Huntington disease is devastating to patients and their families - with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course, and a combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confer toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death. In this Primer, we review the epidemiology of Huntington disease, noting that prevalence is higher than previously thought, geographically variable and increasing. We describe the relationship between CAG repeat length and clinical phenotype, as well as the concept of genetic modifiers of the disease. We discuss normal huntingtin protein function, evidence for differential toxicity of mutant huntingtin variants, theories of huntingtin aggregation and the many different mechanisms of Huntington disease pathogenesis. We describe the genetic and clinical diagnosis of the condition, its clinical assessment and the multidisciplinary management of symptoms, given the absence of effective disease-modifying therapies. We review past and present clinical trials and therapeutic strategies under investigation, including impending trials of targeted huntingtin-lowering drugs and the progress in development of biomarkers that will support the next generation of trials. For an illustrated summary of this Primer, visit: http://go.nature.com/hPMENh.
Clinical decision making for Parkinson's disease patients is supported by a combination of three distinct information resources: best available scientific evidence, professional expertise, and the personal needs and preferences of patients. All three sources have clear value but also share several important limitations, mainly regarding subjectivity, generalizability and variability. For example, current scientific evidence, especially from controlled clinical trials, is often based on selected study populations, making it difficult to translate the outcome to the care for individual patients in everyday clinical practice. Big data, including data from real-life unselected Parkinson populations, can help to bridge this information gap. Finegrained patient profiles created from big data have the potential to aid in identifying therapeutic approaches that will be most effective given each patient's individual characteristics, which is particularly important for a disorder characterized by such tremendous interindividual variability as Parkinson's disease. In this viewpoint, we argue that big data approaches should be acknowledged and harnessed, not to replace existing information resources, but rather as a fourth and complimentary source of information in clinical decision making, helping to represent the full complexity of individual patients. We introduce the 'quadruple decision making' model and illustrate its mode of action by showing how this can be used to pursue precision medicine for persons living with Parkinson's disease.
BackgroundIn a rare disorder such as Huntington’s disease (HD) a global network of clinical trial sites with access to patients speeds up recruitment into clinical trials.AimsTo test the hypothesis that demographics, HTT genotype, clinical spectrum and progression are similar in HD participants of two large observational HD studies, the European Huntington’s Disease Network’s European REGISTRY study and the North American COHORT study.MethodsREGISTRY cross-sectional data were available from a total of 7,398 participants (1,125 (15.2%) premanifest, 6,273 (84.8%) manifest HD). COHORT cross-sectional data from 1,499 participants at 44 study sites were available (175 pre-HD (11.7%), 1,324 manifest HD (88.3%)). Participants were assessed clinically using the Unified Huntington’s Disease Rating Scale (UHDRS). Longitudinal data was available for total motor score or cognitive performance in more than 50% of REGISTRY participants and more than 70% of COHORT participants.ResultsDemographics, HTT genotypes, phenotype and progression, were similar in the two studies. Patients in Europe were prescribed anti-dyskinetics more frequently, and anti-depressants less frequently, than in North America. In either study, participants on anti-dyskinetic medication had higher UHDRS total motor scores, worse function assessment scores and worse cognitive scores than those taking anti-depressants or no medication. In contrast, motor, function assessment and cognitive scores were broadly similar in participants taking anti-depressants or no medication. The differences in cognitive performances between languages were small.ConclusionsOur data suggest that HD patients, and the way they are assessed, are similar across two continents with different cultures and languages.
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