Huntington's
Disease
This pamphlet was written and published by the
National Institute of Neurological Disorders and Stroke (NINDS), the
United States' leading supporter of research on disorders of the brain
and nervous system, including Huntington's disease. NINDS, one of the
U.S. Government's 17 National Institutes of Health in Bethesda,
Maryland, is part of the Public Health Service within the U.S.
Department of Health and Human Services.
Table of Contents:
Introduction
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 names was chorea,*
which, as in "choreography," is the Greek word for dance. The
term 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.
In the United States alone, about 30,000 people have
HD; estimates of its prevalence are about 1 in every 10,000
persons. 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 and 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 a significant number
of breakthroughs in the area of HD research. With these advances, our
understanding of the disease continues to improve.
This brochure presents information about HD, and about
current research progress, to health professionals, scientists,
caregivers, and, most importantly, to those already too familiar with
the disorder: the many families who are affected by HD.
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*see glossary
What Causes Huntington’s Disease?
HD results from genetically programmed degeneration of
brain 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 a
number of 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.
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How is HD Inherited?
HD 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.
A single abnormal gene, the basic biological unit of
heredity, produces HD. Genes are composed of deoxyribonucleic acid
(DNA), a molecule shaped like a spiral ladder. Each rung of this
ladder is composed of two paired chemicals called bases. There are four
types of bases--adenine, thymine, cytosine, and guanine--each
abbreviated by the first letter of its name: A, T, C, and G. Certain
bases always "pair" together, and different combinations of
base pairs join to form coded messages. A gene is a long string of this
DNA that is composed of various combinations of A, T, C, and G. These
unique combinations determine the gene's function, much like letters
join together to form words. Each person has about 100,000 genes--three
billion base pairs of DNA or bits of information repeated in the nuclei
of human cells--which determine individual characteristics or traits.
Genes are arranged in precise locations along 23
rod-like pairs of chromosomes. One chromosome from each pair
comes from an individual's mother, the other from the father. Each half
of a chromosome pair is similar to the other, except for one pair, which
determines the sex of the individual. This pair has two x chromosomes in
females and one x and one y chromosome in males. The gene that produces
HD lies on chromosome 4, one of the 22 non-sex-linked, or "autosomal,"
pairs of chromosomes, placing men and women at equal risk of acquiring
the disease.
The impact of a gene depends partly on whether it is dominant
or recessive. If a gene is dominant, then only one of the paired
chromosomes is required to produce its called-for effect. If the gene is
recessive, both parents must provide chromosomal copies for the trait to
be present. HD is called an autosomal dominant disorder because
only one copy of the defective gene, inherited from one parent, is
necessary to produce the disease.
The genetic defect responsible for HD is a small
sequence of DNA on chromosome 4 in which several base pairs are repeated
many, many times. The normal gene has three DNA bases, composed of the
sequence CAG. In people with HD, the sequence abnormally repeats itself
dozens of times. Over time--and with each successive generation--the
number of CAG repeats may expand further.
Each parent has two copies of every chromosome but
gives only one copy to each child. Each child of an HD parent has a
50-50 chance of inheriting the HD gene. If a child does not inherit the
HD gene, he or she will not develop the disease and cannot pass it to
subsequent generations. A person who inherits the HD gene, and survives
long enough, will sooner or later develop the disease. In some families,
all the children may inherit the HD gene; in others, none do. Whether
one child inherits the gene has no bearing on whether others will or
will not share the same fate.
A small number of cases of HD are sporadic, that is,
they occur even though there is no family history of the disorder. These
cases are thought to be caused by a new genetic mutation—an alteration
in the gene that occurs during sperm development and that brings the
number of CAG repeats into the range that causes disease.
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What are the Major Effects of the
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. Other persons develop choric movements later on as the disease
progresses. They may stumble or appear uncoordinated. Chorea often
creates serious problems with walking, increasing the likelihood of
falls.
The disease can progress to the point where speech is
slurred and vital functions, such as swallowing, eating, speaking, and
especially walking, continue to decline. Some individuals are unable to
recognize others. 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.
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At What Age Does HD Appear?
The rate of disease progression and the age of onset
vary from person to person. Adult-onset or classic HD, with its
disabling, uncontrolled movements, most often begins during middle age.
There are, however, other variations of HD distinguished not just by age
of 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.
These individuals are said to have akinetic-rigid HD or the Westphal
variant of HD.
Some individuals develop symptoms of HD when they are
very young--before age 20. The terms early-onset HD 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. People
with juvenile HD may also have seizures and mental disabilities. As
mentioned previously, the earlier the onset of HD, 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.
It appears that individuals with juvenile HD have
usually inherited the disease from their fathers. These individuals also
tend to have the largest number of CAG repeats. Scientists believe that
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, scientists theorize that there is
an increased possibility for genetic mistakes to occur. To verify that
there was a link between the number of CAG repeats in the HD gene and
the age of onset of the disease, scientists studied a young boy who
developed HD 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 they had 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 juvenile patients with HD have the longest segments
of CAG repeats, the only proven correlation between repeat length and
age at onset.
A few individuals develop HD after age 55. Diagnosis
in these persons 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 an earlier onset of HD. These
individuals may also show signs 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 complex called senile
chorea. Some elderly individuals display the symptoms of HD,
especially choreic movements, but 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. Others, however,
believe senile chorea is a late-onset form of HD.
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How is HD Diagnosed?
The great American folk singer and composer Woody
Guthrie died on October 3, 1967, after suffering from HD for 13 years.
He had been misdiagnosed, considered an alcoholic, and shuttled in and
out of mental institutions and hospitals for years before being properly
diagnosed. His case, sadly, is not extraordinary, although the diagnosis
can be made easily by experienced neurologists.
The discovery of the HD gene in 1993 resulted in a
direct genetic test to make or confirm a diagnosis of HD in an
individual who is exhibiting HD-like symptoms. Using a blood sample, the
genetic test analyzes DNA for the HD mutation by counting the number of
repeats in the HD gene region. Individuals who do not have HD usually
have 28 or fewer CAG repeats. Individuals with HD usually have 40 or
more repeats. A small percentage of individuals, however, have a number
of repeats that fall within a borderline region (see table
1).
Table 1
| No. of CAG repeats |
Outcome
|
| < 28 |
Normal range; individual will not
develop HD |
| 29-34 |
Individual will not develop HD but
the next generation is at risk |
| 35-39 |
Some, but not all, individuals in
this range will develop HD; next generation is also at risk |
| > 40 |
Individual will develop HD |
The physician will interview the individual
intensively to obtain the medical history and rule out other conditions.
He or she will perform a neurological examination including tests of the
person's hearing, eye movements, strength, sensation, reflexes, balance,
movement, and mental status, and will probably order a number of
laboratory tests as well. Together, these tests form the neurological
examination. In addition, the physician will ask about recent
intellectual or emotional problems, which may be indications of HD.
In addition to direct testing, another tool used by
physicians to diagnose HD is to take the family history, sometimes
called a pedigree or genealogy. It is extremely important for family
members to be candid and truthful with a doctor who is taking a family
history.
People with HD commonly have impairments in the way
the eye follows or fixes on a moving target. Abnormalities of eye
movements vary from person to person and differ depending on the stage
and duration of the illness.
The physician may ask the individual to undergo a
brain imaging test. The computed tomography (CT) scanner provides
an excellent image of brain structures with little if any discomfort.
Those with HD may show shrinkage of some parts of the
brain--particularly two areas known as the caudate nuclei and putamen--and
enlargement of cavities within the brain called ventricles. These
changes do not definitely indicate HD however, because they can also
occur in other disorders. In addition, a person can have early symptoms
of HD and still have a normal CT scan. When used in conjunction with a
family history and record of clinical symptoms, however, CT can be an
important diagnostic tool.
Other technologies for brain visualization, such as magnetic
resonance imaging (MRI) and positron emission tomography (PET),
are an important part of HD research efforts, but their usefulness to
physicians trying to diagnose HD has not yet been established.
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What is Pre-symptomatic Testing?
Pre-symptomatic testing is a method for identifying
persons carrying the HD gene before symptoms appear. 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 pre-symptomatic 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 pre-symptomatic 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.
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. These are among the
many complicating factors that reflect the complexity of diagnosing HD.
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How is the Pre-symptomatic Test
Conducted?
An individual who wishes to be tested should contact
the nearest testing center. (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 counseling, the individual will learn about HD, about his
or her own level of risk, and 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 counselors, 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 counseling sessions by a spouse, a friend, or a
relative who is not at risk. Other interested family members may
participate in the counseling 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 centers 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
counseling 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 pre-implantation 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 center 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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How Does a Person Decide Whether
to be Tested?
The anxiety that comes from living with a 50 percent
risk for HD can be overwhelming. How does a young person make important
choices about long-term education, marriage, and children? How do older
parents of adult children cope with their fears about children and
grandchildren? How do people come to terms with the ambiguity and
uncertainty of living at risk?
Some individuals choose to undergo the test out of a
desire for greater certainty about their genetic status. They believe
the test will enable them to make more informed decisions about the
future. Others choose not to take the test. They are at peace with being
at risk and with all that that may entail. There is no right or wrong
decision, as each choice is highly individual. The guidelines for
genetic testing for HD, discussed in the previous section, were
developed to help people with this life-changing choice.
Whatever the results of genetic testing, the at-risk
individual and family members can expect powerful and complex emotional
responses. The health and happiness of spouses, brothers and sisters,
children, parents, and grandparents are affected by a positive test
result, as are an individual's friends, work associates, neighbors, and
others. Because receiving test results may prove to be devastating,
testing guidelines call for continued counseling even after the test is
complete and the results are known.
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Is There a Treatment for HD?
Physicians may prescribe a number of medications to
help control emotional and movement problems associated with HD. It is
important to remember however, that while medicines may help keep these
clinical symptoms under control, there is no treatment to stop or
reverse the course of the disease.
Antipsychotic drugs, such as haloperidol, or other
drugs, such as clonazepam, may help to alleviate choreic movements and
may also be used to help control hallucinations, delusions, and violent
outbursts. Antipsychotic drugs, however, are not prescribed for another
form of muscle contraction associated with HD, called dystonia, and may
in fact worsen the condition, causing stiffness and rigidity. These
medications may also have severe side effects, including sedation, and
for that reason should be used in the lowest possible doses.
For depression, physicians may prescribe fluoxetine,
sertraline hydrochloride, nortriptyline, or other compounds.
Tranquilizers can help control anxiety and lithium may be prescribed to
combat pathological excitement and severe mood swings. Medications may
also be needed to treat the severe obsessive-compulsive rituals of some
individuals with HD.
Most drugs used to treat the symptoms of HD have side
effects such as fatigue, restlessness, or hyperexcitability. Sometimes
it may be difficult to tell if a particular symptom, such as apathy or
incontinence, is a sign of the disease or a reaction to medication.
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What Kind of Care Does the
Individual with HD Need?
Although a psychologist or psychiatrist, a genetic
counselor, and other specialists may be needed at different stages of
the illness, usually the first step in diagnosis and in finding
treatment is to see a neurologist. While the family doctor may be able
to diagnose HD, and may continue to monitor the individual’s status,
it is better to consult with a neurologist about management of the
varied symptoms.
Problems may arise when individuals try to express
complex thoughts in words they can no longer pronounce intelligibly. It
can be helpful to repeat words back to the person with HD so that he or
she knows that some thoughts are understood. Sometimes people mistakenly
assume that if individuals do not talk, they also do not understand.
Never isolate individuals by not talking, and try to keep their
environment as normal as possible. Speech therapy may improve the
individual’s ability to communicate.
It is extremely important for the person with HD to
maintain physical fitness as much as his or her condition and the course
of the disease allows. Individuals who exercise and keep active tend to
do better than those who do not. A daily regimen of exercise can help
the person feel better physically and mentally. Although their
coordination may be poor, individuals should continue walking, with
assistance if necessary. Those who want to walk independently should be
allowed to do so as long as possible, and careful attention should be
given to keeping their environment free of hard, sharp objects. This
will help ensure maximal independence while minimizing the risk of
injury from a fall. Individuals can also wear special padding during
walks to help protect against injury from falls. Some people have found
that small weights around the ankles can help stability. Wearing sturdy
shoes that fit well can help too, especially shoes without laces that
can be slipped on or off easily.
Impaired coordination may make it difficult for people
with HD to feed themselves and to swallow. As the disease progresses,
persons with HD may even choke. In helping individuals to eat,
caregivers should allow plenty of time for meals. Food can be cut into
small pieces, softened, or pureed to ease swallowing and prevent
choking. While some foods may require the addition of thickeners, other
foods may need to be thinned. Dairy products, in particular, tend to
increase the secretion of mucus, which in turn increases the risk of
choking. Some individuals may benefit from swallowing therapy, which is
especially helpful if started before serious problems arise. Suction
cups for plates, special tableware designed for people with
disabilities, and plastic cups with tops can help prevent spilling. The
individual's physician can offer additional advice about diet and about
how to handle swallowing difficulties or gastrointestinal problems that
might arise, such as incontinence or constipation.
Caregivers should pay attention to proper nutrition so
that the individual with HD takes in enough calories to maintain his or
her body weight. Sometimes people with HD, who may burn as many as 5,000
calories a day without gaining weight, require five meals a day to take
in the necessary number of calories. Physicians may recommend vitamins
or other nutritional supplements. In a long-term care institution, staff
will need to assist with meals in order to ensure that the individual's
special caloric and nutritional requirements are met. Some individuals
and their families choose to use a feeding tube; others choose not to.
Individuals with HD are at special risk for
dehydration and therefore require large quantities of fluids, especially
during hot weather. Bendable straws can make drinking easier for the
person. In some cases, water may have to be thickened with commercial
additives to give it the consistency of syrup or honey.
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What Community Resources are
Available?
Individuals and families affected by HD can take steps
to ensure that they receive the best advice and care possible.
Physicians and state and local health service agencies can provide
information on community resources and family support groups that may
exist. Possible types of help include:
•Legal and social aid. HD affects a person's
capacity to reason, make judgments, and handle responsibilities.
Individuals may need help with legal affairs. Wills and other important
documents should be drawn up early to avoid legal problems when the
person with HD may no longer be able to represent his or her own
interests. Family members should also seek out assistance if they face
discrimination regarding insurance, employment, or other matters.
•Home care services. Caring for a person with
HD at home can be exhausting, but part-time assistance with household
chores or physical care of the individual can ease this burden. Domestic
help, meal programs, nursing assistance, occupational therapy, or other
home services may be available from federal, state, or local health
service agencies.
•Recreation and work centers. Many people
with HD are eager and able to participate in activities outside the
home. Therapeutic work and recreation centers give individuals an
opportunity to pursue hobbies and interests and to meet new people.
Participation in these programs, including occupational, music, and
recreational therapy, can reduce the person’s dependence on family
members and provides home caregivers with a temporary, much needed
break.
•Group housing. A few communities have group
housing facilities that are supervised by a resident attendant and that
provide meals, housekeeping services, social activities, and local
transportation services for residents. These living arrangements are
particularly suited to the needs of individuals who are alone and who,
although still independent and capable, risk injury when they undertake
routine chores like cooking and cleaning.
•Institutional care. The individual’s
physical and emotional demands on the family may eventually become
overwhelming. While many families may prefer to keep relatives with HD
at home whenever possible, a long-term care facility may prove to be
best. To hospitalize or place a family member in a care facility is a
difficult decision; professional counseling can help families with this.
Finding the proper facility can itself prove
difficult. Organizations such as the Huntington's Disease Society of
America (see Information Resources) may be able to refer the family to
facilities that have met standards set for the care of individuals with
HD. Very few of these exist however, and even fewer have experience with
individuals with juvenile or early-onset HD who require special care
because of their age and symptoms.
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What Research is Being Done?
Although HD attracted considerable attention from
scientists in the early 20th century, there was little sustained
research on the disease until the late 1960s when the Committee to
Combat Huntington’s Disease and the Huntington’s Chorea Foundation,
later called the Hereditary Disease Foundation, first began to fund
research and to campaign for federal funding. In 1977, Congress
established the Commission for the Control of Huntington's Disease and
Its Consequences, which made a series of important recommendations.
Since then, Congress has provided consistent support for federal
research, primarily through the National Institute of Neurological
Disorders and Stroke, the government’s lead agency for biomedical
research on disorders of the brain and nervous system. The effort to
combat HD proceeds along the following lines of inquiry, each providing
important information about the disease:
•Basic neurobiology. Now
that the HD gene has been located, investigators in the field of
neurobiology—which encompasses the anatomy, physiology, and
biochemistry of the nervous system—are continuing to study the HD gene
with an eye toward understanding how it causes disease in the human
body.
•Clinical research.
Neurologists, psychologists, psychiatrists, and other investigators are
improving our understanding of the symptoms and progression of the
disease in patients while attempting to develop new therapeutics.
•Imaging. Scientific
investigations using PET and other technologies are enabling scientists
to see what the defective gene does to various structures in the brain
and how it affects the body's chemistry and metabolism.
•Animal models.
Laboratory animals, such as mice, are being bred in the hope of
duplicating the clinical features of HD and can soon be expected to help
scientists learn more about the symptoms and progression of the disease.
•Fetal tissue research.
Investigators are implanting fetal tissue in rodents and nonhuman
primates with the hope that success in this area will lead to
understanding, restoring, or replacing functions typically lost by
neuronal degeneration in individuals with HD.
These areas of research are slowly converging and, in
the process, are yielding important clues about the gene's relentless
destruction of mind and body. The NINDS supports much of this exciting
work.
Molecular Genetics
For 10 years, scientists focused on a segment of
chromosome 4 and, in 1993, finally isolated the HD gene. The process of
isolating the responsible gene--motivated by the desire to find a
cure--was more difficult than anticipated. Scientists now believe that
identifying the location of the HD gene is the first step on the road to
a cure.
Finding the HD gene involved an intense molecular
genetics research effort with cooperating investigators from around the
globe. In early 1993, the collaborating scientists announced they had
isolated the unstable triplet repeat DNA sequence that has the HD gene.
Investigators relied on the NINDS-supported Research Roster for
Huntington's Disease, based at Indiana University in Indianapolis, to
accomplish this work. First started in 1979, the roster contains data on
many American families with HD, provides statistical and demographic
data to scientists, and serves as a liaison between investigators and
specific families. It provided the DNA from many families affected by HD
to investigators involved in the search for the gene and was an
important component in the identification of HD markers.
For several years, NINDS-supported investigators
involved in the search for the HD gene made yearly visits to the largest
known kindred with HD--14,000 individuals--who live on Lake
Maracaibo in Venezuela. The continuing trips enable scientists to study
inheritance patterns of several interrelated families.
The HD Gene and Its Product
Although scientists know that certain brain cells die
in HD, the cause of their death is still unknown. Recessive diseases are
usually thought to result from a gene that fails to produce adequate
amounts of a substance essential to normal function. This is known as a
loss-of-function gene. Some dominantly inherited disorders, such as HD,
are thought to involve a gene that actively interferes with the normal
function of the cell. This is known as a gain-of-function gene.
How does the defective HD gene cause harm? The HD gene
encodes a protein--which has been named huntingtin--the function
of which is as yet unknown. The repeated CAG sequence in the gene causes
an abnormal form of huntingtin to be made, in which the amino acid
glutamine is repeated. It is the presence of this abnormal form, and not
the absence of the normal form, that causes harm in HD. This explains
why the disease is dominant and why two copies of the defective
gene--one from both the mother and the father--do not cause a more
serious case than inheritance from only one parent. With the HD gene
isolated, NINDS-supported investigators are now turning their attention
toward discovering the normal function of huntingtin and how the altered
form causes harm. Scientists hope to reproduce, study, and correct these
changes in animal models of the disease.
Huntingtin is found everywhere in the body but only
outside the cell’s nucleus. Mice bred in the laboratory to produce no
huntingtin fail to develop past a very early embryo stage and quickly
die. Huntingtin, scientists now know, is necessary for life.
Investigators hope to learn why the abnormal version of the protein
damages only certain parts of the brain. One theory is that cells in
these parts of the brain may be supersensitive to this abnormal protein.
Return to table of contents
Cell Death in HD
Although the precise cause of cell death in HD is not
yet known, scientists are paying close attention to the process of
genetically programmed cell death that occurs deep within the brains of
individuals with HD. This process involves a complex series of
interlinked events leading to cellular suicide. Related areas of
investigation include:
- Excitotoxicity. Overstimulation of cells by
natural chemicals found in the brain.
- Defective energy metabolism. A defect in the
power plant of the cell, called mitochondria, where energy
is produced.
- Oxidative stress. Normal metabolic activity
in the brain that produces toxic compounds called free radicals.
- Trophic factors. Natural chemical substances
found in the human body that may protect against cell death.
Several HD studies are aimed at understanding losses
of nerve cells and receptors in HD. Neurons in the striatum are
classified both by their size (large, medium, or small) and appearance
(spiny or aspiny). Each type of neuron contains combinations of neurotransmitters.
Scientists know that the destructive process of HD affects different
subsets of neurons to varying degrees. The hallmark of HD, they are
learning, is selective degeneration of medium-sized spiny neurons in the
striatum. NINDS-supported studies also suggest that losses of certain
types of neurons and receptors are responsible for different symptoms
and stages of HD.
What do these changes look like? In spiny neurons,
investigators have observed two types of changes, each affecting the
nerve cells' dendrites. Dendrites, found on every nerve cell, extend out
from the cell body and are responsible for receiving messages from other
nerve cells. In the intermediate stages of HD, dendrites grow out of
control. New, incomplete branches form and other branches become
contorted. In advanced, severe stages of HD, degenerative changes cause
sections of dendrites to swell, break off, or disappear altogether.
Investigators believe that these alterations may be an attempt by the
cell to rebuild nerve cell contacts lost early in the disease. As the
new dendrites establish connections, however, they may in fact
contribute to nerve cell death. Such studies give compelling, visible
evidence of the progressive nature of HD and suggest that new
experimental therapies must consider the state of cellular degeneration.
Scientists do not yet know exactly how these changes affect subsets of
nerve cells outside the striatum.
Return to table of contents
Animal Models for HD
As more is learned about cellular degeneration in HD,
investigators hope to reproduce these changes in animal models and to
find a way to correct or halt the process of nerve cell death. Such
models serve the scientific community in general by providing a means to
test the safety of new classes of drugs in nonhuman primates. NINDS-supported
scientists are currently working to develop both nonhuman primate and
mouse models to investigate nerve degeneration in HD and to study the
effects of excitotoxicity on nerve cells in the brain.
Investigators are working to build genetic models of
HD using transgenic mice. To do this, scientists transfer the
altered human HD gene into mouse embryos so that the animals will
develop the anatomical and biological characteristics of HD. This
genetic model of mouse HD will enable in-depth study of the disease and
testing of new therapeutic compounds.
Another idea is to insert into mice a section of DNA
containing CAG repeats in the abnormal, disease gene range. This mouse
equivalent of HD could allow scientists to explore the basis of CAG
instability and its role in the disease process.
Return to "Research"
section or table of contents
Fetal Tissue Research
A relatively new field in biomedical research involves
the use of brain tissue grafts to study, and potentially treat,
neurodegenerative disorders. In this technique, tissue that has
degenerated is replaced with implants of fresh, fetal tissue, taken at
the very early stages of development. Investigators are interested in
applying brain tissue implants to HD research. Extensive animal studies
will be required to learn if this technique could be of value in
individuals with HD.
Return to "Research"
section or table of contents
Clinical Studies
Scientists are pursuing clinical studies that may one
day lead to the development of new drugs or other treatments to halt the
disease's progression. Examples of NINDS-supported investigations, using
both asymptomatic and symptomatic individuals, include:
•Genetic studies on age of onset,
inheritance patterns, and markers found within families.
These studies may shed additional light on how HD is passed from
generation to generation.
•Studies of cognition, intelligence, and
movement. Studies of abnormal eye movements, both
horizontal and vertical, and tests of patients' skills in a number of
learning, memory, neuropsychological, and motor tasks may serve to
identify when the various symptoms of HD appear and to characterize
their range and severity.
•Clinical trials of drugs.
Testing of various drugs may lead to new treatments and at the same time
improve our understanding of the disease process in HD. Classes of drugs
being tested include those that control symptoms, slow the rate of
progression of HD, and block effects of excitotoxins, and those that
might correct or replace other metabolic defects contributing to the
development and progression of HD.
Return to "Research"
section or table of contents
Imaging
NINDS-supported scientists are using positron emission
tomography (PET) to learn how the gene affects the chemical systems of
the body. PET visualizes metabolic or chemical abnormalities in the
body, and investigators hope to ascertain if PET scans can reveal any
abnormalities that signal HD. Investigators conducting HD research are
also using PET to characterize neurons that have died and chemicals that
are depleted in parts of the brain affected by HD.
Like PET, a form of magnetic resonance imaging (MRI)
called functional MRI can measure increases or decreases in certain
brain chemicals thought to play a key role in HD. Functional MRI studies
are also helping investigators understand how HD kills neurons in
different regions of the brain.
Imaging technologies allow investigators to view
changes in the volume and structures of the brain and to pinpoint when
these changes occur in HD. Scientists know that in brains affected by
HD, the basal ganglia, cortex, and ventricles all show atrophy or other
alterations.
Return to "Research"
section or table of contents
How Can I Help?
In order to conduct HD research, investigators require
samples of tissue or blood from families with HD. Access to individuals
with HD and their families may be difficult however, because families
with HD are often scattered across the country or around the world. A
research project may need individuals of a particular age or gender or
from a certain geographic area. Some scientists need only statistical
data while others may require a sample of blood, urine, or skin from
family members. All of these factors complicate the task of finding
volunteers. The following NINDS-supported efforts bring together
families with HD, voluntary health agencies, and scientists in an effort
to advance science and speed a cure.
Return to table of contents
The NINDS-sponsored HD Research Roster at the Indiana
University Medical Center in Indianapolis, which was discussed earlier,
makes research possible by matching scientists with patient and family
volunteers. The first DNA bank was established through the roster.
Although the gene has already been located, DNA from individuals who
have HD is still of great interest to investigators. Of continuing
interest are twins, unaffected individuals who have affected offspring,
and individuals with two defective HD genes, one from each parent—a
very rare occurrence. Participation in the roster and in specific
research projects is voluntary and confidential. For more information
about the roster and DNA bank, contact:
Indiana University Medical Center
Department of Medical and Molecular Genetics
Medical Research and Library Building
975 W. Walnut Street
Indianapolis, IN 46202-5251
(317) 274-5744 (call collect)
Return to table of contents
Brain tissue is also critical to the HD research
effort, and many individuals are willing to donate their brains and
other organs to research after they die. The NINDS supports two national
human brain specimen banks, one at the Wadsworth Veterans Administration
Medical Center in Los Angeles, and the other at McLean Hospital near
Boston. These banks supply investigators around the world with tissue
not only from individuals with HD but also from those with other
neurological or psychiatric diseases. Both banks need brain tissue to
enable scientists to study these disorders more intensely. Prospective
donors should contact:
Wallace W. Tourtellotte, M.D., Ph.D.
Director, National Neurological Research Specimen Bank
VA Wadsworth Medical Center Neurology Research
Wilshire & Sawtelle Boulevards
Los Angeles, CA 90073
(310) 268-3536 (call collect)
Francine M. Benes, M.D., Ph.D.
Director, Harvard Brain Tissue Resource Center
Mailman Research Center, McLean Hospital
115 Mill Street
Belmont, MA 02178
(617) 855-2400 (call collect)
(800) 272-4622
Return to table of contents
What is the Role of Voluntary
Organizations?
Private organizations have been a mainstay of support
and guidance for at-risk individuals, people with HD, and their
families. These organizations vary in size and emphasis, but all are
concerned with helping individuals and their families, educating lay and
professional audiences about HD, and promoting medical research on the
disorder. Some voluntary health agencies support scientific workshops
and research and some have newsletters and local chapters throughout the
country. These agencies enable families, health professionals, and
investigators to exchange information, learn of available services and
benefits, and work toward common goals. The organizations listed in the
Information Resources section of this brochure welcome inquiries from
the public.
Return to table of contents
Glossary
- akinesia—impaired body movement.
- at-risk—a description of a person
whose mother or father has HD or has inherited the HD gene and who
therefore has a 50-50 chance of inheriting the disorder.
- autosomal dominant disorder—a
non-sex-linked disorder that can be inherited even if only one
parent passes on the defective gene.
- basal ganglia—a region located at
the base of the brain composed of four clusters of neurons, or nerve
cells. This area is responsible for body movement and coordination.
The neuron groups most prominently and consistently affected by
HD--the pallidum and striatum--are located here. See neuron,
pallidum, striatum.
- caudate nuclei—part of the striatum
in the basal ganglia. See basal ganglia, striatum.
- chorea—uncontrolled body movements.
Chorea is derived from the Greek word for dance.
- chromosomes—the structures in cells
that contain genes. They are composed of deoxyribonucleic acid (DNA)
and proteins and, under a microscope, appear as rod-like structures.
See deoxyribonucleic acid (DNA), gene.
- computed tomography (CT)—a
technique used for diagnosing brain disorders. CT uses a computer to
produce a high-quality image of brain structures. These images are
called CT scans.
- cortex—part of the brain
responsible for thought, perception, and memory. HD affects the
basal ganglia and cortex. See basal ganglia.
- deoxyribonucleic acid (DNA)—the
substance of heredity containing the genetic information necessary
for cells to divide and produce proteins. DNA carries the code for
every inherited characteristic of an organism. See gene.
- dominant—a trait that is apparent
even when the gene for that disorder is inherited from only one
parent. See autosomal dominant disorder, recessive, gene.
- gene—the basic unit of heredity,
composed of a segment of DNA containing the code for a specific
trait. See deoxyribonucleic acid (DNA).
- huntingtin—the protein encoded by
the gene that carries the HD defect. The repeated CAG sequence in
the gene causes an abnormal form of huntingtin to be formed. The
function of the normal form of huntingtin is not yet known.
- kindred—a group of related persons,
such as a family or clan.
- magnetic resonance imaging (MRI)—an
imaging technique that uses radiowaves, magnetic fields, and
computer analysis to create a picture of body tissues and
structures.
- marker—a piece of DNA that lies on
the chromosome so close to a gene that the two are inherited
together. Like a signpost, markers are used during genetic testing
and research to locate the nearby presence of a gene. See
chromosome, deoxyribonucleic acid (DNA).
- mitochondria—microscopic,
energy-producing bodies within cells that are the cells’
"power plants."
- mutation—in genetics, any defect in
a gene. See gene.
- myoclonus—a condition in which
muscles or portions of muscles contract abnormally.
- neuron—a nerve cell, the basic
impulse-conducting unit of the nervous system. Nerve cells
communicate with other cells through an electrochemical process
called neurotransmission.
- neurotransmitters—special chemicals
that transmit nerve impulses from one cell to another.
- pallidum—part of the basal ganglia
of the brain. The pallidum is composed of the globus pallidus and
the ventral pallidum. See basal ganglia.
- positron emission tomography (PET)—a
tool used to diagnose brain functions and disorders. PET produces
three-dimensional, colored images of chemicals or substances
functioning within the body. These images are called PET scans.
- prevalence—the number of cases of a
disease that are present in a particular population at a given time.
- putamen—an area of the brain that
decreases in size as a result of the damage produced by HD.
- receptor—recognition sites on cells
that cause a response in the body when stimulated by certain
chemicals called neurotransmitters. They act as on-and-off switches
for the next nerve cell. See neuron, neurotransmitters.
- recessive—a trait that is apparent
only when the gene or genes for it are inherited from both parents. See
dominant, gene.
- senile chorea—a relatively mild and
rare disorder found in elderly adults and characterized by choreic
movements. It is believed by some scientists to be caused by a
different gene mutation than that causing HD.
- striatum—part of the basal ganglia
of the brain. The striatum is composed of the caudate nucleus,
putamen, and ventral striatum. See basal ganglia, caudate
nuclei.
- trait—any genetically determined
characteristic. See dominant, gene, recessive.
- transgenic mice—mice
that receive injections of foreign genes during the embryonic stage
of development. Their cells then follow the "instructions"
of the foreign genes, resulting in the development of a certain
trait or characteristic. Transgenic mice can serve as an animal
model of a certain disease, telling researchers how genes work in
specific cells.
- ventricles—cavities within the
brain that are filled with cerebrospinal fluid. In HD, tissue loss
causes enlargement of the ventricles.
Return to table of contents
Information Resources (last
updated April 7, 1998)
NIH Neurological Institute
P.O. Box 5801
Bethesda, MD 20824
(301) 496-5751
(800) 352-9424
The National Institute of Neurological Disorders and
Stroke, a component of the National Institutes of Health, is the leading
Federal supporter of research on disorders of the brain and nervous
system. The Institute also sponsors an active public information program
with staff who can answer questions about diagnosis and research related
to Huntington's disease.
Private voluntary organizations that provide the
public with information on treatment, diagnosis, and services include
the following:
Huntington's Disease Society of America (HDSA)
140 West 22nd Street, 6th Floor
New York, NY 10011-2420
(212) 242-1968
(800) 345-HDSA (345-4372)
The HDSA supports research, assists and educates
families, trains professionals about Huntington's disease, and monitors
testing guidelines. The Society publishes brochures, pamphlets, a
newsletter, reprints, and listings of testing centers. It also sponsors
conferences, training programs, and nationwide chapters and support
groups.
Hereditary Disease Foundation
1427 Seventh Street, Suite 2
Santa Monica, CA 90401
(310) 458-4183
This foundation promotes research on genetic disorders
and sponsors workshops and fellowship programs. The group provides
additional support to the two brain banks noted above.
National Institute of Neurological Disorders and
Stroke
National Institutes of Health
Bethesda, MD 20892
