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A four-year prospective study of cognitive functioning in Huntington's disease
- JULIANNA WARD, JEANNIE-MARIE SHEPPARD, BARNETT SHPRITZ, RUSSELL L. MARGOLIS, ADAM ROSENBLATT, JASON BRANDT
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- Journal:
- Journal of the International Neuropsychological Society / Volume 12 / Issue 4 / July 2006
- Published online by Cambridge University Press:
- 14 July 2006, pp. 445-454
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The contribution of neurologic, genetic, and demographic variables to decline in cognition was examined in 70 early- to mid-stage patients with Huntington's disease (HD) using random effects modeling. Study participants were followed prospectively at baseline and at four annual reevaluations. Only modest decline was noted on most neuropsychological variables. Neurologic dysfunction, assessed using the Quantified Neurologic Examination (QNE), proved to be the strongest predictor of cognitive decline. While significantly predictive of more rapid decline in neurologic functioning, CAG repeat length was not generally related to cognitive decline after adjusting for QNE, with the exception of performance on a single test of visual scanning and psychomotor speed (i.e., Trail Making Test, Part A). We propose that CAG repeat length is more closely linked with changes in basal ganglia that predominate in early- to mid-stage HD than with cortical degeneration seen later in disease progression. Such a relationship would explain the predictive value that CAG repeat length plays in changes associated with automatic motor response programs (e.g., QNE and Trail Making Test, Part A) but not in dysfunction on tasks requiring higher-order processing. (JINS, 2006, 12, 445–454.)
Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy
- Dobrila D. Rudnicki, Russell L. Margolis
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- Journal:
- Expert Reviews in Molecular Medicine / Volume 5 / Issue 21 / 22 August 2003
- Published online by Cambridge University Press:
- 13 February 2004, pp. 1-24
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Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.
118 - Huntington's disease
- from PART XVI - DEGENERATIVE DISORDERS
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- By Christopher A. Ross, Department of Psychiatry and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Russell L. Margolis, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Edited by Arthur K. Asbury, University of Pennsylvania School of Medicine, Guy M. McKhann, The Johns Hopkins University School of Medicine, W. Ian McDonald, University College London, Peter J. Goadsby, University College London, Justin C. McArthur, The Johns Hopkins University School of Medicine
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- Book:
- Diseases of the Nervous System
- Published online:
- 05 August 2016
- Print publication:
- 11 November 2002, pp 1896-1910
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Summary
History
George Huntington saw his first cases of HD when he was about 8 years old, while accompanying his father and grandfather on their medical rounds in East Hampton, Long Island. His longitudinal experience with several families of patients, as part of a three-generation family of physicians, was crucial to his famously concise and accurate account of the disease that now bears his name (Huntington, 1872). As William Osler commented in his paper reporting two additional families with HD (Osler, 1893), ‘In the whole range of descriptive nosology there is not, to my knowledge, an instance in which a disease has been so accurately and fully delineated in so few words.’ George Huntington's description over a century ago identified the key aspects of the disease, an adult onset hereditary disorder progressing inexorably to death, and characterized by abnormal movements, as well as cognitive and emotional changes. The pathologic changes in the corpus striatum and cerebral cortex were later described by Meynert, Alzheimer and Hunt in the early part of the twentieth century.
The discovery of the CAG repeat expansion mutation in the gene huntingtin in 1993 greatly facilitated the application of modern molecular and cellular techniques to the study of HD. The consequent development of biochemical, cellular and animal models of the disorder has led to new insights into its pathogenesis. The hope is that these approaches will foster the development of rational therapeutics in the near future.
Clinical course
HD can be described as a triad of motor, cognitive, and emotional disturbances (Folstein, 1989; Harper, 1996; Penney et al., 1990; Ross et al., 1997). Onset is usually insidious, and may occur at any time from childhood to old age, though mid-life onset is most common. Early complaints include clumsiness, difficulty with balance, and jerky movements or tremor. Death occurs an average of 15 to 20 years after the appearance of symptoms, with some patients dying earlier from falls or suicide and others surviving for 30 to 40 years (Fig. 118.1).
The most striking movement disorder of HD consists of abnormal involuntary movements. Chorea or choreoathetosis, continuous and irregular jerky or writhing motions, are the clinical manifestation most frequently associated with Huntington disease. While most commonly present in the limb and trunk, movements may also include motor tics or chorea involving respiratory, laryngeal, pharyngeal, oral or nasal musculature.