of these, 663 are pre-manifest, defined as carrying the HD gene mutation and having a diagnostic confidence score of less than 4 on the UHDRS motor scale,3 and 375 are spousal or companion controls. On 3473 participants, data from at least two visits, and on 2057 participants, data from at least three visits, are available. CAG repeat information from the local laboratory is present in 5183 participants. BioRep has so far isolated DNA from whole blood in 4510 participants with CAG repeat measurements available from 3306. A total of 4053 lymphoblastoid cell lines have been established.

The strength of our study is the large number of participants with data collected across Europe following the same study protocol. We demonstrate that such studies can be conducted effectively across different countries and multiple languages. In addition, investigators are regularly trained and certified to improve data quality. REGISTRY, unlike many observational clinical research initiatives, engages data monitoring based on the principles of ICH-GCP. Participating sites are visited regularly by a team of trained monitors in order to ensure the plausibility and accuracy of the data, and to promote adherence to the study protocol and its procedures. Data monitoring is not a prerequisite for cohort studies but it is an investment to enhance the collection of more robust and reliable data. The unparalleled large collection of clinical data and biomaterials in REGISTRY will enable research projects to be conducted on a scale that has not previously been possible. The initiative will expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments, thus offering a promising new direction towards slowing down or preventing this debilitating disease.


We wish to acknowledge the time and effort of all participants in this study.


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  • Funding The European Huntington's Disease Network is funded by the CHDI Foundation, Inc.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of each of the contributing study sites.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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