Genetic Disorders - Huntington's Disease

Named for an American physician, George Sumner Huntington (1850–1916), Huntington's disease (HD), or Huntington's chorea, is an inherited, progressive brain disorder. It causes the degeneration of cells in the basal ganglia, a pair of nerve clusters deep in the brain that affect both the body and the mind. HD is caused by a single dominant gene that affects men and women of all races and ethnic groups. Figure 5.14 shows the inheritance pattern of HD.

Gene Responsible for HD Found

The gene mutation that produces HD was mapped to chromosome 4 in 1983 and cloned in 1993. In the HD gene the mutation involves a triplet of nucleotides, cytosine (C), adenine (A), and guanine (G), known as CAG. The mutation is an expansion of a nucleotide triplet repeat in the DNA that codes for the protein huntingtin. In unaffected persons the gene has thirty or fewer of these triplets, but HD patients have forty or more. These increased multiples either destroy the gene's ability to make the necessary protein or cause it to produce a misshapen and malfunctioning protein. Either way, the defect results in the death of brain cells.

The international team of scientists from the United States and the United Kingdom that discovered the gene responsible for HD examined seventy-five families with a history of HD and found the abnormal expansion in each case of an afflicted patient. The number of repeated triplets is inversely related to the age when the individual first experiences symptoms—the more repeated triplets, the younger the age of onset of the disease. Like myotonic dystrophy, in which the symptoms of the disease often increase in severity from one generation to the next, the unstable triplet repeat sequence can lengthen from one generation to the next, with a resultant decrease in the age when symptoms first appear.

HD does not usually strike until mid-adulthood, between ages thirty and fifty, although there is a juvenile form that can affect children and adolescents. Early symptoms, such as forgetfulness, a lack of muscle coordination, or a loss of balance, are often ignored, delaying the diagnosis. The disease gradually takes its toll over a ten- to twenty-five-year period.

Within a few years, characteristic involuntary movement (chorea) of the body, limbs, and facial muscles appears. As HD progresses, speech becomes slurred and swallowing becomes difficult. The patients' cognitive abilities decline, and there are distinct personality changes—depression and withdrawal, sometimes countered with euphoria. Eventually, nearly all patients must be institutionalized, and they usually die as a result of choking or infections.

Prevalence of HD

HD, once considered rare, is now recognized as one of the more common hereditary diseases. It is known to affect about 30,000 Americans, according to the National Institute of Neurological Disorders and Stroke (NINDS) in Huntington's Disease: Hope through Research (NIH Publication No. 98-49). Another 150,000 are at a 50% risk of inheriting it from an affected parent. NINDS estimates its prevalence at about one in 10,000 persons.

Prediction Test

In 1983 researchers identified a DNA marker that made it possible to offer a test to determine whether an individual has inherited the HD gene before symptoms appear. In some cases it is even possible to make a prenatal diagnosis on an unborn child. Many people, however, prefer not to know whether or not they carry the defective gene. Currently, they are trying to determine if the exact number of excess triplets indicates when in life a person will be affected by the disease. Some scientists fear that the ability to tell people that they are going to develop an incurable disease and pinpoint when they will develop it will make genetic testing, already a difficult decision, even more complicated.

A testing center at Johns Hopkins Hospital in Maryland reports that a high proportion of the people who come in for testing find out that they are not carrying the gene. Of the people who do not choose to be tested, the center's physicians believe that many may already have very mild symptoms and suspect that they have the disease.

Promising Research Findings

In December 2001 researchers at the University of South Florida reported that fetal tissue—neurons obtained from fetuses—transplanted into the damaged areas of the brains of patients with HD remained disease-free. Earlier in the same year French researchers had reported similar FIGURE 5.14
The inheritance pattern of Huntington's disease (HD)
SOURCE: "The Inheritance Pattern of Huntington's Disease (HD)," Gale Group results, confirming that HD does not appear to enter or affect the implanted fetal tissue.

The HD patients who received the transplants showed measurable improvement in motor and cognitive functions and did not appear to reject the transplanted tissue, leading investigators to speculate that fetal tissue grafts might become the first effective treatment for HD.