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Huntington's disease (HD)

       Huntington’s disease also known as Huntington chorea, is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea The disease is caused by an autosomal dominant mutation on either of an individual's two copies of a gene called Huntingtin (Htt). It is much more common in people of Western European descent than in those of Asian or African ancestry. Symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. It typically becomes noticeable in middle age.

       HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3.  HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract).  A sequence of 36 or more glutamines results in a protein with abnormal characteristics.  The presence of this altered form, called mHtt (mutant Htt) leads to gradual damage to specific areas of the brain. The exact way this happens is not fully understood. HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the basal ganglia called the neostriatum, which is composed of the caudate nucleus and putamen. Other areas affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, the hippocampus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.

       Symptoms of the disease can vary with individuals and among affected members of the same family, but progress predictably for most individuals. The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements. The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral and psychiatric problems. Cognitive abilities are impaired progressively. The prevalence of psychiatric symptoms is variably reported between 33% and 76%. For many sufferers and their families, these symptoms are among the most distressing aspects of the disease. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years after symptoms begin.

       Genetic testing can be performed at any stage of development, even before the onset of symptoms.  About 99% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. There is no cure for HD, and full-time care is required in the later stages of the disease.

Reference:

R. Roos: Huntington's disease: a clinical review. Orphanet Journal of Rare Diseases  5:40, 2010.

S. C. Warby et al: Huntington Disease (GeneReviwes). (2010 updated) Bookshelf ID: NBK1305PMID: 20301482