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February 2002
Vol. 5, No. 2, p 56.
diseases and disorders

Huntington’s disease

opening artIn 1692, residents of Salem, MA, stared at the strange “dancing” movements and violent outbursts of temper of some of their neighbors. Horrified, they concluded that anyone with such bizarre behavior must have been flirting with the devil. Two centuries later, New York physician George Huntington determined that some of his patients with strange twitching behaviors were members of families who had been treated by his father and grandfather. Huntington traced the condition to a family of immigrants from Bures in Suffolk, England, who came to Boston in 1630. He noted that if either parent had the disease, one or more offspring suffered from it. In 1872, Huntington fully described the disease that became known as Huntington’s chorea, from the Greek word for “dance”.

Huntington’s chorea, also called Huntington’s disease (HD), is an inherited degenerative brain disorder affecting about 30,000 people in North America. In addition, about 150,000 people are at risk. Because symptoms do not develop until adult life, parents may pass the disease to their offspring without knowing it. Abnormal movements are accompanied by progressive mental deterioration, personality changes, and loss of speech; death usually comes in 10–15 years. Psychological symptoms may begin more than 10 years before complete onset. The dominant gene, carried on chromosome 4, affects men and women of all ethnic groups.

In 1969, when New York psychologist Nancy Wexler found out that her mother had HD and she had a 50-50 chance of inheriting it, her life changed. Shocked by a film showing dozens of people living on Lake Maracaibo in Venezuela who had the “dance” of HD, she headed for the village and convinced the people to let her take 2000 samples of blood for DNA analysis. Through interviews, Wexler constructed a pedigree map of 10,000 people. James Gusella, director of the department of molecular genetics at Massachusetts General Hospital, and a team of researchers analyzed the DNA samples, looking for a marker for the gene, and were shocked when they found it on only the third try.

The federal government has recognized HD as a model for other neurodegenerative diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease.

In 2000, Boston researcher Robert Friedlander reported progress in understanding how inhibiting caspase-1 activity delayed the 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, Elena Cattaneo in Milan, Italy, found that the normal protein helps regulate the production of brain-derived neurotrophic factor (BDNF), a compound essential for survival of the striatal cells. Berlin scientist Erick Wanker has developed a library of 180,000 chemical compounds to screen for ones that prevent agglutination or clumping of neurons, a common characteristic of HD and other neurodegenerative conditions. He has identified 687 promising substances and is concentrating on 100 of these for therapies in cell model cultures.

In March 2001, Christopher Ross and his team at Johns Hopkins University described how the HD gene causes the death of cells. A key molecule, chlorobiphenyl degradation pathway (CBP) protein, plays a vital role in activating genes needed to reverse cell death. The abnormal gene produces a flawed form of the huntingtin protein, which causes clumping in the 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. The researchers were able to reverse the process in vitro but not in a mouse model. Since finding that the mutant huntingtin protein causes cell death, researchers have been optimistic about its potential as a drug target.

Intrastriatal transplantations of fetal striatal neuroblasts have restored motor and cognitive function in experimental animals. Two separate studies have shown that grafts of human striatal tissues have detectable effects in a small number of patients with mild to moderate HD. Although the use of fetal tissue is limited in the United States and probably will never be widespread, researchers believe that the transplant principles may apply to other cells, such as stem cells, that can be grown in the laboratory.

Sources: Huntington’s Disease Society of America, www.hdsa.org; Huntington Study Group, http://huntington-study-group.org.

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