Affects 3 to 7 per 100,000 people of European ancestry, meaning it affects about 30,000 people in North America with about 100,000 at risk; less common in people of Asian and African descent
Huntington chorea; Huntington chronic progressive hereditary chorea; Huntington's disease; progressive chorea, chronic hereditary (Huntington)
In 1692, residents of Salem stared at the strange “dancing” movements and violent outburst of tempers of some of their neighbors. Horrified, they concluded that anyone with such bizarre behavior must be flirting with the devil. Two centuries later, New York doctor George Huntington determined that patients with strange twitching behaviors were members of families who had been treated by his father and grandfather for the same disorder. Huntington traced the condition to a family of immigrants from Bures in Suffolk, who came to Boston in 1630. He noted that if either parent had the disease, one or more offspring suffered from it. In 1872, he fully described the disease that became known as Huntington's chorea, from the Greek word meaning “dance”; it is now just called Huntington disease.
Huntington disease (HD) is a progressive, degenerative brain disorder characterized by uncontrolled movements, emotional outbursts, and mental deterioration. Although HD can begin at any age, the most common age of onset is between 35 and 44. The disease affects about 30,000 people in North America, with about 100,000 at risk. Since symptoms develop in adult life, the person with Huntington disease may pass HD to their offspring without knowing it.
Early symptoms of the disorder include the following:
Lack of coordination
An unsteady gait
Small involuntary movements or twitches
Trouble learning new information
Trouble making decisions
Then the disease progresses with the following symptoms:
Jerky body movements more apparent
Behavior more erratic
Decline in mental abilities and cognition
Problems with speaking and swallowing
Complications such as pneumonia, heart disease, and injury from falls
Eventually, the person is in complete decline and may live 15 to 20 years after the first diagnosis.
A less common early-onset form of Huntington disease begins in early childhood or adolescence. This form is called the juvenile, akinetic-rigid, Westphal variant. The symptoms of abnormal movements, emotional disturbances, and mental disorders are similar. Additional signs of the early-onset form include drooling, slurred speech, and seizures. The early-onset form appears to progress more rapidly, and persons usually live 10 to 15 years after the onset of symptoms.
Changes in the “huntingtin” gene, or HTT gene, cause Huntington disease. Normally, this gene encodes for a protein labeled “huntingtin,” which appears to play an important role in the embryonic development of nerve cells in the developing brain. The highest level of huntingtin is in the brain, but it is also present in many other cells, with a variety of functions. Huntingtin may be involved in cell chemical signaling, transporting materials, binding proteins, and the extremely important activity of protecting cells from self-destruction, a process called apoptosis. A region of HTT gene has a segment of repeats called CAG, or cytosine-adenine-guanosine repeats. The normal number of repeats is 10 to 35 times.
The mutation in huntingtin is a the result of the CAG nucleotide repeat expansion. Instead of repeating the normal 10 to 35 times, people with the disorder may have more than 40 repeats. Individuals with the juvenile form may have between 60 and 120 repeats. The CAG nucleotides instruct the protein synthesis process to include a glutamine amino acid. As the repeats expand the gene, an abnormally long version of the huntingtin protein is produced, having many extra glutamines. This long protein is then cut into smaller, toxic fragments that gather in the neurons. The substances gather especially in the area of the brain called the striatum and cerebral cortex that control movement, thinking, and emotions. The disruption of the neurons and their eventual death lead to the characteristic symptoms of Huntington disease.
As the CAG repeat goes from one generation to another, the size tends to increase. Those who may have 27 to 35 repeats do not develop Huntington disease but can pass the gene to their children, who may develop the disorder. HTT is inherited in a dominant pattern and is located on the short arm (p) of chromosome 4 at 16.3.
Because it is a genetic disorder, no treatment exists. However, some efforts have been made to reduce the severity of the symptoms. A lot of research is focused on help with daily living, in addition to research for new medication. For example, nutritional management may involve adding thickening agents to help swallow and giving very small pieces of food to eat. Physical therapy, occupational therapy, and speech therapy may help some of the cognitive decline.
The Hereditary Disease Foundation and Huntington's Disease Society of America have worked to create public awareness, research, and family support. The death of prominent folk singer Woody Guthrie from complications of Huntington disease and a multitude of efforts by local support groups eventually led to the designation of June 25 as National Huntington's Disease Awareness Day by the U.S. Senate in 2008.
Huntington disease was one of the first diseases diagnosed using the new technique called “genetic testing.” This test has caused social, legal, and ethical concerns over access and use of the results. In 1910, Charles Davenport, a leader of the eugenics movement in the United States, proposed forced sterilization for people with Huntington disease. Today, many guidelines have strict procedures over the results; individuals choose how and to whom to reveal the results. For example, testing on a child may result in no medical benefits for that child, but may show that the child has a preexisting condition. The counterargument is that patients and their caregivers need to know about the results so they can make important life decisions and plans.
Huntington disease has been dubbed the “Crown Jewel of Genetic Research,” as the story of Nancy Wexler and James Gusella, shows.
When Nancy Wexler, a New York psychologist, found out that her mother had Huntington disease and that she had a 50-50 chance of inheriting it, her life was changed. In 1972, at a meeting of the World Federation of Neurological Research on Huntington Disease, a young physician presented video of dozens of people living on Lake Maracaibo in Venezuela who had the writhing “dance” of “Huntington's Chorea.” She had talked with several scientists about the idea of finding the causative gene. In 1979, she headed for the two isolated villages of Barranquitas amd Laguenetas and convinced the people there to let her take blood, which yielded 2,000 samples of blood. Through interviews, she constructed a pedigree map of 10,000 people.
She brought the blood samples and pedigree maps to James Gusella and a team of researchers at Harvard who analyzed the DNA samples looking for a marker for the gene that was cross-linked with the traits on the map. They were shocked when they found the marker on the third try. This landmark discovery in 1983 developed other innovations in DNA-marking methods, which became an important step in making the Human Genome Project possible.
In 1993, researchers from the Huntington Collaboration Group found the gene designated IT 15 on chromosome 4 and later called it “huntingtin.” All mutations are some form of exaggerated CAG trinucleotide repeats in the coding region of the gene. The research into Huntington disease became known as the “Crown Jewel of Genetic Research” and became a model for research into other neurodegenerative disorders. The federal government has recognized HD as a model for other neurodegenerative diseases, such as Parkinson's, ALS, and Alzheimer disease.
In 2000, Boston researcher Dr. Robert Friedlander reported progress in understanding how inhibiting caspase-1 activity delayed symptoms of HD in mouse models. Using the antibiotic minocycline, his team blocked production of caspases 1 and 3. Although mutant huntingtin protein causes striatal neurons to die, Milan scientist Elena Cattaneo found the normal protein helps regulate the production of BDNF, a protein essential for survival of the striatal cells. Berlin scientist Dr. Erick Wanker has developed a library of 180,000 chemical compounds to screen for prevention of agglutination or clumping of neurons, a characteristic common in HD and other neurodegenerative conditions. He has identified 687 promising substances, concentrating on 100 of these for therapies in cell model cultures.
In March 2001, Dr. Christopher Ross and a Johns Hopkins team described how the HD gene causes the death of cells. A key molecule, CPB, plays a vital role in activating genes needed to reverse cell death. The abnormal gene produces a flawed form of the protein huntingtin that causes clumping in brain cells of HD patients. When the clumped molecules become entangled with the critical protein CBP in the cell nucleus, that regulatory molecule is hijacked, and the pathway essential for cell survival is never activated. They were able to reverse the process in vitro, but not in a mouse model. Since finding the abnormal protein huntingtin that causes cell death, researchers are optimistic that here is a needed target for developing new drugs.
Intrastriatal transplantations of fetal striatal neuroblasts have restored motor and cognitive function in experimental animals. Results from two separate studies showed that grafts of human striatal tissues have detectable effects in a limited number of patients with mild to moderate HD. While the use of fetal tissue is limited in the United States and will probably never be used for widespread treatment, researchers believe the transplant principles may apply to other cells such as stem cells that can be grown in the laboratory.
While investigators are working on basic research of understanding mechanisms, several clinical trials are studying drugs and surgical techniques. A disappointing trial (347 patients) found neither the drug remacemide (AstraZeneca) nor coenzyme Q10 (CoQ10) had a statistically significant effect on slowing the progress (Neurology 2001 57: 397–404).
Related Credo Articles
Huntington disease (HD) is a neurodegenerative disorder that involves the loss of neurons in the basal ganglia (particularly the caudate nucleus...
Huntington disease is a serious neurodegenerative disorder resulting from an expanded CAG repeat in a specific gene on chromosome 4. The highly...
a hereditary brain disorder that is a progressive, neurodegenerative condition marked especially by impairments in thinking and reasoning, disturban