Huntington's disease

ALSO KNOWN AS: Huntington’s chorea

ANATOMY OR SYSTEM AFFECTED: Brain, nerves, nervous system

DEFINITION:An autosomal dominant genetic neurodegenerative disease in which patients have uncoordinated movements as a result of neuron degeneration

CAUSES: Genetic protein defect

SYMPTOMS: Uncoordinated movements (chorea), loss of muscle control (dystonias), personality changes, gradual loss of cognition, death

DURATION: Progressive, eventually fatal

TREATMENTS: Tricyclic antidepressants for psychological problems and neuroleptics for chorea

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.

Huntington's disease typically manifests symptoms when a patient is in their thirties or forties. However, onset may occur earlier or later depending on the individual, and the earlier the disease begins the more rapid its progression. In some cases onset can occur before the age of twenty, in which case it is considered juvenile Huntington's disease, which can exhibit different symptom presentation. Genetic testing may be done to determine if one will develop the disease. Because of the significant emotional implications for at-risk individuals regarding testing, counseling is suggested in order to help decide whether to undergo the test, and some may decide not to pursue it. Prenatal testing can also be used to determine whether a fetus is carrying the associated gene, while in vitro fertilization methods can help at-risk adults screen embryos for the Huntington's disease mutation.

Treatment and Therapy

There is no known cure for Huntington's disease and no way of effectively slowing its progression and the patient's declining mental and physical health. However, some drugs can be used to help ease specific symptoms. 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. Some of the common medications used to treat the movement issues related to the disease include tetrabenazine (Xenazine); haloperidol (Haldol), chlorpromazine, and other antipsychotics; amantadine; levetiracetam (Keppra); and clonazepam (Klonopin). Most of these drugs can also produce significant negative side effects, and at certain doses may even worsen the mental effects of the disease.

Other treatment options have also been explored, with some helping to manage certain symptoms. Techniques like psychotherapy and talk therapy may have positive results in reducing behavioral symptoms, building coping mechanisms, and communicating with family. Physical therapy and speech therapy can aid in the management of declining control of muscles used in talking, eating, and swallowing. Occupational therapy and other methods can be used to manage life with the disease and the challenges it presents to everyday tasks; in later stages patients will require full-time caretaking. Beginning in the twenty-first century, clinical trials examined the effects of implanting fetal neurons into the brains of Huntington’s disease patients.

Perspective and Prospects

Huntington's disease and other disorders manifesting symptoms of jerking motion were observed throughout history, though the causes were not understood or connected. 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." He recognized that the disease ran in families but was not always passed on, an early example of recognizing the process of genetic inheritance. 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.

Various support groups and research foundations have been created to study Huntington's disease and work to develop a cure. After folksinger Woody Guthrie died of complications from the disease in 1967, his wife, Marjorie Guthrie, helped found the Committee to Combat Huntington's Disease, which became the Huntington's Disease Society of America. The Hereditary Disease Foundation and the CHDI Foundation are other organizations that have played a prominent role in researching the disease and promoting outreach efforts.

Bibliography

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, 17 May 2022, www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117. Accessed 2 Apr. 2024.

“Huntington Disease.” Medline Plus, 1 July 2020, medlineplus.gov/genetics/condition/huntington-disease/. Accessed 2 Apr. 2024.

"Huntington's Disease: Hope Through Research." National Institute of Neurological Disorders and Stroke. Natl. Institutes of Health, 28 Jan. 2016. 26 Apr. 2016.

Jiang, Andrew, et al. "From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research." International Journal of Molecular Sciences, vol. 24, no. 16, 21 Aug. 2023, doi.org/10.3390/ijms241613021. Accessed 2 Apr. 2024.

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.