What is Huntington's disease?

Causes and Symptoms

The mutated gene responsible for Huntington’s disease is located on one arm of chromosome 4 and produces the protein huntingtin. The gene contains repeats of the triplet nucleotide sequence CAG. Normal individuals have between nine and thirty-five (on average eighteen or nineteen) CAG repeats in their genes; affected individuals have forty or more repeats, with an average of forty-six repeats. Individuals with between thirty-six and thirty-nine repeats may or may not develop Huntington’s disease. The disease always occurs if the expansion is forty or more repeats. The larger the number of repeats above forty, the earlier the onset of the disease. The disease-causing gene is dominant, so those who inherit the mutated gene develop the disease and have a 50 percent chance of passing the defective gene on to their children.

The triplet CAG codes for the amino acid glutamine. Mutant forms of the huntingtin proteins have forty or more glutamines in the protein. Huntington’s disease appears to be caused by a mutation involving a gain of function, in which the expanded polyglutamine region makes the mutant huntingtin protein toxic. Aggregates of mutant huntingtin are observed in the neurons of those who died from Huntington’s disease. Normal huntingtin appears to keep neurons alive by stopping programmed cell death.

The neuropathology of Huntington’s disease is primarily the degeneration of neurons of the striatum (part of the basal ganglia) and the motor cortex. Clinical manifestations of Huntington’s disease typically begin in midlife (thirties and forties), with characteristic motor abnormalities such as uncoordinated movements (chorea) and loss of muscle control (dystonias), personality changes, a gradual loss of cognition, and eventually, death. Huntington’s disease primarily affects the central nervous system, but most patients actually die of heart or respiratory complications from long confinement to bed or from head injuries caused by frequent falls.

Treatment and Therapy

The present treatment for Huntington’s disease is the use of drugs such as tricyclic antidepressants to control psychological problems and neuroleptics to treat the associated chorea. In 2003, clinical trials were examining the effects of implanting fetal neurons into the brains of Huntington’s disease patients.

Perspective and Prospects

In 1872, George Huntington first reported this hereditary disease that he observed in a Long Island, New York, family. Because of the uncoordinated movements of patients, he termed the condition “chorea,” from the Greek word for “dance.” In 1981, Nancy Wexler began to study a large extended family with Huntington’s disease in an isolated village on Lake Maracaibo, Venezuela. Studies of this family aided the work of localizing the gene responsible for this disease. In 1993, that gene was identified by the collaborative work of fifty-eight scientists, led by James R. Gusella and Francis S. Collins.

Bibliography

Alan, Rick. "Huntington's Disease." Health Library, September 10 , 2012.

Baréma, Jean. The Test: Living in the Shadow of Huntington’s Disease. New York: Franklin Square Press, 2005.

Bates, Gillian, Peter S. Harper, and Lesley Jones, eds. Huntington’s Disease. 3d ed. New York: Oxford University Press, 2007.

Cattaneo, Elena, Dorotea Rigamonti, and Chaiara Zuccato. “The Enigma of Huntington’s Disease.” Scientific American 287 (December, 2002): 92–97.

"Huntington's Disease." Mayo Clinic, May 5, 2011.

"Huntington's Disease: Hope Through Research." National Institute of Neurological Disorders and Stroke, April 24, 2013.

Lewis, Ricki. Human Genetics: Concepts and Applications. 9th ed. Dubuque, Iowa: McGraw-Hill, 2009.

Nussbaum, Robert L., Roderick R. McInnes, and Willard F. Huntington. Thompson and Thompson Genetics in Medicine. 7th ed. Philadelphia: Saunders/Elsevier, 2006.

Rubinsztein, David C. “Lessons from Animal Models of Huntington’s Disease.” Trends in Genetics 18 (April 4, 2002): 202–209.