Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY

Background: Huntington's disease (HD) is a rare triplet repeat (CAG) disorder. Advanced, multi-centre, multi-national research frameworks are needed 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. Methods: We report on cross-sectional data of the first 1766 participants in REGISTRY, the European Huntington's Disease Network's (EHDN), multi-lingual, multi-national prospective observational study of HD in Europe. Data collection (demographics, phenotype, genotype, medication, co-morbidities, biosamples) followed a standard protocol. Results: Phenotype, and the HD genotype, of manifest HD participants across different European regions was similar. Motor onset was most common (48%) with a non-motor onset in more than a third of participants. Motor signs increased, and cognitive abilities and functional capacity declined as the disease burden (CAGn-35.5) X age) increased. A life-time history of behavioural symptoms was common, but the behavioural score was not related to disease burden. One fifth of participants had severe psychiatric problems, e.g. suicidal ideation and attempts, and/or irritability/aggression, with psychosis being less common. Participants on anti-dyskinetic medication had a higher motor and lower cognitive score, were older, and more prone to physical trauma. A higher motor and a lower cognitive score predicted more advanced disease. Conclusions: The unparalleled collection of clinical data and biomaterials within the EHDN's REGISTRY can 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.

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 5e8/100 000, 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; http://www.euro-hd.net), 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 premanifest HD expansion mutation carriers, individuals at risk of HD, non-mutation gene carriers and controls (no family history of HD) (figure 1  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 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 (http://www.euro-hd.net) where a username determines access rights within the web portal. Entries for medication are coded according to the Anatomical Therapeutic Chemical classification (http:// www.whocc.no/atcddd), 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 analysed 5 (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 (k¼0.98). Mid stream urine samples are collected. DNA and urine are stored at À808C.
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. Neuronal intermediate filament inclusion disease (NIFID) is a neurodegenerative disorder of a heterogeneous clinical phenotype, encompassing behavioural changes, language impairment, perseveration, executive dysfunction with or without early onset dementia, extrapyramidal features, and subclinical or clinical involvement of upper and lower motor neurons, with age at onset of reported cases ranging from 23 to 56 years (table 1). 1e5 NIFID was initially characterised neuropathologically on the basis of intraneuronal cytoplasmic inclusions of variable morphology which immunostained for all class IV intermediate filament (IF) proteins, namely NF-H, NF-M, NF-L and alpha-internexin. 1e3 5 More recently it has been shown that a much larger proportion of the inclusions in NIFID are immunoreactive with the fused in sarcoma (FUS) protein than with IF, 6 leading to changes in the suggested nomenclature. 7 8 We present a further case demonstrating the broad phenotypic features, overlapping with both corticobasal degeneration and motor neuron disease.
A 62-year-old right-handed woman presented with a 2-year history of progressive difficulty with coordination and balance. She noticed weak grip and poor coordination in her right hand when playing tennis and had difficulty assembling familiar scuba diving equipment. She developed involuntary twitching of the fingers in the right hand and heaviness in the right arm. Over the next few months asymmetric leg weakness (right > left) developed, with difficulty initiating gait and climbing stairs with occasional falls. Dysarthria also became apparent, conversation became more laborious and her writing became smaller.
Examination showed bradykinesia and cogwheel rigidity in the right arm but no rest tremor. Myoclonic jerks were seen in the right little and index fingers, and there was exaggerated response to startle and sound. Neither muscle wasting nor fasciculations were seen; power was preserved. Reflexes were globally brisk with bilateral downgoing plantars. All modalities of sensation were normal. Gait showed slow initiation and wide base. The clinical picture of an asymmetric akineticerigid syndrome with some pyramidal features and myoclonus was thought most in keeping with a corticobasal syndrome. 9 Salient findings on investigation were elevated creatine kinase (620 U/l, normal <175), normal MR brain imaging, EEG and CSF analysis. Formal neuropsychological assessment showed no evidence of cognitive decline. EMG showed active denervation and fasciculations in all limbs and paraspinal muscles. Hence the investigations indicated a subclinical anterior horn cell disorder typical of motor neuron disease.
Symptoms progressively deteriorated over the next 2 years. Although clonazepam improved the myoclonus, the extrapyramidal syndrome was levodopa unresponsive and the patient became wheelchair bound.