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About Huntington Disease (HD) |
Huntington disease (HD) is an inherited brain disorder affecting the nervous system. It causes progressive deterioration of physical and mental capabilities, leading ultimately to severe incapacitation and eventual death, generally 15-25 years after onset. Primarily, it affects adults, usually appearing between the ages of 30 and 45. Occasionally, HD symptoms appear earlier (before age 20, the juvenile form) or later (after age 50.) Common symptoms of adult-onset HD are involuntary movements, abnormal gait, slurred speech, difficulty with swallowing, cognitive impairment and personality changes.
Each child of an affected parent has a 50% chance of inheriting HD.
The symptoms of Huntington disease most frequently appear between the ages of 30 and 45. If symptoms have not appeared by 45, the probability that a person will develop HD grows less with each year of life. Symptoms rarely appear in a person who is 70 or over. It must be emphasized that there is much variation and not every person has all the difficulties mentioned here. While some individuals may have a great deal of difficulty with involuntary movements, others have very little. Similarly, some individuals may have more marked emotional or cognitive problems than others.
Early symptoms may appear as slight physical, cognitive or emotional changes. Physical symptoms may initially consist of "nervous" activity, fidgeting, a twitching in the extremities, or excessive restlessness. The individual may notice a certain clumsiness, alterations in handwriting, or difficulty with normal daily physical skills such as driving. These initial motor symptoms will gradually develop into more marked involuntary movements such as jerking and twitching of the head, neck, arms and legs, which may interfere with walking, speaking and swallowing. There are exceptions to this. Sometimes people with HD have a minimum of difficulty with chorea (involuntary movements). Where chorea is present, the movements usually increase during voluntary effort, stress or excitement, tend to decrease during rest, and disappear entirely during sleep for many people.
In addition to the initial physical symptoms of HD, there are often very subtle cognitive signs as well. These may involve little more than a reduced ability to organize routine matters or to cope effectively with new situations. There may be a loss of short-term memory which may occur several times each day. Work activities may become more time-consuming. Decision making and attention to details may be impaired.
Early emotional symptoms may be equally subtle. There may be more periods of depression, apathy, irritability, or impulsiveness, or there may be a change in personality. Rarely, a person may become delusional or paranoid.
All of these signs add to the concerns of the person living at risk of HD because on an "off day" all of us experience such things. It is quite usual for healthy people to be somewhat clumsy, or a bit fidgety when anxious or under stress, or to twitch or jerk when dropping off to sleep. At risk or presymptomatic (those with an increased risk after testing) individuals are well advised not to worry too much about the occasional stumble or forgetting a phone number, as these experiences happen to all of us and do not necessarily signify the onset of the disease.
Similarly, an at-risk or presymptomatic person must not assume that
every little outburst or bout of depression is the start of HD. From time
to time, all of us are depressed, apathetic, irritable or impulsive. Anyone
who becomes concerned about changes in his/her physical, cognitive or emotional
behaviour should consult a doctor familiar with the detection and treatment
of Huntington's and related neurological disorders.
There has been relatively little meticulous research into the progressive development of the disorder in people with Huntington disease, though the situation is now changing thanks largely to the work of the Huntington Study Group.
One study suggests that the course of HD may not be as rapidly progressive or incapacitating as widely believed. Dr. Ira Shoulson, Professor of Neurology, Pharmacology & Medicine, University of Rochester Medical Center and his team have proposed a five-stage functional approach to HD. Briefly, these stages are as follows:
Death usually occurs 15 to 25 years after onset of the disease. The
person dies, not from the disease itself, but from complications such as
pneumonia, heart failure or infection developing from the weakened condition
of the body.
Until recently, no test was available to tell if a person showing possible signs and symptoms of Huntington disease was indeed carrying the gene that causes HD. In addition, a variety of subtle early symptoms may also be present in other conditions. A physician, very often a neurologist, diagnoses HD by evaluating clinical signs and symptoms and obtaining a family history. It is extremely important for family members to give all relevant information to the doctor who is taking a family history, because this is a vital part of the diagnostic process. Be sure to mention any relatives who have experienced mental problems, or been diagnosed as having other neurological or psychiatric conditions, e.g. Parkinson Disease, schizophrenia.
With our current knowledge, the physician may request confirmatory testing
to see if the gene that causes HD is present. This may occur in cases where
HD is suspected or where there is no, or an inconclusive, family history.
In hereditary diseases, such as Huntington's, earlier than average onset of symptoms usually means more severe disease. There is usually a shorter course and a greater variety of symptoms. Children with HD show a disorder of movement and posture somewhat different than the usual HD adult, a disorder of mental function, and often a convulsive disorder or tendency to epileptic seizures, something almost never seen in HD adults. The earlier the disease onset, the more likely the child is to be very rigid and very different in appearance form the majority of adult cases. Clinical symptoms differ between early onset and adult onset HD. In 1969, it was determined that children with HD, both boys and girls, were much more likely to have an affected father than an affected mother. Through research and observation, we are learning more about this rare form of HD each day. For more information, the booklet Living with Juvenile Huntington Disease is available from HSC.
There are four main areas of HD research:
In 1872, Dr. George Huntington published an article describing a disease that was subsequently named after him. Over a hundred years later, in 1983, Dr. Jim Gusella�s research team at Massachusetts General Hospital in Boston narrowed down the location of the gene that causes HD to chromosome 4. In 1993, after ten more years of arduous research, an international consortium of scientists announced the discovery of the Huntington gene.
This discovery was a tremendous breakthrough, but the gene is only the first in a series of biochemical steps that ultimately lead to brain cell death in people with Huntington�s. Researchers are now investigating the other steps to find out what the gene does and why it behaves differently in people with HD.
It was recognized very early on that the error in the Huntington�s gene lies in an area called the �CAG� repeat region. Genes are made up of DNA, and DNA molecules consist of four bases known as adenine (A), thymine (T), guanine (G), and cytosine (C). The gene that causes HD contains a region in which a specific sequence of three bases (CAG) is repeated many times. In the normal gene, there are 26 or fewer CAG repeats,the intermediate range is 27 to 41, while the mutant version of the gene contains 42 or more. For more detailed information on CAG repeats.
The HD gene produces a protein called �huntingtin�. This protein, like the gene, has one section that is too long - this is called a �polyglutamine expansion�. The extra CAG repeats in the gene code for extra glutamines at one end of the protein, so the mutant form of huntingtin is longer than its normal counterpart.
Although researchers don�t know what huntingtin does, they have made some important discoveries about this protein. We know that everyone has huntingtin in their body, and that huntingtin is found in virtually all of our cells. What we need to find out is why the version of the protein that causes Huntington�s causes cell death only in certain types of brain cells.
Recent findings are moving us steadily closer to solving this mystery. For example, we now know that huntingtin gets broken down into a smaller protein by a process called cleavage, and we know that the smaller protein is much more toxic than the normal full-length version.
These smaller pieces of huntingtin stick to one another and form a �protein ball�, and this protein ball is thought to be involved in brain cell death. It�s particularly interesting that similar protein balls are formed in several other neurodegenerative diseases, including Alzheimer�s, which suggests that there may be some common mechanism at work.
The protein balls can be found in both the nucleus and cytoplasm of brain cells, but they appear to be most toxic when they are found in the cell nucleus.
So we know now of three main biochemical events that occur in Huntington�s: protein cleavage, the formation of protein balls, and the movement of protein balls to the cell nucleus. This gives scientists three possible strategies for preventing cell death: preventing cleavage, preventing the formation of protein balls, and preventing protein balls from accumulating in the nucleus of the cell.
Animal models give scientists a crucial tool for studying the development of the disease and the process of brain cell death that occurs in Huntington�s. Furthermore, once drugs or other forms of treatment are developed, they can be tested on the animal model to make sure they are safe and effective before they are used on humans.
We now have several models for Huntington�s, including mice, worms, fruit flies, and yeast. For example, researchers have been able to take the human HD gene and put it into mice embryos. As the mice grow up, they begin to show symptoms of the disease. By the time the HD mouse is three to six weeks old, it begins to lose weight and exhibit abnormal, hyperactive movements. As it gets older, it develops chorea-like movements of the neck and face. And after the mouse dies, autopsies show that certain areas of the brain have died -- the same areas that are affected in humans with Huntington�s.
There have also been big steps forward in clinical research, thanks to the efforts of the Huntington Study Group, an international consortium of physicians, psychologists, psychiatrists and neurologists.
There are several abnormalities in the brain cells of people with HD that may cause them to die. One is over-reaction to glutamate, a neurotransmitter that occurs naturally in the brain. Remacemide reduces the activity of glutamate, and it may therefore help to protect the brain cells.
Another problem in the brain cells of people with HD is a lack of energy -- their mitochondria don�t seem to produce as much energy as the mitochondria in normal cells. Co-enzyme Q10 increases energy production, and also protects the cells from the damage caused by harmful free radicals.
The 340 patients in the CARE-HD study have been divided into four groups. One group is receiving remacemide, one group is receiving co-enzyme Q10, the third group is receiving both, and the fourth group is receiving a placebo. Studies began at four Canadian sites in 1997, but because CARE-HD is a multi-year study, the results won�t be available for some time.
Brain cell transplantation is a surgical technique that replaces the brain tissue that has degenerated in someone with HD with implants of fresh brain cells that will grow and multiply, form connections with the existing brain cells, and eventually take over the function of the cells that have died. Because adult brain cells can�t normally regenerate, scientists have relied on brain tissue from aborted fetuses as a source of new cells.
Several studies on animal models of HD have shown this can be done successfully, and the animals gain back some of the functions they lost as a result of the disease. A few centres around the world have performed fetal brain transplants on individuals with HD, but this surgery is still highly experimental, and it is too early to judge whether it works.
In late 1998 and early 1999, there were a number of exciting discoveries that created the possibility of generating large quantities of brain cells without relying on an ongoing supply of fetal tissue. Scientists can now take �stem cells�-- a type of immature cell that has the potential to grow into brain cells -- and grow them in the laboratory.
There is still a lot of research to do to demonstrate that brain cell transplantation can be effective in humans, and there are some important details to be worked out, but the early results are very promising.
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