Huntington Disease | History | Symptoms

Huntington disease (HD), also called Huntington’s disease, is a rare, incurable genetic disease that results in the progressive degeneration of both physical and mental abilities. Huntington disease was formerly known as Huntington chorea since the most obvious symptoms involve uncontrollable body movements known as chorea. The term chorea comes from the Greek word choreia, which means to dance. The term aptly describes the fitful, jerking movements associated with the condition, and the more advanced symptoms such as abnormal posture, dementia, and involuntary movements. As the disease progresses, its symptoms worsen and patients eventually die of respiratory failure or complications related to the neurodegenerative progression of the disease.Huntington disease is a late onset disorder, where affected individuals usually become symptomatic after 40 years of age. When someone is diagnosed with Huntington disease at age 20 years or younger, it is called juvenile Huntington disease. A genetic test for the disease is available, and its use brings to the forefront ethical and social issues related to the clinical diagnosis, particularly in the absence of a cure.

History

Huntington disease is named for American physician George Sumner Huntington (1850-1916), who described the illness in an 1872 paper titled “On Chorea.” Huntington practiced medicine on the eastern tip of Long Island, New York. His description of the disease was drawn from his familiarity with several affected families in his community. Both Huntington’s father and grandfather had practiced medicine in the same area. Their encounters with the disease gave Huntington an appreciation of the heredity aspect of the illness.

Historically, the mental and emotional deterioration that marks the illness has frequently led to the confinement of Huntington disease patients to psychiatric hospitals. Some historians speculate that a few of the women accused of witchcraft in Salem, Massachusetts, may have exhibited the involuntary twitches and turns that are hallmarks of the disease.

Symptoms

The symptoms in Huntington disease begin with noticeable behavioral changes including aggression, paranoia, and irritability. Affected individuals may seem restless, with tapping feet or odd twitches. Patients begin to suffer from impaired judgment and an inability to be organized. They become forgetful and their I.Q. (intelligence quotient) declines, coinciding with the deterioration of the brain. Emotionally, they may suffer from psychiatric disorders and even suicidal thoughts or actions. They may drop things and become less efficient in their usual activities. Depression, anxiety, and apathy are also common experiences in the beginning stages of the disease. As the illness progresses, the chorea worsens. The entire body moves in uncoordinated, jerky movements.

Although wide variations in clinical manifestations exist, the illness typically lasts 13 to 16 years. In later stages of the illness, patients cannot walk or care for themselves. They may barely speak and may fail to recognize friends and family. They eventually require full time nursing care. Eating is quite difficult and death is very frequently caused by choking or by the pneumonia that results after accidentally inhaling bits of food. Although some symptoms can be treated with medication, currently no cure exists to delay the onset of Huntington disease or to slow its course.

Huntington disease is a hereditary disease caused by a dominant gene and, therefore, follows an autosomal dominant pattern of inheritance. This means that only one copy of the gene is necessary to cause the disease. It is transmitted from one generation to the next. The child of a mother or father suffering from Huntington disease has a 50% chance of inheriting the disease gene and, thus, of contracting the disease later in life. About 30,000 Americans suffer from Huntington disease and another 150,000 are at risk for developing it. One of the best-known disease victims was American folk singer Woody Guthrie (1912-1967), who died of the disease.

Genetic defect responsible for disease

In 1993, scientists discovered the genetic defect that causes Huntington disease. A gene located on the chromosome 4 normally contains a sequence of three nucleotide bases (the alphabet of the genetic code) that repeats several times. The sequence is cytosine, adenine, and guanine (or CAG), which codes for the amino acid glutamine that is a building block for protein synthesis. In Huntington disease, patients have too many repeats. While unaffected individuals normally have 11 to 24 repeats, a person with Huntington disease may have anywhere from 36 to 100 or more repeats. Clinical research studies have demonstrated that the greater the number of repeats, the earlier the disease will develop and the clinical manifestations will be more severe. If the expanded trinucleotide sequence is passed from the father to the offspring, the offspring that inherit this expansion can have an earlier age of onset of the disease. This phenomenon is called anticipation and is paternal in origin if the father inherited the disease gene from his mother. There are also other diseases characterized by expansion of a repetitive sequence in the DNA (deoxyribonucleic acid) and developmental delay, such as fragile X.

Despite the discovery of the Huntington disease gene, scientists were baffled by how this genetic defect produces such a devastating disease course. The Huntington disease gene codes for a large protein with no similarities to known proteins. It has been named the huntingtin (htt) protein. It is important for normal development of the nervous system and interacts with many other proteins. Through autopsy, it was shown that an abnormality in the huntingtin protein caused the destruction of brain cells in the basal ganglia, a region of the brain with unknown functions. The mutated form of Htt, which causes the disease, is named mHtt. Using genetic engineering, scientists have developed strains of mice that express the Huntington disease gene. These mice display the symptoms of the disease. It has been found that the huntingtin protein, normally present in the cytoplasm (internal fluid-like content) of cells, collects in the brain cell nuclei, forming masses that kill the cell. This dominant-negative effect explains why clinically asymptomatic patients develop progressive neurodegeration of the brain in the fourth decade of life.

The quest for the Huntington disease gene

The quest for the Huntington disease gene was made possible by a new era in medicine and biology. The researcher who found the first genetic marker for the disease used a novel scientific approach. Much of the credit for the discovery of the gene belongs to Nancy S. Wexler (1945-), a American clinical psychologist who organized and championed the gene hunt with unflagging enthusiasm, in part due to the fact that she had a positive family history of the disease.

In 1968, at the age of 23 years, Nancy and her sister, Alice, learned from their father, Milton Wexler, that their mother had been diagnosed with Huntington disease. With their mother’s diagnosis, Nancy and Alice had a 50% risk of developing the disease themselves. Milton Wexler, a lawyer and psychoanalyst, later founded the Hereditary Disease Foundation. The foundation worked to attract scientists to the study Huntington disease. It formed a board of scientific advisors, held conferences, and funded workshops particularly for younger scientists. It successfully urged the U.S. Congress to appropriate money for the study of the disease. Nancy Wexler, a graduate student, became increasingly involved in her father’s foundation and eventually became president.

Lake Maracaibo

In 1972, Wexler learned of several large, interrelated families affected with Huntington diseasewho lived in small villages along Lake Maracaibo in Venezuela. Wexler realized that this was a unique and valuable resource due to the large family pedigree. The larger the family tree, the easier it is to find genes by linking their location on the chromosome to specific DNA markers within the genome. In 1979, she began making annual trips to Lake Maracaibo. With the help of a team of investigators, she created a genealogy of the families and, beginning in 1981, took blood samples from both sick and the healthy family members. Wexler was convinced that the key to Huntington disease lay locked in the DNA of these families.

In 1983, James Gusella, a young scientist at Massachusetts General Hospital, began applying a new technique of molecular biology to the blood samples from Venezuela. He was looking for patterns that were present in the DNA sequences of people with Huntington disease but absent in the DNA of people without the disease. If one particular pattern of DNA was always associated with the illness in a given family, then it could be used as a marker for the disease gene. For instance, if it were true that people who developed the disease always had green eyes, then scientists could say that the gene that is responsible for green eyes located in a position along the DNA strand that is close to the gene that causes the disease. This genetic evaluation is called linkage analysis.

Eventually, Gusella found a genetic marker for Huntington disease, and remarkably it was almost immediate. Although the gene itself was still unknown, the discovery of this genetic marker made it possible to create a genetic test for the disease (linkage analysis), in the following year. By studying blood samples from several family members, persons who had a parent die of Huntington disease could be told whether or not they had inherited the genetic marker linked to the disease in their family. Other scientific teams also began using linkage analysis to search for disease genes as a result of these studies.

Even though the discovery of the marker indicated to scientists the general location of the gene itself, that gene hunt proceeded slowly. At Wexler’s urging, and in a break from usual scientific practice, a consortium of six scientific teams worked together to find the gene. Finally, on March 26, 1993, in the scientific journal Cell, the 58 members of the Huntington’s Collaborative Research Group announced to the world the discovery of the gene that causes Huntington disease. In June 2006, researchers from Merck Labs and the University of British Columbia announced that the neurological degeneration caused by mHtt is associated with the caspase-6 enzyme, which cleaves the Htt protein.

Ethical questions

The genetic test for Huntington disease raises profound ethical questions. It offers people who are at risk the opportunity to know whether they inherited the

KEY TERMS

Dominant gene —An allele of a gene that results in a visible phenotype if expressed in a heterozygote.

Genetic marker —DNA segment that can be linked to an identifiable trait, although it is not the gene for that trait.

Nucleotides —Building blocks of DNA: a phosphate and a sugar attached to one of the bases, adenine (A), cytosine (C), guanine (G), or thymine (T).

RFLP (restriction fragment length polymorphism) —A variation in the DNA sequence, identifiable by restriction enzymes.

gene. Yet many people at risk choose not to be tested. Currently, no treatment existed to cure Huntington disease or even to delay the onset of the disease. Given this reality, many people would rather live with uncertainty than take the chance of learning that they will develop an incurable, fatal illness. Additionally, an ethical dilemma arises in cases where a grandson or granddaughter desires testing but their parent does not. If a grandparent is affected and the grandchild is affected, then by default the parent that is biological related to both is affected. Other concerns related to genetic testing of Huntington disease involves guilt associated with not having the disease gene when a sibling is a carrier. The parent that is responsible for passing the disease gene to their offspring also commonly experiences guilt. These emotional experiences can have a profound effect on the family dynamics.

Prenatal testing, now offered for several genetic diseases, is also available to parents whose fetus is at risk for Huntington disease. Genetic testing also raises the right to privacy. Do employers, health insurers, or the government have the right to know whether a person at risk has been tested, or the right to know the results of the test? Most researchers and ethicists, including Wexler, promote the need for privacy. These ethical questions are not unique to Huntington disease.

As the genetic components of other illnesses are discovered, especially for late-onset illnesses like Alzheimer disease and certain cancers, these questions will become more relevant and pressing. In many ways, the implementation of the genetic test for Huntington disease may serve as a model for how genetic testing is used in medicine and impacts society.

See also Genetics; Gene therapy.

Resources

BOOKS

Bates, Gillian, Peter S. Harper, and Lesley Jones, eds. Huntington’s Disease. Oxford, UK, and New York: Oxford University Press, 2002.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Genetics in Medicine. Philadelphia, PA: Saunders, 2001.

Rimoin, David L. Emery and Rimoin’s Principles and Practice of Medical Genetics. London; New York: Churchill Livingstone, 2002.

OTHER

Online Mendelian Inheritance in Man. “143100 HUNTINGTON DISEASE; HD.” December 17, 2002. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143100> (accessed November 15, 2006).

Liz Marshall