Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by the triad of a movement disorder, dementia, and various psychiatric disturbances. HD is caused by the abnormal expansion of a trinucleotide (CAG) repeat in the huntingtin gene of chromosome 4—a mutation that is inherited as an autosomal dominant. When the number of CAG repeats exceeds 39, the individual harboring it goes on to develop HD. The most common time of onset is in the fourth or fifth decade, but the age of onset is inversely correlated with the size of the triplet repeat expansion. In rare instances, persons with very large expansions may have onset in childhood, and those with expansions only just into the abnormal range may have onset late in life. Children of affected fathers, if they receive the abnormal allele, tend to inherit an allele that is even further expanded, and thus usually experience the onset of symptoms at a younger age than their fathers; this phenomenon is known as paternal anticipation. The progression of HD is inexorable and usually leads to death within 15 to 20 years of symptom onset; patients in the final stages have severe dementia and are unable to speak, eat, or purposefully move. Death typically results from the consequences of immobility such as pneumonia or malnutrition. The movement disorder of HD has two major manifestations: involuntary movements (eg, chorea, dystonia) and impairments of voluntary movement (eg, clumsiness, dysarthria, swallowing difficulties, falls, bradykinesia, rigidity). Chorea generally predominates early in the course and is gradually eclipsed by motor impairment as the disease becomes more advanced. In the end stages, patients are rigid and immobile. A variety of medications are used to suppress chorea in HD, including neuroleptics, benzodiazepines, and dopamine-depleting agents such as tetrabenazine, but it remains controversial whether these agents convey functional, as opposed to cosmetic, benefits. HD, like many other neurodegenerative disorders, is associated with a variety of psychiatric problems. Some of these problems such as insomnia or demoralization may be thought of as nonspecific. They have a variety of causes and are associated with many different medical conditions.
Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease
