Huntington's disease
Huntington's disease is a degenerative brain disorder that usually appears in mid-life. Its symptoms, which include involuntary movement of the face and limbs, mood swings, and forgetfulness, get worse as the disease progresses. It is generally fatal within 20 years.
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 have made a number of breakthroughs in the area of HD research. With these advances, our understanding of the disease continues to improve.
Causes
HD 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?
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 DNA (deoxyribonucleic acid), 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 in 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 30,000 genes – a 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.
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. 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 HD 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.
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.
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.
Diagnosis
The great American folk singer and composer Woody Guthrie died on Oct 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.
A neurologist will interview the individual intensively to obtain the medical history and rule out other conditions. A 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.
The doctor will also ask about recent intellectual or emotional problems, which may be indications of HD, and will test the person's hearing, eye movements, strength, coordination, involuntary movements (chorea), sensation, reflexes, balance, movement, and mental status, and will probably order a number of laboratory tests as well.
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 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 below).
| No. of CAG repeats | Outcome |
| < or = 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 |
| > or = 40 | Individual will develop HD |
The physician may ask the individual to undergo a brain imaging test. Computed tomography (CT) and magnetic resonance imaging (MRI) provide excellent images 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 fluid-filled 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.
Another technology for brain imaging includes positron emission tomography (PET,) which is important in HD research efforts but is not often needed for diagnosis.
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.
How the presymptomatic test is conducted
An individual who wishes to be tested should contact the nearest testing center. (In the United States, 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, 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 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 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 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.
How does a person decide whether to be tested?
The anxiety that comes from living with a 50% 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 able to make peace with the uncertainty of being at risk, preferring to forego the emotional consequences of a positive result, as well as possible losses of insurance and employment. 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.
Treatment
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, 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.
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.
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 listing on the Information Resources card in the back pocket of this brochure) 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.
Research
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 called "knockout mice" are bred in the laboratory to produce no huntingtin; they 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.
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:
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.
Animal models of 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.
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 patients with HD.
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.
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.
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 on the Information Resources card in the back pocket of this brochure welcome inquiries from the public.
