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HUNTINGTON'S DISEASE

In 1872, the American physician George Huntington wrote about an illness that he called

"an heirloom from generations away back in the dim past." He was not the first to describe

the disorder, which has been traced back to the Middle Ages at least. One of its earliest

The term names was chorea, which, as in "choreography," is the Greek word for dance.

chorea describes how people affected with the disorder writhe, twist, and turn in a

constant, uncontrollable dance-like motion. Later, other descriptive names evolved.

"Hereditary chorea" emphasizes how the disease is passed from parent to child. "Chronic

progressive chorea" stresses how symptoms of the disease worsen over time. Today,

physicians commonly use the simple term Huntington's disease (HD) to describe this highly

complex disorder that causes untold suffering for thousands of families.

More than 15,000 Americans have HD. At least 150,000 others have a 50 percent risk of

developing the disease and thousands more of their relatives live with the possibility that

they, too, might develop HD.

Until recently, scientists understood very little about HD & could only watch as the disease

continued to pass from generation to generation. Families saw the disease destroy their

loved ones' ability to feel, think, and move. In the last several years, scientists working

with support from the National Institute of Neurological Disorders and Stroke (NINDS) have

made several breakthroughs in the area of HD research. With these advances, our

understanding of the disease continues to improve.

This article presents information about HD, and about current research progress, to health

professionals, scientists, caregivers, and, most important, to those already too familiar with

the disorder: the many families who are affected by HD.

What causes Huntington's disease?

Huntington's disease results from genetically programmed degeneration of nerve cells, called

neurons, in certain areas of the brain. This degeneration causes uncontrolled movements,

loss of intellectual faculties, and emotional disturbance. Specifically affected are cells of the

basal ganglia, structures deep within the brain that have many important functions, including

coordinating movement. Within the basal ganglia, HD especially targets neurons of the

striatum, particularly those in the caudate nuclei and the pallidum. Also affected is the

brain's outer surface, or cortex, which controls thought, perception, and memory.

How is Huntington's disease inherited?

Huntington's disease is found in every country of the world. It is a familial disease, passed

from parent to child through a mutation or misspelling in the normal gene.

What are the symptoms and major effects of Huntington's disease?

Early signs of the disease vary greatly from person to person. A common observation is that

the earlier the symptoms appear, the faster the disease progresses.

Family members may first notice that the individual experiences mood swings or becomes

uncharacteristically irritable, apathetic, passive, depressed, or angry. These symptoms may

lessen as the disease progresses or, in some individuals, may continue and include hostile

outbursts or deep bouts of depression.

HD may affect the individual's judgment, memory, and other cognitive functions. Early signs

might include having trouble driving, learning new things, remembering a fact, answering a

question, or making a decision. Some may even display changes in handwriting. As the

disease progresses, concentration on intellectual tasks becomes increasingly difficult.

In some individuals, the disease may begin with uncontrolled movements in the fingers, feet,

face, or trunk. These movements - which are signs of chorea - often intensify when the

person is anxious. HD can also begin with mild clumsiness or problems with balance. Some

people develop choreic movements later, after the disease has progressed. They may

stumble or appear uncoordinated. Chorea often creates serious problems with walking,

increasing the likelihood of falls.

The disease can reach the point where speech is slurred and vital functions, such as

swallowing, eating, speaking, and especially walking, continue to decline. Some individuals

cannot recognize other family members. Many, however, remain aware of their environment

and are able to express emotions.

Some physicians have employed a recently developed Unified HD Rating Scale, or UHDRS, to

assess the clinical features, stages, and course of HD. In general, the duration of the illness

ranges from 10 to 30 years. The most common causes of death are infection (most often

pneumonia), injuries related to a fall, or other complications.

At what age does Huntington's disease appear?

The rate of disease progression and the age at onset vary from person to person.

Adult-onset HD, with its disabling, uncontrolled movements, most often begins in middle age.

There are, however, other variations of HD distinguished not just by age at onset but by a

distinct array of symptoms. For example, some persons develop the disease as adults, but

without chorea. They may appear rigid and move very little, or not at all, a condition called

akinesia.

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Some individuals develop symptoms of HD when they are very young - before age 20. The terms "early-onset" or "juvenile" HD are

often used to describe HD that appears in a young person. A common sign of HD in a younger individual is a rapid decline in school

performance.

Symptoms can also include subtle changes in handwriting and slight problems with movement, such as slowness, rigidity, tremor,

and rapid muscular twitching, called myoclonus.

Several of these symptoms are similar to those seen in Parkinson's disease, and they differ from the chorea seen in individuals who

develop the disease as adults. These young individuals are said to have "akinetic-rigid" HD or the Westphal variant of HD. People

with juvenile HD may also have seizures and mental disabilities. The earlier the onset, the faster the disease seems to progress. The

disease progresses most rapidly in individuals with juvenile or early-onset HD, and death often follows within 10 years.

Individuals with juvenile HD usually inherit the disease from their fathers. These individuals also tend to have the largest number of

CAG repeats. The reason for this may be found in the process of sperm production. Unlike eggs, sperm are produced in the millions.

Because DNA is copied millions of times during this process, there is an increased possibility for genetic mistakes to occur. To verify

the link between the number of CAG repeats in the HD gene and the age at onset of symptoms, scientists studied a boy who

developed HD symptoms at the age of two, one of the youngest and most severe cases ever recorded. They found that he had the

largest number of CAG repeats of anyone studied so far - nearly 100. The boy's case was central to the identification of the HD

gene and at the same time helped confirm that juveniles with HD have the longest segments of CAG repeats, the only proven

correlation between repeat length and age at onset.

What is presymptomatic testing?

Presymptomatic testing is used for people who have a family history of HD but have no symptoms themselves. If either parent had HD,

the person's chance would be 50-50. In the past, no laboratory test could positively identify people carrying the HD gene - or those

fated to develop HD - before the onset of symptoms. That situation changed in 1983, when a team of scientists supported by the

NINDS located the first genetic marker for HD - the initial step in developing a laboratory test for the disease.

A marker is a piece of DNA that lies near a gene and is usually inherited with it. Discovery of the first HD marker allowed scientists to

locate the HD gene on chromosome 4. The marker discovery quickly led to the development of a presymptomatic test for some

individuals, but this test required blood or tissue samples from both affected and unaffected family members in order to identify

markers unique to that particular family. For this reason, adopted individuals, orphans, and people who had few living family members

were unable to use the test.

Discovery of the HD gene has led to a less expensive, scientifically simpler, and far more accurate presymptomatic test that is

applicable to the majority of at-risk people. The new test uses CAG repeat length to detect the presence of the HD mutation in blood.

This is discussed further in the next section.

There are many complicating factors that reflect the complexity of diagnosing HD. In a small number of individuals with HD - 1 to 3

percent - no family history of HD can be found. Some individuals may not be aware of their genetic legacy, or a family member may

conceal a genetic disorder from fear of social stigma. A parent may not want to worry children, scare them, or deter them from

marrying. In other cases, a family member may die of another cause before he or she begins to show signs of HD. Sometimes, the

cause of death for a relative may not be known, or the family is not aware of a relative's death. Adopted children may not know

their genetic heritage, or early symptoms in an individual may be too slight to attract attention.

A few individuals develop HD after age 55. Diagnosis in these people can be very difficult. The symptoms of HD may be masked by

other health problems, or the person may not display the severity of symptoms seen in individuals with HD of earlier onset. These

individuals may also show symptoms of depression rather than anger or irritability, or they may retain sharp control over their

intellectual functions, such as memory, reasoning, and problem-solving.

There is also a related disorder called senile chorea. Some elderly individuals display the symptoms of HD, especially choreic

movements, but do not become demented, have a normal gene, and lack a family history of the disorder. Some scientists believe

that a different gene mutation may account for this small number of cases, but this has not been proven.

How is the presymptomatic test conducted?

An individual who wishes to be tested should contact the nearest testing centre. (A list of such centers can be obtained from the

Huntington Disease Society of America at 1-800-345-HDSA.) The testing process should include several components. Most testing

programs include a neurological examination, pretest counseling, and follow-up. The purpose of the neurological examination is to

determine whether or not the person requesting testing is showing any clinical symptoms of HD. It is important to remember that if

an individual is showing even slight symptoms of HD, he or she risks being diagnosed with the disease during the neurological

examination, even before the genetic test. During pretest counselling, the individual will learn about HD, and about his or her own

level of risk, about the testing procedure. The person will be told about the test's limitations, the accuracy of the test, and possible

outcomes. He or she can then weigh the risks and benefits of testing and may even decide at that time against pursuing further

testing.

If a person decides to be tested, a team of highly trained specialists will be involved, which may include neurologists, genetic

counsellors, social workers, psychiatrists, and psychologists. This team of professionals helps the at-risk person decide if testing is

the right thing to do and carefully prepares the person for a negative, positive, or inconclusive test result.

Individuals who decide to continue the testing process should be accompanied to counselling sessions by a spouse, a friend, or a

relative who is not at risk. Other interested family members may participate in the counselling sessions if the individual being tested

so desires.

The genetic testing itself involves donating a small sample of blood that is screened in the laboratory for the presence or absence of

the HD mutation. Testing may require a sample of DNA from a closely related affected relative, preferably a parent, for the purpose of

confirming the diagnosis of HD in the family. This is especially important if the family history for HD is unclear or unusual in some way.

Results of the test should be given only in person and only to the individual being tested. Test results are confidential. Regardless of

test results, follow-up is recommended.

In order to protect the interests of minors, including confidentiality, testing is not recommended for those under the age of 18 unless

there is a compelling medical reason (for example, the child is exhibiting symptoms).

Testing of a fetus (prenatal testing) presents special challenges and risks; in fact some centres do not perform genetic testing on

fetuses. Because a positive test result using direct genetic testing means the at-risk parent is also a gene carrier, at-risk individuals

who are considering a pregnancy are advised to seek genetic counselling prior to conception.

Some at-risk parents may wish to know the risk to their fetus but not their own. In this situation, parents may opt for prenatal testing

using linked DNA markers rather than direct gene testing. In this case, testing does not look for the HD gene itself but instead indicates

whether or not the fetus has inherited a chromosome 4 from the affected grandparent or from the unaffected grandparent on the side

of the family with HD. If the test shows that the fetus has inherited a chromosome 4 from the affected grandparent, the parents then

learn that the fetus's risk is the same as the parent (50-50), but they learn nothing new about the parent's risk. If the test shows

that the fetus has inherited a chromosome 4 from the unaffected grandparent, the risk to the fetus is very low (less than 1%) in

most cases.

Another option open to parents is in vitro fertilization with preimplantation screening. In this procedure, embryos are screened to

determine which ones carry the HD mutation. Embryos determined not to have the HD gene mutation are then implanted in the woman's

uterus.

In terms of emotional and practical consequences, not only for the individual taking the test but for his or her entire family, testing is

enormously complex and has been surrounded by considerable controversy. For example, people with a positive test result may risk

losing health and life insurance, suffer loss of employment, and other liabilities. People undergoing testing may wish to cover the cost

themselves, since coverage by an insurer may lead to loss of health insurance in the event of a positive result, although this may

change in the future.

With the participation of health professionals and people from families with HD, scientists have developed testing guidelines. All

individuals seeking a genetic test should obtain a copy of these guidelines, either from their testing centre or from the organizations

listed on the card in the back of this brochure. These organizations have information on sites that perform testing using the

established procedures and they strongly recommend that individuals avoid testing that does not adhere to these guidelines.


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