The differential diagnosis of chorea

Chorea is a hyperkinetic movement disorder characterised by excessive spontaneous movements that are irregularly timed, randomly distributed and abrupt. In this article, the authors discuss the causes of chorea, particularly Huntington's disease and the genetic syndromes that may resemble it, including HDL1-3, inherited prion disease, spinocerebellar ataxias 1, 3 and 17, neuroacanthocytosis, dentatorubro-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders, Wilson's disease, benign hereditary chorea, Friedreich's ataxia and mitochondrial disease. Acquired causes of chorea include vascular disease, post-infective autoimmune central nervous system disorders (PANDAS), drugs, systemic lupus erythematosus, antiphospholipid syndrome, thyrotoxicosis, AIDS, chorea gravidarum, and polycythaemia rubra vera. The authors suggest an approach to the clinical assessment of chorea, the value of investigations, including genetic tests (for which they offer a structured framework highlighting the importance of prior counselling), and finally briefly discuss symptomatic drug treatment of chorea

Biomarkers for Huntington's disease: an update

Huntington's disease (HD) is a devastating autosomal-dominant neurodegenerative condition caused by a CAG repeat expansion in the gene encoding huntingtin which is characterised by progressive motor impairment, cognitive decline and neuropsychiatric disturbances. There are currently no disease-modifying treatments available to patients, but a number of therapeutic strategies are currently being investigated, chief among them are nucleotide-based 'gene silencing' approaches, modulation of huntingtin post-translation modification and enhancing clearance of the mutant protein. In 2008, the authors' review highlighted the need to develop and validate biomarkers and provided a systematic head-to-head comparison of such measures. They searched the PubMed database for publications, which covered each of the subheadings mentioned below. They identified from these list studies which had relevance to biomarker development, as defined in their previous review. Building on a tradition of collaborative research in HD, great advances have been made in the field since that time and a range of outcome measures are now being recommended in order to assess efficacy in future therapeutic trials

Targets for future clinical trials in Huntington's disease: What's in the pipeline?

The known genetic cause of Huntington's disease (HD) has fueled considerable progress in understanding its pathobiology and the development of therapeutic approaches aimed at correcting specific changes linked to the causative mutation. Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc-finger transcriptional repression is another innovative method to reduce mHTT expression. Modulation of mHTT phosphorylation, chaperone upregulation, and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signaling provides several tractable targets, but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach. with several approaches being pursued, including brain-derived neurotrophic factor (BDNF) mimesis through tyrosine receptor kinase B (TrkB) agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues, including kynurenine monooxygenase inhibition, immunomodulation by laquinimod, CB2 agonism, and others. The complex metabolic derangements in HD remain under study, but no clear therapeutic strategy has yet emerged. We conclude that many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies. © 2014 International Parkinson and Movement Disorder Society

Psychogenic non-epileptic seizures in early Huntington's disease

Huntington's disease (HD) is a neurodegenerative condition characterised by motor dysfunction with involuntary movements and loss of voluntary control, cognitive deterioration and psychiatric problems. We report a 51-year-old man with early HD who experienced stereotyped episodes of repetitive, purposeless complex movements and unresponsiveness. His neurological examination was compatible with HD as were all investigations. We diagnosed psychogenic non-epileptic seizures. While seizures are common in juvenile-onset HD, they are no more prevalent in adult-onset HD than in the general population. However, neuropsychiatric symptoms are common in HD and can involve a number of different complaints. Patients may experience dissociative attacks soon after manifesting a HD diagnosis. Such episodes can be managed with patient and carer education, cognitive behavioural therapy and anxiolytic selective serotonin reuptake inhibitors

Cerebrospinal Fluid Biomarkers for Huntington's Disease.

Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD

HDBuzz: empowering patients through accessible education

Research and patient communities are firmly interdependent. Engaged patient communities provide biological samples and data that drive discoveries which, in turn, fuel the development of novel therapies. Historically, Huntington's disease (HD) has benefited from trusting interactions between scientists and patients. However, even for HD, communication between the research and patient communities is suboptimal. The web platform HDBuzz was created to rectify this situation by providing accurate, accessible information on the latest HD research to patients and their supporters

George Huntington: a legacy of inquiry, empathy and hope

On the centenary of George Huntington's death, Wexler et.al. reconsider the setting and the collaborative effort that produced his description of “hereditary chorea,” today Huntington's disease. Tracing the changing identity of this illness, they discuss the legacy of eugenics, the search for the gene, and ongoing research toward a cure

Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself