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Stages of Huntington’s Disease

Stages-of-HD

People with Huntington’s disease (HD) follow a path of disease progression once symptoms begin. While patients can remain highly functional in the first years of the disease, independence gives way as symptoms get worse. This article discusses the ways in which HD symptoms change from one stage to the next, the degree to which individuals are independent in day-to-day life at each stage, and some common concerns along the way.

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The Basics of Huntington’s Disease (Text and Audio)

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The Basics of Huntington’s Disease

Huntington’s disease (often abbreviated “HD”) was first described in medical literature in 1872 by Dr. George Huntington, a physician from Long Island, New York. The disease affects men and women alike, occurring at a rate of about one in every 10,000 in most Western countries. People with HD need dedicated care and support from their loved ones, which makes the number of lives touched by the disease even greater.

The age of onset of Huntington’s disease is normally between 30 and 50 years old, although there is also a form of HD that affects children and teenagers. People with HD may express a wide variety of symptoms, which physicians typically group into three categories: movement, cognitive, and psychiatric symptoms.

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  • Some of the movement symptoms of HD include muscle spasms, tics, rigidity, falling down, difficulty physically producing speech, and, in the later stages of the disease, difficulty swallowing (which can lead to significant weight loss). Uncontrollable movements such as writhing and twisting are also quite common symptoms of HD. Physicians sometimes refer to these uncontrollable movements as “chorea”.
  • The most significant cognitive symptoms of HD are the altered organization and generally slowed processing of information in the brain. These symptoms can lead to difficulty learning new things, difficulty planning and prioritizing, impairment of one’s perception of space (where one is in relation to tables, walls, etc.), and difficulty “multitasking” (paying attention to several things at once). Individuals frequently adhere to common routines because these routines are the easiest for them to accomplish. Finally, because they have trouble organizing incoming and outgoing words in their brains, many people with HD experience difficulty communicating with others.
  • Depression is the most common of the psychiatric symptoms of HD. Other symptoms include personality changes, apathy, anxiety, irritability, obsession with certain activities (such as hand washing), delirium, and mania. Denial of having HD is also a common symptom of the disease.

Sadly, somewhere between 10 and 25 years after symptoms first appear, HD usually takes such a toll on individuals that they die of pneumonia, heart failure, or other complications.

HD causes deterioration of the nerve cells in the brain, prompting significant changes in one’s ability to think, feel, and move. The cause of these symptoms remained a mystery for quite some time until doctors noticed that the disease “ran in families” and suspected its hereditary basis. The inheritance of HD (like other hereditary traits) is now known to depend upon a “chemical code” of information contained in a substance called deoxyribonucleic acid, or DNA, which exists within living cells. Understanding a bit about this chemical code helps to give better insight into the causes of HD and into treatments that may one day lead to its cure.

Fig A-1: DNA Language

The chemical code of DNA is a lot like the English language: both use specific letters in a specific order to communicate specific things. But while the English language has 26 letters, the DNA code only has four–A, C, G, and T (which stand for chemical subunits of DNA). Also, while English words can consist of either a few or many letters, DNA “words” are always three letters long. In the study of genetics, these three-letter “words” are called codons. Aptly named, codons code for the future building that goes on in the nerve cell. They are a bit like blueprints. Consider this example: when a passage contains the letters C-A-T in English, this paints a picture of our favorite lazy pet. In much the same manner, when the code of DNA contains the letters G-G-C, this tells the cell to build with proline, an amino acid. For more about DNA, click here.

If codons are like blueprints, then we can think of the amino acids that result from them as unique building blocks. When these blocks are put together chemically, they create a structure known as a protein. Like buildings in modern society, proteins are where the work of the nerve cell gets done. Proteins have many different jobs: they help the cell maintain its structure, produce energy, and communicate with other cells. If it were not for the body’s millions of proteins, life as we know it could not occur.

Fig A-2: Protein Shape

The specific actions of a protein are determined by its unique 3-dimensional shape. This shape controls how the protein can “fit in” and interact with other parts of the cell. The shape is determined by the type of amino acids that compose the protein, as well as by the specific order they are in. Thus, as with any well-engineered building, a successfully functioning protein starts with the “blueprints” (codons).

All human cells contain a protein called huntingtin. (Please note that although “Huntington’s disease” is spelled with an “o”, the correct spelling of the protein involved is “huntingtin” with an “i.”) Although scientists have yet to determine huntingtin’s exact function, it seems to play a critical role in the events that help nerve cells function effectively. Like many other proteins, huntingtin contains within it the amino acid glutamine. In people with HD, however, there is an excess number of glutamines in a particular segment of the protein. These extra glutamines come from having too many copies of the corresponding codon (the one that codes for glutamine) in the chemical code of DNA. That codon has the letters C-A-G. In a very real sense, HD results from having too many copies of C-A-G in the DNA that codes for huntingtin protein. That is why HD is often referred to as a trinucleotide repeat disorder (“trinucleotide” being a fancy word for codon).

Tbl A-1: Number of CAG Repeats

Exactly how many copies of C-A-G are too many? A great deal of research has been done in this area and there are many different opinions throughout the scientific literature in answer to this question. Rough estimates are as follows: People with 10 to about 35 copies of C-A-G have a normally functioning form of the huntingtin protein. Those with 40 or more have the altered huntingtin and will eventually develop symptoms of HD. For people who have 36 to 39 copies of C-A-G, the outcome is less clear. Some will develop the symptoms of Huntington’s disease and some will not. To learn more about how HD is passed on through generations, click here:

To summarize the above, Huntington’s disease is caused by too many copies of the codon C-A-G in human DNA, which puts too many copies of glutamine in the huntingtin protein. But exactly how is the altered huntingtin damaging? Unfortunately, despite valiant efforts by researchers, a definite answer to this question has yet to be found. Since the shape of the protein determines its interactions with other parts of the cell (as we learned earlier), much of the research to this point has sought to understand exactly how a shape alteration affects huntingtin’s interactions with the other components of the cell. One study suggests that the overabundance of glutamines in huntingtin causes rigid groupings of proteins. Since the components of the nerve cell are accustomed to a more flexible environment, they cannot work under the increased rigidity. The end result is basically early cell death of the nerve cell through a process called apoptosis. Another recent study suggests that the altered (and larger-than-normal) huntingtin “kidnaps” smaller proteins in the nerve cell, keeping them from doing their jobs. In this way, the altered huntingtin could indirectly damage the nerve cell. (For more information about altered huntingtin protein, click here.)

Fig A-3: Cell & the City

While scientists continue to work out the fine details of HD, the basic mechanism is clear. Continuing with our construction analogy, what happens when huntingtin is made in the altered form is that the “building” (the protein) does not have the specific size and shape that it was meant to have, and thus cannot function correctly in the “metropolis” that is the nerve cell. When it cannot function correctly, it hinders the action of other proteins that depend on it. The end result is a snowball effect, where the problems are continually compounded and the nerve cell becomes more and more damaged. Ultimately, after enough damage occurs, the nerve cell dies. When many other nerve cells follow suit, the problems of thinking, feeling, and moving that are associated with HD can result. For more information on nerve cells and how their deaths relate to the symptoms of HD, click here:

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Further reading:

  • Australia’s “Cooperative Research Centre for Discovery of Genes for Common Human Diseases” (Gene CRC) Web site has some fabulous tutorials at various levels of understanding.
  • Cummings, C. J and Zoghbi, H.Y. “Trinucleotide Repeats: Mechanisms and Pathophysiology.” Annu. Rev. Genomics Hum. Genet. 2000. 1:281-328.
    A fairly technical chapter explaining the symptoms of HD, as well as a breakdown of the number of CAG repeats in people with and without the disease. Also discussed are theories regarding the function of the altered huntingtin protein.
  • Falush D, et al. “Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial under ascertainment of late-onset cases.” Am J Hum Genet 68 (2) 2001 Feb: 373-385.
    A technical analysis of the number of CAG repeats that is believed to determine whether one will develop the symptoms of HD.
  • “Huntington’s Disease”. Online Mendelian Inheritance in Man.
    A compilation of abstracts from a multitude of different studies on HD. From case studies regarding inheritance to new methods of diagnosing HD, this is an excellent site for all the various types of HD research going on today.
  • “Huntington’s Disease”. Web MD.
    A very reader-friendly overview of HD. Explains generally the history, symptoms, and treatment of the disease.
  • Li SH, Lam S, Cheng AL, Li XJ. “Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis.” Human Molecular Genetics, 2000, Vol. 9, No. 19: 2859-2867.
    A highly technical paper regarding the manner in which altered huntingtin protein may cause early death (apoptosis) of the nerve cell.
  • Nucifora, Frederick C. Jr., et al. “Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis.” Human Molecular Genetics, 2000, Vol. 9, No. 19: 2859-2867.
    Another highly technical paper regarding the manner in which altered huntingtin protein may cause early death (apoptosis) of the nerve cell.

-M. Stenerson, 7-15-03

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-S.Jourin, 4-05-05
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The Motor Symptoms of Huntington’s Disease

Huntington’s disease (HD), an inherited neurodegenerative disorder, damages specific areas of the brain, resulting in movement difficulties as well as cognitive and behavioral changes. HD is often characterized by the motor symptoms that it causes.

Huntington’s disease (HD), an inherited neurodegenerative disorder, damages specific areas of the brain, resulting in movement difficulties as well as cognitive and behavioral changes. HD is often characterized by the motor symptoms that it causes. In fact, when HD was first discovered it was called Huntington’s chorea, as a reference to the uncontrollable, dance-like movement that is common among people with HD. Motor symptoms, though not always the first symptoms to appear, are often the reason that people with HD first see a doctor. Before genetic testing for the expanded CAG repeat within the Huntington gene became available, doctors could only make diagnoses according to motor symptoms. Even today, these symptoms are an important part of the criteria for clinical diagnosis; they generally define the age of onset of HD in an individual.

marker control range basic inhibition oxygen neurotrophic factor

What are the motor symptoms that occur with HD?^

The progression of HD is different in every individual, but the following list contains most of the physical conditions that occur frequently in adult-onset HD. Keep in mind that not everyone with HD will experience all symptoms, and the progression from stage to stage is only a generalization. The time it takes to move from one stage to the next is also highly variable. It is important to note as well that juvenile HD exhibits motor symptoms that can be quite different from the adult form. (For more information on juvenile HD, click here).

Early stage^

  • Changes in coordination
  • Some involuntary movement (such as irregular, sudden jerks of limbs)
  • Fidgeting
  • Restlessness, desire to move about
  • Twitching, muscle spasms, tics
  • Less control over handwriting
  • Facial grimaces
  • Difficulty with coordinated activities, such as driving
  • Some rigidity

Middle Stage^

  • Dystonia (prolonged muscle contractions), often of the face, neck, and back
  • More involuntary movements
  • Trouble with balance and walking
  • Chorea, twisting and writhing motions, jerks
  • Staggering, swaying, disjointed gait (can seem like intoxication)
  • Speech difficulties, including poor articulation, grunting, and abnormal speech patterns
  • Problems swallowing
  • Trouble with activities that require manual dexterity
  • Slow voluntary movements, difficulty initiating movement
  • Inability to control speed and force of movement
  • Slow reaction time
  • General weakness

Late Stage^

  • Rigidity
  • Bradykinesia (difficulty initiating and continuing movements)
  • Severe chorea (less common)
  • Serious weight loss
  • Inability to walk
  • Inability to speak
  • Swallowing problems, which create danger of choking
  • Inability to care for oneself

Though HD is not fatal in and of itself, the conditions that it causes can eventually lead to death. One of the most serious concerns for people with late stage HD is loss of control of the throat muscles. This condition makes swallowing difficult, and ultimately, dangerous. Everyone’s body is constructed with two tubes that begin below the throat; one, the esophagus, leads to the stomach, and the other, the trachea, leads to the lungs. Usually, we have no trouble making sure that food passes through our esophagus and not into our trachea. We do this without thinking, and rarely does something go “down the wrong pipe.” For people with late stage HD, however, this process of sorting food and air often functions poorly. As a result, food can get caught in the trachea and lead to choking. If food gets caught in the lungs, it can lead to an infection known as aspiration pneumonia. Although most people recover from pneumonia, people with HD usually have compromised immune systems, and therefore are unlikely to recover from such a severe infection. (For more information on other potential complications of HD, click here.

If you would like to learn more about the specifics of motor symptoms and how they are used to diagnose and assess the stage of HD, click here).

What exactly is chorea?^

Chorea is a disorder of the nervous system that occurs in multiple clinical conditions. In other words, it is not limited to HD, even though it is one of the classic symptoms associated with this particular disease. Chorea is characterized by spontaneous, uncontrollable, irregular movements, generally of the limbs and face. It can appear as unexpected jerks or twisting, writhing motions. These unpredictable movements contribute to poor balance, and the resulting walking difficulties lead to the staggering, swaying gait associated with HD. It is this irregular walking pattern that can make people with HD appear intoxicated, and also explains the root of the word chorea, which is the Greek word for dance. In the extreme, chorea can be a constant stream of violent movement. Severe choreic motions are known as ballismus.

Chorea occurs in 90% of people with HD, and increases over the first 10 years following onset. Although the specific motions of chorea can vary from one individual to the next, there are often consistent patterns within individuals. Chorea is usually present during waking hours, and cannot generally be suppressed. As HD progresses, chorea normally gives way to other movement difficulties, such as rigidity and bradykinesia.

To view a video clip showing chorea, please here. Footage is from Lake Maracaibo, Venezuela, courtesy of Dr. Nancy Wexler. HOPES would like to thank Julie Porter and the HD Foundation as well.

How can motor symptoms be treated?^

Unfortunately, as there is no cure for HD, there is also no cure for the motor symptoms that accompany the disease. There are, however, drugs and supplements available that may lessen certain motor symptoms of HD. It is also possible to treat many of the behavioral symptoms, which can greatly improve quality of life. (For more information on drugs and supplements that are used to treat HD, click here, and for information about behavioral symptoms, click here). Under certain circumstances, there is a surgical procedure that can be performed, which involves making stereotactic lesions in a part of the brain called the thalamus. This procedure may alleviate motor symptoms, but it can only be performed when no cognitive decline is evident, and ultimately it does not halt the progression of the disease. (For more information, please visit the UCLA Medical Center website by clicking here).

In addition to clinical treatments, there are other means of dealing with motor difficulties. One place to start is with health professionals: speech pathologists, physical therapists, and occupational therapists. Speech pathologists help with the mechanics of eating and drinking, as well as the loudness and articulation of speech. They can provide strategies for improving communication within the family and can also begin discussions about the use of a feeding tube, in the event that such a step becomes necessary. Exercise can be a very positive means of therapy, with physical, psychological, and emotional benefits. Physical therapists develop specialized exercise programs, usually to improve stretching and range of motion. They also advise people with HD about the use of walkers and wheelchairs. (For more information on exercise and HD, click here). Occupational therapists find ways to help people compensate for their inability to perform daily tasks, like eating and dressing. Often this involves adjusting the surrounding environment to better suit the needs of the individual with HD. Even small changes can make him or her feel more comfortable and capable, and thereby make his or her symptoms less problematic in daily life. (For suggestions on environmental adjustments, click here).

Motor symptoms can also be managed through lifestyle adjustments. Exercise, as previously mentioned, diet, and stress all affect overall health, and may contribute to the severity of symptoms. You should always consult your doctor before making any changes to your normal routine, but by clicking here, you can learn more about lifestyle adjustments that could potentially have positive effects.

What causes motor symptoms?^

The reasons why HD causes motor symptoms are very complex and not entirely clear. However, researchers have learned a great deal about what may be at the root of the problem. In order to begin discussing why motor symptoms occur, we first have to look at how movement is organized in the brain. Motor control operates through two main pathways, which link the cortex (the outer part of the brain, responsible for sophisticated functions) with the basal ganglia (a grouping of cells found deep within the brain, responsible for more basic functions). These pathways are termed “direct” and “indirect.” Before continuing, you may want to take a moment to review these two pathways described here, in the Neurobiology of HD section.

After reviewing the basics of the direct and indirect motor pathways, we can examine this schematic diagram that combines the two (Figure 1). Notice that there is an additional pathway: nerve cells in the striatum also project, or link, onto a region of the basal ganglia called the substantia nigra (as well as the globus pallidus), which then projects directly back onto the striatum. Though it may seem odd to have a simple loop added to this system, we will see that this pathway, the striatonigral pathway, is very important to motor function.

Fig MS-1: Motor pathways

In looking at the diagram, notice that along each projection arrow there is the name of a particular chemical, known as a neurotransmitter. Neurotransmitters are the means by which cells (and brain regions) communicate with each other. One cell, the presynaptic cell, releases a neurotransmitter and another cell, the postsynaptic cell, absorbs it. This chemical signal causes the postsynaptic cell to take some sort of action, such as releasing a neurotransmitter or actively not releasing one. Its response will then influence other cells farther down the line. This progression of cell-to-cell chemical communication is the nuts and bolts of the motor control pathways that we have been discussing.

You can see from the diagram that each motor pathway involves a complex combination of neurotransmitters. Let’s walk through the various pathways to get a clearer picture of how this all works. Remember though, it is the overall concept of the pathways that is important, not the names of each brain region and neurotransmitter.

The first step for all motor pathways is the cortex receiving sensory information from the outside world, via sight, touch, hearing, etc. It transmits this information to the striatum (part of the basal ganglia) in chemical form, using a common neurotransmitter called glutamate. Glutamate then causes the cells of the striatum to take action in the following ways:

The direct pathway: Nerve cells in the striatum project onto the internal part of the globus pallidus, using the neurotransmitters GABA and substance P. The cells of the globus pallidus then use GABA in their projections to the thalamus, a major relay and control center of the brain. The thalamus completes the loop back to the cortex using more neurotransmitters, sending its signals directly to the part of the cortex devoted to motor control, the motor cortex. The motor cortex responds to these signals (which originated in the basal ganglia, remember) by physically moving the body in the appropriate way.

The indirect pathway: Striatal cells (cells in the striatum) use GABA and enkephalin to project onto the outer part of the globus pallidus. Globus pallidus cells then project to the subthalamus using GABA, which in turn projects to the internal globus pallidus using glutamate. From there the pathway is the same as the direct pathway, progressing to the thalamus and then the motor cortex.

An important note: Certain neurotransmitters are termed “excitatory” and others “inhibitory.” Excitatory neurotransmitters cause an action to take place in another cell or part of the body. Inhibitory neurotransmitters prevent an action from occurring. All projections that come from the basal ganglia (including the striatum, globus pallidus, and substantia nigra) are inhibitory. We know that these cells are involved in controlling the movement of the body, so therefore the neurotransmitters from cells in the basal ganglia serve to prevent (or inhibit) movement. Imagine you are sitting at a desk, writing on a piece of paper. You are moving your hand and arm, but the rest of your body is still. In order to keep the rest of your body still, the cells in your basal ganglia are releasing inhibitory neurotransmitters constantly. In this state, cells are said to be operating at their baseline firing rate. “Baseline” refers to what is normal, because most of the time we want to prevent movement in at least some parts of our body, and “firing rate” refers to how frequently the neurotransmitters are released. Consider that while you are at the desk writing, you see that you have made a mistake. This visual sensory information reaches your cortex, and then is sent to your basal ganglia. The basal ganglia realize that you will need to tell your other arm to reach for an eraser. In order to stop inhibiting movement in that arm, the basal ganglia must adjust its release of inhibitory neurotransmitters. This modified signal is passed to the thalamus and then the motor cortex. Because the motor cortex is no longer inhibited as much, it can tell your other arm to reach for the eraser. When you have finished using that arm, neurotransmitter release returns to normal, to the baseline firing rate.

How does all this work in HD? Mutant huntingtin protein is expressed in all the cells of the body, but the most and earliest damage is seen in the basal ganglia, and the striatum in particular. The precise mechanism by which mutant huntingtin harms cells and causes them to behave differently is not clear. However, we know that mutant huntingtin causes serious problems with cell function and eventually leads to cell death. Here is where an understanding of motor pathways comes in handy. The early motor symptoms seen in HD are the result of damage to the striatum that impacts the indirect pathway (although both pathways are affected at the same time in juvenile HD). Damage from HD causes the striatum to release a weaker chemical signal, resulting in less inhibitory neurotransmitters, less inhibition of the motor cortex, and more movement. This movement is unintended, the result of a pathway error, and is therefore called “involuntary.” Involuntary movements include the fidgeting, tics, and chorea associated with early to middle stage HD. Later on in the disease the direct pathway becomes increasingly affected. In this case, the striatum still releases less inhibitory neurotransmitters, but in the direct pathway this action leads to more inhibition of the motor cortex and less movement. The result is rigidity of the body and bradykinesia, common to late stage HD. So, looking at how the direct and indirect motor pathways work and the motor symptoms we know to occur in HD, we can follow a logical route from damage in the striatum to actual symptoms. But what causes the neurotransmitter signals from the striatum to decrease in the first place? Let’s first take a look at the third motor pathway in the diagram.

Fig MS-2: Third motor</p> <p>pathway

The striatonigral pathway: Nerve cells in the striatum also project onto the substantia nigra, using GABA. The substantia nigra then responds with dopamine, projecting straight back onto the striatum. This dopamine signal influences both the direct and indirect pathways, but with different results, even though both pathways are responding to the same chemical signal. This is accomplished by having two different kinds of dopamine receptors on the post-synaptic cells in the striatum: D1 receptors link to the direct pathway and D2 receptors link to the indirect. Dopamine that goes to D1 receptors causes the striatum to release less inhibitory neurotransmitters, which ripples through the whole direct pathway and ultimately leads to inhibition of the motor cortex (preventing movement). Dopamine that goes to D2 receptors also causes the striatum to release less inhibitory neurotransmitters, but because of a different pathway progression, ultimately leads to less inhibition of the motor cortex (causing movement).

Fig MS-3

Researchers think that the answer to why HD causes the striatum to release a weaker chemical signal may be the striatonigral pathway and dopamine. As we have discussed, HD seems to over-stimulate the motor cortex via the indirect pathway and under-stimulate the motor cortex via the direct pathway. Interestingly, this pattern matches up with the influence of the striatonigral pathway on the other two pathways. When dopamine is released from the substantia nigra, it inhibits the striatum, causing it to release less inhibitory neurotransmitters. Let’s put these ideas together: if an excess of dopamine is released from the substantia nigra, the indirect pathway would over-stimulate the motor cortex and the direct pathway would under-stimulate it, just like in HD. You can see why researchers started to think that the striatonigral pathway and dopamine might be the key.

Fig MS-4

So what causes the substantia nigra to release more dopamine? For a potential answer we must trace the pathway back even further. Remember that as soon as the striatum receives a sensory message from the cortex, it sends a signal to the substantia nigra, via the neurotransmitter GABA, which then influences the substantia nigra’s release of dopamine. These two neurotransmitters go back and forth like a seesaw: more GABA means less dopamine and vice versa. Researchers have found that cells in the striatum that release GABA selectively degenerate due to damage from mutant huntingtin. GABA is an inhibitory neurotransmitter like all those in the basal ganglia. Therefore, if striatal cells are damaged and release less GABA, the substantia nigra is less inhibited and will release more dopamine. An increase in dopamine would inhibit the striatum, which is consistent with the pattern seen in HD.

It is important to note, however, that scientific studies have not been able to show conclusively that dopamine levels are increased in HD. Indeed, post-mortem studies of people with HD have shown elevated, depleted, and unchanged levels of dopamine in the brain. Additionally, the striatum uses GABA in its projections to both parts of the globus pallidus, not just the substantia nigra. Therefore, damage to the striatum from HD could lessen the release of GABA to the globus pallidus and thus the two main pathways directly, not just via the striatonigral pathway.

Nonetheless, many researchers are confident that dopamine is important to HD, even at endogenous, or natural, levels. Dopamine may in fact play an even more integral role in striatal cell damage, by causing the damage, not just influencing the pathway. One major question for researchers has been, why the striatum? Why is the basal ganglia harmed by mutant huntingtin, and not other cells? Recent studies suggest that the presence of dopamine is correlated with cell damage in HD. If this is the case, only cells in which dopamine was present would degenerate, and those with more dopamine would degenerate first. This theory would explain why cells in the striatum degenerate first. Charvin and others (2005) have shown that both dopamine and mutant huntingtin can activate a transcription factor known as c-jun. Transcription factors can influence a cell in many different ways; c-jun leads to programmed cell death, or apoptosis. When dopamine and mutant huntingtin are present together, the level of c-jun is greatly increased. The way that dopamine activates c-jun is as follows: dopamine can autooxidize, or in other words, spontaneously undergo a reaction that leads to reactive oxygen species (ROS). ROS are bad for the cell, and usually lead to cell damage. To prevent this damaged cell from hurting the rest of the body, the cell activates c-jun to start the process of programmed cell death (apoptosis). Therefore, the apoptosis of one cell is a good defense mechanism for the body. When mutant huntingtin is present, however, far too many cells induce apoptosis. Also, as we age, autooxidation of dopamine naturally increases. You can imagine that in someone with HD, more and more apoptosis due to dopamine combined with the presence of mutant huntingtin, could result in significant problems. This theory may therefore explain HD’s late age of onset. (For more information about the theory of oxidative stress and HD, click here).

Charvin and others proposed another role for dopamine in striatal cell damage. As previously mentioned, there are two kinds of dopamine receptors in the striatum: D1 for the direct pathway and D2 for the indirect. D2 receptors are more significantly implicated in HD. This makes sense, given that the indirect pathway is affected first. Charvin et al. suggest that D2 receptors are over-stimulated. Their theory also says that, as dopamine passes through the D2 receptors, it contributes to the formation of aggregates (or clumps) of the mutant huntingtin protein within the cell. Aggregates of mutant huntingtin are a common pathological marker in HD, meaning that they are present in cells affected by HD. It is unclear, however, what the function of these aggregates actually is. They may be harmful, helpful, or not have any effect on the cell at all. (For more information on protein aggregates, click here).

Scientific studies have consistently noted that dopamine receptors (D1 and D2) are depleted in HD. This may seem strange, as we have been suggesting that the presence of dopamine (or perhaps the excess of dopamine) is the reason why HD motor symptoms occur. Although the depletion of receptors is well known, the cause of the depletion is not. D2 receptors, for the indirect pathway, are depleted first, with more D1 receptors, for the direct pathway, disappearing as HD progresses. One possibility is that too much dopamine may be toxic to the receptors, thus killing them off. It may also be the case that cells try to protect themselves from an excess of dopamine, or its toxic influence in the presence of mutant huntingtin, by actively losing receptors. Another possibility is related to brain-derived neurotrophic factor (BDNF). BDNF is a chemical that protects cells in the brain, and its function has been shown to be impaired in HD. The loss of BDNF could make it much easier for receptors to be damaged, as well as allowing for the mutant huntingtin/dopamine synergistic damage to occur in the first place. (For more information on BDNF, click here). It is also possible that mutant huntingtin harms receptors directly. Regardless of the specific cause of receptor depletion, much damage from dopamine can occur by the time depletion becomes significant. Additionally, if the striatum is absorbing less dopamine, an increased release of dopamine could be triggered in the substantia nigra. A reduced number of receptors can also lead to greater sensitivity of the remaining receptors, ultimately resulting in more dopamine absorption and damage. As you can see, cell-to-cell communication is very complex and intricate. Though this fact makes it difficult to determine just how HD affects the brain, it does give researchers many ideas about what to look at next, as well as offer many possibilities for treatments.

So what does all this mean for HD treatments? Currently in the U.S. there are few medications that are prescribed to treat motor symptoms of HD, and none that are particularly aimed at chorea. However, experimental drugs that deplete dopamine have been reported to have positive effects on motor symptoms. The best-studied drug, tetrabenazine, should soon be available in the U.S. and will be discussed in detail in the chapter linked to below. As we learn more and more about the cause of HD damage in the brain, we can develop new treatments that are aimed at specific mechanisms. Future medications may target ROS production, dopamine absorption through D2 receptors, or initiation of the c-jun pathway, to name a few. These new kinds of treatments will hopefully prove to be more effective than current options, impacting the progression of HD in a meaningful way.

Tetrabenazine^

Click here for an article about Tetrabenazine

For further reading^

  1. Bates, G., Harper, P., & Jones, L. Huntington’s Disease. New York: Oxford University Press, 2002. pp. 28-37, 276-281.
    This book is a thorough review of current knowledge about HD, but is very scientifically-oriented.
  2. Canals, J.M., et al. “Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease.” 2004.Journal of Neuroscience. 24(35): 7727-7739.
    An article about BDNF and HD.
  3. Charvin, D. “Unraveling a role for dopamine in Huntington’s disease: the dual role of reactive oxygen species and and D2 receptor stimulation.” 2005. PNAS? 102(34): 12218-12223.
    This article presents the possible mechanisms for how dopamine may damage striatal cells.
  4. Dr. Joseph F. Smith Medical Library. “Huntington’s disease.” http://www.chclibrary .org/micromed/00051720.html
    A description of motor symptoms and alternative treatments for HD, such as occupational, speech, and physical therapies.
  5. Emedicine.com. “Huntington disease dementia.” http://www.emedicine.com/me d/topic3111.htm
    Brief review of motor symptoms associated with HD.
  6. Gazzaniga, M.S., Irvy, R.B., & Mangun, G.R. Cognitive Neuroscience: The Biology of the Mind. New York: W.W. Norton & Company, 2002. pp. 488-492.
    This is a textbook covering many topics in neurobiology. It is rather technical.
  7. HDNY at Columbia University. “Speech pathology”: http://www.hdny.org/speech.html, “Social implications of motor disorders”: http://www.hdny.org/problems.htm, “Environmental adjustments”: http://www.hdny.org/rehab.html
    The HDNY website is very helpful as a general resource, even outside the NY area. These pages are particularly relevant to motor symptoms.
  8. Health-cares.net. “What is Huntington’s chorea?”: http://neurol ogy.health-cares.net/huntingtons-chorea.php, “What causes chorea?”: http://neurology.he alth-cares.net/chorea-causes.php
    This website discusses HD and other forms of chorea.
  9. Hickey, M.A., et al. “The role of dopamine in motor systems in the R6/2 transgenic mouse model of Huntington’s disease.” 2002. Journal of Neurochemistry. 81: 46-59.
    A good study of dopamine and HD in a mouse model.
  10. Indiana State University. “Huntington’s disease.” http://web.indstate.ed u/thcme/anderson/RPI.html
    This site has a good schematic diagram of motor pathways, and a more involved discussion of energy metabolism in HD.
  11. International Huntington Association. “Huntington’s disease.” http://www.huntington-assoc .com/huntin.htm
    A summary of the progression of HD, in terms of motor, cognitive, and behavioral symptoms.
  12. Jakel, R.J., & Maragos, W.F. “Neuronal cell death in Huntington’s disease: a potential role for dopamine.” 2000. Trends in Neuroscience, 23: 239-245.
    This is a good article that reviews the potential mechanisms for cell damage as a result of HD.
  13. Nieuwenhuys, R., Voogd, J., & van Huijzen, C. The Human Central Nervous System: a Synopsis and Atlas. New York: Springer-Verlag, 1981. pp. 169-173.
    A highly technical book that details neuroanatomy.
  14. Petersen, A., et al. “Mice transgenic for exon1 of the Huntington’s disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine.” 2001. European Journal of Neuroscience. 14:1425-1435.
    This is a rather complex article that discusses the potential for dopamine toxicity in striatal cells.
  15. Pineda, J.R., et al. “Brain-derived neurotrophic factor modulates dopaminergic deficits in a mouse model of Huntington’s disease.” 2005. Journal of Neurochemistry. 93: 1057-1068.
    More on BDNF.
  16. Reynolds, D., et al. “Dopamine modulates the susceptibility of striatal neurons to 3-nitropropionic acid in the rat model of Huntington’s disease.” 1998. Journal of Neuroscience. 18(23): 10116-10127.
    This article is one of the earlier articles to show that dopamine is important to cell damage in HD.
  17. UCLA Medical Center. “How is Huntington’s disease treated?” http://neurosurgery.ucla.edu/Diagnoses/Movement/MovementDis_2.html
    A brief overview of medical and surgical treatment options, from the neurosurgery department at UCLA.
  18. We Move. “Medical management of Huntington’s disease.” http://www.wemove.org/hd/hd_tr e_mm.html
    A brief discussion of available medical treatments for HD and their potential consequences.

C. Tobin 6-29-06

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The Behavioral Symptoms of Huntington’s Disease

Behavioral-Symptoms-of-HD

Huntington’s Disease (HD), an inherited neurodegenerative disease, damages specific areas of the brain, resulting in movement difficulties as well as cognitive and behavioral changes. Behavioral changes are a characteristic feature of HD and are often the most distressing aspect of the condition for individuals and families dealing with HD. Although there is a great deal of variation in behavioral symptoms among individuals with HD, HD damages specific parts of the brain, resulting in specific and predictable behavioral changes. However, it is important to look at what may be triggering the behaviors in order to provide an environment that minimizes difficult behaviors, behaviors that disrupt the ability of the individual or caretaker to function effectively in a safe environment.

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The Cognitive Symptoms of Huntington's Disease

Cognitive-Symptoms-of-HD

Huntington’s Disease (HD), an inherited neurodegenerative disorder, damages specific areas of the brain, resulting in movement difficulties as well as cognitive and behavioral changes. The term “cognitive” refers to tasks of the brain that involve knowing, thinking, remembering, organizing, and judging. Certain changes in cognitive abilities are characteristic of HD and can significantly impact the lives of individuals with the disease. For example, cognitive changes may affect the ability of a person with HD to work, manage a household or properly care for him or herself

range folding marker basic control

What are some of the cognitive abilities that may be impaired by HD?^

Communication^

Communication is a complex process, requiring the cognitive ability to express and understand as well as physical abilities such as muscle control and breathing. Typically, neural degeneration, resulting from HD, begins in the core of the brain at the caudate nucleus and may spread to areas on the left and right side of the brain, such as the control centers for cognitive function, speech and language. Thus, communication problems tend to become more prominent as the disease progresses.

Throughout the course of the disease, communication problems vary in nature and severity. However, variations in the nature and severity of communication problems also occur from person to person. While one individual may have difficulty initiating conversation, another may have very little difficulty initiating, but severe difficulty word-finding (an aspect of memory recall). Although there are a number of communication problems that may arise for people with HD, the most common communication difficulties are four: speaking clearly, initiating conversation, organizing what is to be said and understanding what is being said.

Fig X-1: Damaged Neurons

As HD damages neurons in the caudate, proper regulation of motor information that tells the body how to move specific muscles at precise times may be impaired. The caudate’s inability to regulate motor information can result in slurred speech and stuttering as well as the uncontrolled bodily movements, often referred to as chorea.

The ability to initiate conversation or activities is a very complex brain function. Damage to the caudate affects the brain’s ability to regulate the sequence and amount of information being transmitted, which may result in difficulty starting and stopping communication. The inability to initiate conversation may also be the result of word- finding difficulty. As neurons in the caudate die, the intact neurons have more difficulty sending information along the neural “circuit.” For example, it may take longer than expected for a person with HD to answer a question because it may be more difficult to find the right word. While word-finding is often impaired, knowledge of vocabulary is retained.

As the caudate and its connections with other areas of the brain deteriorate, some kinds of information may not reach the frontal lobes. Without the frontal lobes to sequence and prioritize outgoing information, the speech of a person with HD may become garbled or seemingly illogical. Damage to the caudate, resulting in impaired access to the frontal lobes may also make it difficult for an HD-affected person to understand what is being said; however, the ability to understand usually remains intact, even in the later stages of the disease. For example, each word of a sentence may be understood, but the frontal lobes and caudate may not be able to organize them properly, possibly resulting in miscommunication. This inability to organize incoming information can also contribute to a slowed response time, even if comprehension remains normal.

If you are interested in reading about strategies and tools that may improve communication for and with a person who has HD, click here.

Memory^

An individual suffering from the cognitive symptoms of HD may have memory difficulties. It is important to note that the memory problems that can occur in people with HD are different from the memory difficulties that can occur in people with Alzheimer’s Disease. Whereas people with Alzheimer’s Disease may get lost in familiar places or forget the names of familiar people, individuals with HD will know and recognize people as well as places.

Tbl X-1: Comparison of Huntington's Disease & Alzheimer Disease

(Table adapted from Paulsen Understanding Behavior in Huntington’s Disease)

Throughout the course of HD, there are two primary memory difficulties that result from cognitive impairment: learning new information and recalling stored information. The impaired ability to learn new information may be the result of damaged neural connections between the frontal lobes and the caudate in the brain. Without efficient use of the frontal lobes, the brain cannot effectively organize and sequence the information to be learned. For example, learning a new phone number may be very difficult for an individual with HD because the brain may not organize or group the numbers together in a way that is easy to remember. For example, the series of numbers “3456978” is much more difficult to remember than “3-4-5-69-78.” When information is not organized in an efficient manner, retaining and recalling the learned information is very difficult.

Fig X-2: Recognition vs. Recall

Recalling stored information is the other primary memory problem for people with HD. For example, a hypothetical person, Silvia, knows what she had for dinner last night, but may not respond very quickly when asked. However, if you ask her whether she had pizza or chicken, she’ll be able to correctly identify which of the two choices she had for dinner. The neurodegenerative nature of HD disrupts the brain’s search mechanism, which makes recalling stored information more difficult, although the memory likely remains intact and can often be recalled through cues or recognition. Also, the person suffering from memory difficulties usually maintains the ability to understand and comprehend information.

Although most memories remain intact, motor memories are often impaired. Motor memories, such as driving a car or tying shoes, are considered implicit or “unconscious” memory. The impairment of these motor memories means that a person has to rely on “conscious memory” to perform these tasks, which requires more concentration. Since these simple, once automatic, tasks may require more concentration, people with HD often have difficulty multi-tasking or dividing their attention. For example, an individual suffering from memory problems due to HD may have difficulty making dinner while listening to the radio.

Tbl X-2: Memory Functions & HD

Recognition memory: stored information can be recalled through a cue. For example, an individual may not remember what time his haircut appointment is scheduled for, but when asked, “are you getting your haircut at 1:00 or 2:00?” he remembers that the appointment is at 2:00

Long-term memory: stores an unlimited amount of rehearsed information; each memory can be stored for a long period of time

Language comprehension: ability to understand the meaning of words as well as how they are organized in order to understand what is being said

Memory retrieval: recalling stored information

Verbal fluency: ability to use and organize words in order to clearly express thoughts, feelings and ideas

Word finding: recalling and using the proper word to communicate

Executive Functions^

Critical to our ability to function effectively at home or work, the “executive functions” include prioritizing, problem solving, judgment, abstract thinking, controlling emotions and awareness of self and others. The frontal lobes, often referred to as the “boss” of the brain, are in charge of the executive functions. The part of the brain responsible for regulation information being sent to the frontal lobes is the caudate nucleus. When HD destroys neurons in the caudate nucleus, a person with HD may have difficulty efficiently performing tasks that were previously simple, such as running errands.

Many of the executive functions that may be impaired in individuals with HD fall into one of three categories: awareness, organization and regulation.

Awareness^

Commonly, denial is used to describe the inability to accept the reality of a distressing circumstance. HD sufferers may deny having HD or be unable to recognize their disabilities. However, this denial is not under the individual’s control, so a lack of awareness or “unawareness” may be a more accurate word for people with HD.

Due to HD, circuits connecting the caudate nucleus, frontal, and parietal lobes may incur damage, resulting in a lack of self-awareness. People with HD may be unable to recognize disabilities or evaluate their own behavior. The inability to evaluate one’s own performance may cause sufferers to be unaware of mistakes that are evident to others. Damage to these neural connections may also impair the ability to experience a range of subtle emotions and see another’s point of view, possibly making social and personal relationships more difficult.

Unawareness often plays a role in seemingly irrational behaviors. For example, a person may become upset if he or she is not allowed to go back to work or live independently, because of the unawareness of failing capabilities. However, a person may be willing to talk about his or her capabilities, but still be unable to acknowledge that failing capabilities are the result of HD. Unawareness, a behavioral as well as a cognitive symptom, is generally accepted as an untreatable component of HD. To learn about the behavioral symptoms of HD, click here.

Organization^

Since HD damages the caudate nucleus, many aspects of behavioral and intellectual functioning can be affected. The task of the caudate is to organize, regulate and prioritize information transmitted from many areas of the brain to the frontal lobes. If the information reaching the frontal lobes is not organized as a result of HD, the individual with HD may experience difficulty organizing his/her thoughts and activities as well.

In order to plan and prioritize efficiently, our brain must be able to organize activities in a logical order, evaluate all of the steps involved in accomplishing a task, and even think about one particular task while performing another. As a result of the damaged caudate, the brain of an individual with HD may not be capable of performing in such a manner. For example, a person without HD may spend one hour on a trip to the grocery store and the bank. However, it may take a person with HD two or three hours to accomplish this same task. While at the grocery store he or she may have to look for each item in the order of the list, possibly failing to get two items from the same aisle because they appeared in different places on the list.

A diminished ability to make decisions may also become a problem as a result of the brain’s failing organizational capabilities. If asked the question, “What would you like to have for dinner?” it may take a while for the brain of a person with HD to organize the words into an understandable question, retrieve the memories of past dinner items, process the feelings regarding each dinner item, and organize the words into a logical response. This difficulty may also be due to memory impairments resulting from HD. Thus, the process of decision making is drastically simplified if a person with HD is given choices, which allows the brain to recognize memories rather than retrieve them. Shorter sentences may also aid in the decision making process, as they contain fewer words for the brain to organize.

Another function affected by the impairment of the brain’s organizational capacity is attention. While simple attention, the ability to focus on one activity, often remains intact, sustained attention as well as divided attention may become impaired. As a result of memory impairments, “unconscious” tasks that were once automatic may require intense concentration. This makes dividing one’s attention very difficult. For example, it may be difficult for a person with HD to walk while carrying on a conversation. With the loss of motor memories, he or she may have to consciously think about each step forward, making conversation difficult. To read more about memory impairment as a cognitive symptom of HD, click here.

Regulation^

The caudate nucleus serves primarily as a regulator and organizer. It controls the order and amount of information traveling from particular areas of the brain to the frontal lobes. As HD progressively destroys the caudate, it may become difficult for individuals with HD to initiate, maintain, and/or stop behaviors or thoughts.

As mentioned above, the ability to initiate activities or conversation is a complex brain function. Damage to the caudate disrupts the brain’s ability to regulate the sequence and amount of information being transmitted, which may result in difficulty starting and stopping communication or activities. The diminished regulatory abilities of the caudate may also result in the inability to maintain an activity or conversation. However, this may be due to the impairment of sustained attention as well. For example, an individual with HD may be able to begin folding laundry but quickly become unable to focus on the task at hand due to distractions. If the radio is playing in the room, the individual may focus his or her attention on the music and be unable to re-initiate and complete the task of folding laundry.

Another possible result of the caudate’s inability to regulate the amount of information traveling to the frontal lobes is a lack of emotional control. A person with HD may over-express a feeling of slight frustration or irritation in the form of a temper tantrum or aggressive behavior. Although the emotion itself is often a legitimate response to something in the individual’s environment, the caudate cannot regulate the proper amount to be expressed. To read about the behavioral symptoms of HD, including frustration, apathy and others, click here.

Visual Spatial Ability^

Visual spatial ability is the ability to perceive one’s body position in the environment. An individual’s perception of his or her body position is useful for judgment of where he or she is in relation to walls or how close his or her hand is to a burner on the stove. Impaired visual spatial ability is often evident even in the early stages of HD. Most commonly, the individual suffering from cognitive symptoms of HD is aware of his or her visual spatial impairment.

For example, due to a diminished visual spatial ability, it may be more difficult for a person with HD to read a map or follow directions, since most directions are given using spatial cues, such as “east” and “west” or distances measured in miles. However, a person suffering from this cognitive symptom of HD may be able to follow directions if they are given using geographic markers, such as: “Go straight on Campus Drive until you reach a stoplight. Turn left and go past the Pet Store. The Post Office will be on the left side of the street with a flag pole in front.” For an individual suffering from visual spatial impairment, directions using “left” and “right” or geographic markers are easier to follow because they do not require the individual to orient his or her body in a particular direction. Regardless of which direction a person is facing, “left” is one way and “right” is the other. However, depending on the orientation of one’s body, “east” may be behind, to the right, to the left or in front of him.

Reading difficulties may also be the result of visual spatial impairment; however, the inability to maintain attention may be a contributing factor as well. For information about attention impairments as a cognitive symptom of HD, click here.

What causes the cognitive symptoms?^

As a neurodegenerative disease, HD damages many neurons and neural connections within the brain, potentially causing cognitive impairment. Most of the damage occurs in the caudate nucleus and putamen, which are structures of the basal ganglia. To learn more about these brain structures, click here. The primary function of the caudate is the regulation and organization of information being transmitted to the frontal lobes from other areas of the brain. The frontal lobes are responsible for many important tasks, some of which are:

  • Organizing
  • Prioritizing
  • Controlling impulses
  • Self-awareness
  • Initiating and ending activities

Thus, damage to the many connections between the caudate and frontal lobes can significantly impair cognitive abilities, such as reasoning, planning, attention, memory, and learning. To read about neurons and neural connections, click here.

The neurodegenerative changes that occur within the brain of a person who has HD are generally the primary cause of the cognitive symptoms of HD, as well as behavioral changes and movement difficulties. An individual suffering from the cognitive symptoms of HD may have difficulty effectively prioritizing his or her daily activities, initiating conversation or activities, recalling memories or making decisions. However, it is important to remember that the cognitive as well as behavioral and physical symptoms of HD vary from person to person. To learn about the behavioral symptoms of HD, click here.

How do the cognitive symptoms change as HD progresses?^

As a general rule cognitive impairments tend to increase in severity as HD runs its course. However, only a few longitudinal studies have been done on the cognitive symptoms of HD, and thus, research has not determined whether the severity of a cognitive symptom can be used as a marker for the underlying progression of the disease.

Although the symptoms of HD vary significantly from person to person, there are some general trends among individuals. Speed of mental processing, organization, and initiation are commonly impaired early in HD and may worsen during the intermediate stages. While individuals with HD are often unable to speak or express their views in the later stages of HD, some cognitive abilities, such as the ability to understand incoming information, may remain relatively intact.

Fig X-3: Common Progression of Cognitive Stages in HD

Do the cognitive symptoms of HD vary from person to person?^

The expression of HD varies significantly from person to person. Although HD is a progressive disease for affected individuals, there is considerable variation in the type and severity of symptoms a person with HD may experience. Some individuals may experience a number of cognitive and behavioral symptoms and fewer physical symptoms, whereas others may suffer more from physical symptoms, such as chorea. The variation in severity means that while some of the cognitive symptoms may be quite pronounced for one person, those particular symptoms may be much less evident in another.

Due to the variation in the type and severity of cognitive symptoms, it may not be useful to use them as an indicator for the onset of HD in an at-risk individual or to diagnose the individual with the disease. Many of the early cognitive symptoms of HD, such as forgetfulness, lack of initiation or fumbling are also fairly common among individuals who are not at risk for HD. “Symptom watching” by individuals at risk for HD may result in a misinterpretation of these thoughts, actions or behaviors as HD. Genetic counselors may be contacted if symptom-watching or anxiety due to being at-risk for HD begins to interfere with one’s ability to function effectively.

Are there treatments available for the cognitive symptoms of HD?^

At the time of this writing (April 2003), there is no cure for the cognitive symptoms of HD or the disease itself. The cognitive symptoms of HD are due to the damage of neurons and neural connections in the brain, which at this time are considered irreversible. However, scientists and researchers continue to investigate the brain’s ability to produce new neurons as well as its ability to form new connections between neurons. For more information about the brain’s natural reparatory ability, click here.

Fortunately, there are a number of strategies for coping with and enhancing cognitive abilities impaired by HD. For example, maintaining a calm, predictable environment and establishing routines can improve organization and planning as well as minimize the occurrence of emotional outbursts. A predictable, routine environment enables a person suffering from the cognitive symptoms of HD to organize daily tasks and adhere to that schedule, resulting in fewer organizational or planning problems. There are a number of resources that provide strategies for improving the cognitive symptoms of HD. If you are interested in learning more about these strategies, click here.

Although there are strategies and treatments that can improve the physical, behavioral and cognitive symptoms of HD, there are currently no treatments available that slow down the progression of HD. However, research continues with the growing hope of discovering effective treatments as well as a cure for HD. For more information on potential treatments for HD, click here.

For further reading^

  1. American Speech-Language-Hearing Association. Huntington’s Disease. http://www.asha.org/speech/disabilities/Huntington-Disease.cfm
    Much like a brochure, this resource explains many of the communication and swallowing problems that may occur as a result of HD. It also lists ways in which a speech-language pathologist can help minimize difficulties.
  2. Australian Huntington’s Disease Association. Information – Huntington’s Disease http://www.ahda.asn.au/content/pages/page.asp?iPage=5
    This website provides basic information about HD as well as support for individuals with HD and their families.
  3. Huntington’s Disease Association. Fact Sheet 10. Behavioral Problems in Huntington’s Disease. http://www.hda.org.uk/charity/download.html
    This clearly-written Fact Sheet is just one of the many informative and helpful Fact Sheets available at this site.
  4. Paulsen, Jane S. “Understanding Behavioral Changes in HD: The Neuropsychology of HD and Strategies for Intervention.” International Huntington Association, 2002. http://www.huntington-assoc.com/jane.html
  5. Paulsen, J. “Understanding Behavior in Huntington’s Disease” (2nd ed.). Huntington’s Disease Society of America, Inc, 1999.
    This is an easy to read and extremely informative resource with the purpose of providing practical and helpful information about the behavioral as well as cognitive symptoms of HD.
  6. Rosenblatt, A., Ranen, G., Nance, M. & Paulsen, J. “A Physician’s Guide to the Management of Huntington’s Disease.” (2nd ed.) Huntington’s Disease Society of America, Inc., 1999.
    This is a guide specifically for physicians. It explains the symptoms of Huntington’s Disease and methods for providing optimal management of the symptoms.
  7. South Shore Neurologic Associates (SSNA). HD: Cognitive Disorders. http://www.southshoreneurologic.com/move-dis/hd/hd-cognitivedisdr.html
    The aim of this site is to provide information and support for individuals with neurological disorders. While there is a substantial amount of information on HD, the information itself isn’t well-organized. However, this site is still a valuable resource for those affected by HD.

K.Hammond 3-29-03; recorded by B. Tatum 8/21/12

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The Inheritance of Huntington's Disease (Text and Audio)

basic

Click on the link below to hear an audio recording of this article:
The Inheritance of Huntington’s Disease

Although records of symptoms have been traced as far back as the Middle Ages, it was not until the late 1800s that physician George Huntington first documented the hereditary nature of the disease that bears his name. It was the late onset and hereditary character that distinguished HD from other diseases with similar symptoms. With so many recent breakthroughs in human genome research, we now know quite a bit about the genetic basis of Huntington’s disease. Having a working familiarity with the basic genetics of HD is key to understanding the inheritance and expression of the disease.

What is a gene? Which parts of the genetic code correspond to genes?^

The material behind genetic inheritance is a surprisingly simple chemical substance called deoxyribonucleic acid (DNA). Each molecule of DNA is a long, continuous chain of smaller molecules called “bases” that are strung one after the other. The four different bases (abbreviated A, T, C, and G) can be arranged in many different ways. It is the sequential order of these bases that provides the chemical information or “instructions” for inheritance. The DNA ladder can be very, very long, twisted and coiled again around proteins into the shape of chromosomes that sit inside each cell’s nucleus. A chromosome is, in fact, one very long “super coiled” molecule of DNA. (For more on the chemical information in DNA, click here.)

Fig C-1: Location of Genes in DNA

Some regions of DNA contain instructions for making a specific functional product, such as a protein. These regions of functional DNA are called genes. Every long molecule of DNA has some segments that are genes and some that are not. Together, they make up the structures called chromosomes that are found in cell nuclei. (See Figure C-1.) The non-gene segments are sometimes half-jokingly called “junk in the genome” – we still have little idea of what, if anything, these sequences do! Fortunately, though, the genes are always found in the same place on a particular chromosome. The gene responsible for causing HD, for example, is always located on chromosome 4. (Humans have 23 pairs of chromosomes, each of which has been assigned a conventional number. Click here for a look at all 23 pairs.) When scientists say that they have “located” a gene for a disease, they usually mean that they have found a region on one of the chromosomes that codes for a protein that somehow contributes to causing the disease.

What are alleles? How many alleles can there be for a gene and how many copies does each individual have?^

Suppose we choose a particular chromosome from two different people and examine the DNA from the same spot on both chromosomes. We will find that the pattern of the bases (A’s, C’s, T’s, and G’s) is similar, but it is often not exactly the same, even if the region is a protein-coding gene. How can a gene code for a product if the pattern is not the same in every person? The answer is that there can be many different versions or variants of a given gene. These different versions of the gene are called alleles. Different alleles of a gene code for the same trait, but they may manifest themselves in different ways. The gene for eye color contains the instructions governing eye pigment, for example, but the specific color is determined by the particular alleles one has. Everyone has the same number of chromosomes and genes, but each person’s genetic code has a unique combination of alleles. This potential for variation explains why we all have similar genomes, yet we still have people of different heights, weights, and faces.

The way in which the Huntington gene varies among individuals is by the number of repeated C-A-G codons it contains. In other words, different alleles of the Huntington gene contain different numbers of CAG codons. It is important to understand that everyone has the Huntington gene, but individuals with Huntington’s disease have a many-CAG version of the gene, one that does not function normally. “Having the HD allele” is somewhat loose terminology, but it is used often and usually implies “having one of the multiple-CAG alleles on the Huntington gene that causes HD.” Within this site, the allele on the Huntington gene with the normal number of CAG repeats (the allele that does not result in HD) is referred to as the non-HD allele. The allele of the Huntington gene with the extra CAG repeats (the allele that does result in HD) is described as the HD allele.

How do genes determine physical traits? What does it mean to say that the HD gene is dominant?^

Since we inherit one complete set of DNA from each parent, chromosomes occur in pairs called “homologues.” (Click here for a picture of homologues.) Hence, a gene that is found on a given chromosome actually has a partner on its matching, or homologous, chromosome. This means that a person actually has two copies of every gene, one allele on each of two homologous chromosomes. This feature raises some important questions about how alleles interact and relate to each other.

Tbl C-1: Expression of Dominant & Recessive Alleles

Alleles can be thought of as having different “strengths.” If two different alleles are present together, the “stronger” one will influence the trait under consideration. This phenomenon is called dominance. A dominant allele influences the resulting trait whether an individual has one or two copies of that allele. In contrast, in order for recessive alleles to be expressed, an individual must always have two copies of the “weaker” allele. (See Table C-1.)

HD is called a dominant trait because individuals with just one copy of the HD allele typically develop HD symptoms. The HD allele (with many CAG repeats) is dominant over the non-HD allele (with few CAG repeats). Again, an individual need have only one copy of the HD allele to inherit the disease. There is also no exact cut-off point for when the number of CAG repeats is considered “abnormal.” (Click here for a table of repeats and their effects.) Occasionally, an individual will have an allele whose CAG codon count falls within a small “gray area” for which the repeat number is slightly higher than normal, but not quite “abnormal.” This version of the allele has a medium strength. Its dominance is said to be “incomplete,” and individuals with this allele may or may not develop the disease.

How are alleles inherited? What are the chances of inheriting the gene?^

Since the Huntington gene is not on a sex-determining chromosome, the disease is not sex-linked. In other words, the inheritance and development of Huntington’s disease are not related to an individual’s sex. This means that males and females have an equal chance of inheriting the disease. Males and females with the disease are also equally likely to pass it on to their children.

Every person inherits two copies of the Huntington gene, one from each parent. Likewise, every person will also pass one of these two copies to each child. The chances of giving either of these two alleles to a child are equal (50/50). A person with Huntington’s disease has one non-HD allele and one HD allele. Hence, there is a 50% chance that the non-HD allele will be passed on and a 50% chance that the HD allele will be passed on. This means that each child of an individual with HD has a 50% chance of getting the HD allele. Individuals with a chance of inheriting the disease are sometimes described as “at-risk.” At-risk individuals have the option of undergoing genetic testing, which shows whether their “50% risk” of developing HD is in reality nearly 0% or nearly 100%. (For more information about genetic testing for HD, click here.)

Individuals without any copies of the HD allele do not have HD, and these individuals are very unlikely to pass HD on to their children. They have two non-HD alleles, and the child will always receive one of these two alleles. The only exception is in the case of a new mutation, a heritable change in a person’s DNA. Very rarely a mutation will occur so that a child’s allele differs from that of the parent from whom it was inherited. Only very rarely, therefore, does an individual without an HD allele have a child with HD. For the same reason, Huntington’s disease does not typically “skip” generations. That is, we do not observe families in which a grandparent and grandchild have HD but the child’s parents do not. If such a pattern were observed, it would be most likely that one of the parents has an HD allele, but has not yet developed symptoms of the disease.

Are my children at risk?^

Let’s switch gears and think about this question from the perspective of the child of a person with HD. The child inherits one allele from each parent. The parent without HD has two non-HD alleles, so the allele from this parent will be non-HD regardless of which one is inherited. The parent with HD has one non-HD allele and HD allele. There is an equal probability of passing either of these alleles to the child. Thus the child has a 50% chance of getting the non-HD allele and a 50% chance of getting the HD allele. Since the chance of getting an HD allele is one in two, the child has a 50% chance overall of inheriting the disease. (See Figure C-2.)

Fig C-2: Risk for Child of HD Individual

What if you discover that you are the grandchild of a person with HD, and your parent who is at risk chooses not to be tested? Recall that you have two copies of the Huntington gene. One copy (allele) will come from the parent who is not at risk. This copy will always be non-HD and does not affect your chances of getting the disease. The second copy comes from your at-risk parent. Since this parent is the child of an individual with HD, he or she has an equal chance of having either two non-HD alleles or one non-HD and one HD allele. (We found this out in Figure C-2.) In the first case, this parent has two non-HD alleles and you will not inherit the disease regardless of which of the two non-HD alleles you get. In the second case, the parent has one HD allele and one non-HD allele. Here, you will inherit the disease if you get the HD allele, but not if you get the non-HD allele. Out of the four possible outcomes, exactly one results in your having a copy of the HD allele. This represents a 25% chance that you have inherited the disease. (See Figure C-3.)

Fig C-3: Risk for Grandchild of HD Individual

There has never been any history of HD in my family…how could the HD allele just suddenly appear?^

Remember that HD alleles are distinguished by the number of CAG codons they contain. The number of repeats is not fixed between generations, and it is possible that the number of repeats changes when cells divide. Usually this change results in a larger number of repeats, although occasionally the number of repeats decreases. No one is sure exactly what causes the number of repeats to multiply, but there is some evidence that codon numbers expand as a result of DNA copying inaccuracies during sperm formation. When DNA is copied, it is reproduced in small sections that are strung together later to make the long, continuous strands of DNA in chromosomes. There is some speculation that codon repeats could expand if these pieces are not hooked together correctly. (For more information about mutations, click here.)

A person who has a “normal allele” with a borderline number of repeats (typically between 36 and 39 copies of CAG) may produce a sperm or egg cell that contains an allele with a few additional codons. On rare occasions, these extra codons may be just enough to cause the child inheriting the allele to have an abnormal repeat number. One researcher speculated that about 10% of HD cases are caused by such changes in repeat number. Although in most cases the HD allele is not inherited in this way, this possibility explains how HD sometimes seems to just “appear” in a family.

If I have the gene, what does that mean? Will it definitely express itself, and if so, when will this happen?^

Historically, an individual known to have an HD allele almost always developed symptoms of the disease, unless he or she died of some other cause prior to onset of symptoms. Individual cases have varied greatly in severity and in rate of progression for reasons that are still not yet fully understood. As a very general rule, the typical age of onset for adult-onset HD is between the ages of 30 and 50. In most instances, individuals live with the disease for 10 to 25 years. Several studies indicate that the number of CAG codons plays a role in how soon symptoms appear. The general trend appears to be “the greater the number of repeats, the earlier the onset of the disease” although there is considerable variation. There is also evidence to suggest that the average age of onset is later for individuals who inherited the HD allele from their mothers than for individuals who inherited the allele from their fathers. It follows then that, as a general rule, onset occurs earlier when the HD allele is inherited via one’s father.

About 10 percent of all HD cases are classified as the juvenile form, which has an age of onset between infancy and 20 years. The juvenile form generally occurs when the number of CAG codons is especially large (on the order of 55 and above). Individuals with juvenile HD have different symptoms, such as rigidity, seizures, and dementia, than do individuals with adult HD. In addition, the progression of juvenile HD is usually much more rapid. (Click here for more about juvenile Huntington’s disease.)

Figure C-4 shows the correlation between increasing number of CAG repeats, from 39 to 50, and decreasing age of onset. The shaded bars show the median age of onset for individuals with a given number of CAG repeats. The exact numbers used for this graph are shown in Table C-2. Table C-2 also shows, in its third column, a way to represent the range in age of onset that occurs at each number of repeats. The figures in the third column correspond to 85% confidence intervals (C.I.) around the average age of onset. A confidence interval means that for a given number of repeats, we can be 85% sure that the actual age of onset lies within the given age range. This range is represented below in Figure C-4 by yellow bars. Please note that these range figures must be interpreted carefully: they specifically do not imply that an individual who remains symptom-free throughout a given range is exempt from HD. Any particular individual may very well develop symptoms at either an earlier or later age than those shown in the table.

Fig C-4: Observed Age of Onset According to Number of CAG Repeats

Tbl C-2: Observed Age of Onset According to Number of CAG Repeats

For further reading^

  1. “Huntington’s Disease: A Brief Explanation” International Huntington Association. Online.
  2. “Huntington’s Disease” Online Mendelian Inheritance in Man. Online.
  3. “GuideLines for Genetic Testing for Huntington’s Disease.” Huntington’s Disease Society of America. Online.

-A. Hsu, updated 7-1-04

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The HOPES Huntington's Disease Timeline (Text)

Scenes 1-5^

Fig R-7: Scene 1

16th Century

Paracelsus, a Renaissance alchemist (1493-1541), coins the term “chorea” to describe the dance-like, uncoordinated movements that are now known to be symptomatic of HD

Fig R-8: Scene 2

1686

English physician Thomas Sydenham attempts to classify different types of chorea and describe their causes.

Fig R-9: Scene 3

1630s

English colonists in Massachusetts, Connecticut, and New York (especially Long Island) use names such as “that disorder” and “Saint Vitus´ dance” to describe HD.

Fig R-10: Scene 4

1692

The Salem Witch Trials occur in Salem, Massachusetts. Some of the “witches” are now believed to have had HD. Their choreic movements and odd behavior were seen as possession by the devil.

Fig R-11: Scene 5

1840s

For the first time, HD is described in the medical literature as “chronic hereditary chorea.” Physicians in the United States, England, and Norway write about people with involuntary movements and mental disturbances that were inherited from a similarly affected parent. Three separate accounts are recorded, all by young physicians.

Scenes 6-10^

Fig R-12: Scene 6

1872

George Huntington writes a landmark paper entitled “On Chorea.” Using personal accounts of his father´s patients, Huntington provided a classic description of HD´s symptoms and emphasizes HD´s hereditary nature. Significant interest in HD, especially its genetic component, occurs due to George Huntington´s paper, “On Chorea” (1872).

Fig R-13: Scene 7

1910-11

The American eugenicist Charles B. Davenport writes Heredity in Relation to Eugenics (1911), in which he uses genetic diseases, including HD, to argue in favor of compulsory sterilization and immigration restriction for those afflicted with HD. Davenport founds the Cold Spring Harbor Biological Laboratory and Eugenics Record Office in 1910 to track families with inherited disorders, and he produces what is, at the time, the largest study of families with HD.

Fig R-14: Scene 8

1910-11

Researchers first note the deterioration the central region of the brains of patients as the disease progresses. They identify the caudate nucleus as the central target of brain cell death.

Fig R-15: Scene 9

1950s

An upsurge in publications on HD research occurs with the growing interest in human genetics and the 1953 discovery of DNA´s structure by Watson and Crick.

Fig R-16: Scene 10

1955

Americo Negrette publishes a book describing communities in Lake Maracaibo, Venezuela, with unusually high numbers of individuals affected by HD.

Scenes 11-15^

Fig R-17: Scene 11

Late 1950s

Arvid Carlsson and Oleh Hornykiewicz, two European scientists, make the breakthrough discovery that dopamine pathways between neurons are destroyed in Parkinson´s disease patients. Since the symptoms of Parkinson´s disease are nearly the opposite of those of HD, the scientists hypothesize that decreasing HD patients´ dopamine levels might be a key step in treating the disease.

Fig R-18: Scene 12

1966

The first Department of Neurobiology is established at Harvard University. Ntinos Myrianthopoulous writes a review article decrying the lack of knowledge of HD.

Fig R-19: Scene 13

1967

Famous poet and songwriter Woody Guthrie dies of HD. Guthrie´s wife, Marjorie, creates the Committee to Combat Huntington´s Disease (CCHD), now called the Huntington´s Disease Society of America (HDSA), to provide public health outreach on HD.

Fig R-20: Scene 14

1970

The Society for Neuroscience (SFN) is a nonprofit organization dedicated to study of the brain and nervous system. SFN, founded in 1970, has grown from 500 members to more than 36,000. Society of Neuroscience is the world’s largest organization of scientists devoted to the study of the brain.

Fig R-21: Scene 15

1972

The International Centennial Symposium on Huntington´s Disease is held on the hundredth anniversary of George Huntington´s historic publication (See 1872). The Symposium aims to gather all HD researchers and assess the current state of knowledge, generating new optimism for HD research.

Scenes 16-20^

Fig R-22: Scene 16

1972

Thomas L. Perry finds diminished levels of GABA in the brains of HD patients.

Fig R-23: Scene 17

1973

John Meeks and Natalie Stein suggest that the HD allele causes premature aging.

Fig R-24: Scene 18

1974

Milton Wexler establishes the Foundation for Research in Hereditary Disease, which will later become the Hereditary Disease Foundation.

Fig R-25: Scene 19

1976

Joseph T. Coyle develops the first rat model of HD by using kainic acid. The rats exhibited HD-like symptoms such as decreased weight, motor dysfunction, brain atrophy, neuronal inclusions and other cognitive impairments.

Fig R-26: Scene 20

1977

The Congressional Commission for the Control of Huntington´s Disease and Its Consequences is held to develop a comprehensive report on HD in the United States.

Scenes 21-25^

Fig R-27: Scene 21

1978

The Second International Centennial Symposium on Huntington´s Disease is held to review progress since the 1972 Symposium. The sheer volume of research that is accomplished over the six years indicates a heightened interest in HD.

Fig R-28: Scene 22

Late 1970s

Researchers find evidence that HD affects cells all over the body, not just in the brain.

Fig R-29: Scene 23

1979

Mike Connely establishes the National HD Research Roster at the Indiana University School of Medicine.

Nancy and Tom Chase go to Venezuela for an exploratory visit to the Lake Maricaibo area, a hot spot for HD (see 1955).

Fig R-30: Scene 24

1980

The National Institute of Neurological Disorders and Stroke (NINDS) funds the first two “Centers Without Walls” in Boston (Harvard/Mass General Hospital) and Baltimore (Johns Hopkins University).

Fig R-31: Scene 25

1981

Nancy Wexler begins her fieldwork in the Venezuelan communities around Lake Maracaibo, a hot spot for HD.

Scenes 26-29^

Fig R-32: Scene 26

1983

Scientists discover a gene marker linked to HD on the short arm of chromosome 4, which indicates that the Huntington gene is also located on chromosome 4. Predictive linkage testing is introduced to assess the likelihood of contracting HD.

Fig R-33: Scene 27

1993

The location of the Huntington gene is discovered at the 4p16.3 gene site on chromosome 4. The gene is found to contain codon C-A-G in varying numbers. An abnormal number of CAG repeats turns out to be a highly reliable way to tell whether someone has the allele for HD.

Fig R-34: Scene 28

2000

The Huntington´s Disease Advocacy Center (HDAC) is created to provide information and support for people with HD and their families.

Fig R-35: Scene 29

2001

HOPES is a team of faculty and undergraduate students at Stanford University dedicated to making scientific information about Huntington´s disease (HD) more readily accessible to the public. Our goal is to survey the rapidly growing scientific literature on HD and to consolidate this information into a coherent, reliable web resource that reflects current scientific understanding of HD.

Scenes 30-35: Notable People and Places^

Fig R-36: Scene 30

Philippus Aureolus Theophrastus Paracelsus Bombastus von Honenheim

1493-1541

Paracelsus was a notable alchemist and reformer during the Renaissance period. He introduced the name chorea sancti viti (Latin for “St. Vitus´ dance”) to describe a peculiar disease characterized by writhing, sporadic movements. Most likely due to the mass hysteria and religious superstition of the time, this “dancing mania” had reached epidemic proportions in Europe. It is now thought that many of the sufferers may have experienced epileptic seizures or ergot poisoning. Near the end of Paracelsus´s lifetime, the spread of the disease began to slow, the symptoms became milder, and Paracelsus termed this new form “chorea naturalis,” or chorea due to natural causes.

Fig R-8: Scene 31

Thomas Sydenham

1624-1689

Thomas Sydenham was an English physician who is considered one of the most important revivers of Hippocrates´ views. He stressed careful observation and bedside attendance, and he remarked keenly on many symptoms commonly associated with HD. He noted, for instance, “The hand cannot be steady for an instant. It passes from one position to another, however the patient may strive to the contrary.” He believed that these movements were caused by “some humor falling on the nerves, and such irritation causes the spasm.” Today, however, Sydenham chorea refers to chorea that is associated with rheumatic fever, even though Thomas Sydenham was an English physician who is considered one of the most important revivers of Hippocrates´ views. He stressed careful observation and bedside attendance, and he remarked keenly on many symptoms commonly associated with HD. He noted, for instance, “The hand cannot be steady for an instant. It passes from one position to another, however the patient may strive to the contrary.” He believed that these movements were caused by “some humor falling on the nerves, and such irritation causes the spasm.” Today, however, Sydenham chorea refers to chorea that is associated with rheumatic fever, even though Sydenham never explicitly made that link.

Fig R-12: Scene 32

George Huntington

1850-1916

George Huntington, an American physician, was only twenty-two years old when he submitted his famous paper “On Chorea” (1872) to The Medical and Surgical Reporter. Much of the paper drew from the written observations of his father and grandfather, both physicians who had noticed the involuntary shaking of some patients. The paper gained Huntington instant notability because, in the words of Sir William Osler, “In the history of medicine there are few instances in which a disease has been more accurately more graphically, or more briefly described.” Huntington was able to explicitly point to genetic inheritance as the mode of transmission, and he noticed that the first symptoms usually appear at an adult age and that they are usually accompanied by mental decline as well. It is due to these significant observations and conclusions that “Huntington´s disease” bears George Huntington´s name.

Fig R-37: Scene 33

Woody Guthrie

1912-1967

Woody Guthrie was one of the most famous Americans with HD. Born in Okemah, Oklahoma, Guthrie gained fame in the 1930s and 1940s as a folk singer and radio entertainer. He was known for putting political and social commentary in the lyrics of his music, and he often celebrated the plight of the American laborer. In his songs, Guthrie includes references to many of the 20th century´s most historic events, including the Great Depression, the “Dust Bowl” migration, World War II, and the Cold War. His most famous songs include “This Land Is Your Land,” “Grand Coulee Dam,” and “I Ain´t Got No Home.”

Guthrie´s mental state began to deteriorate in the early 1950s. His memory declined, and his behavior became unpredictable. He left his wife, Marjorie, and his home in New York to marry a woman twenty years his junior in California. However, due to his mental state, Guthrie was eventually forced to return to New York, where he was placed in one hospital after another. HD

Fig R-31: Scene 34

The Wexler Family

The Wexler family is inextricably tied to the history of Huntington´s disease research. In 1968, Leonore Wexler was diagnosed with HD, which inspired her two daughters, Nancy and Alice, and her husband, Milton, to become involved in the search for a cure for HD.

Milton Wexler, a prominent psychologist, is responsible for bringing world renown researchers together to focus on HD research. He founded the Hereditary Disease Foundation, which funds HD research and sponsors workshops for scientists to share ideas.

Nancy Wexler has played a pivotal role in the scientific research of HD. She pioneered the fieldwork in Lake Maracaibo, Venezuela that led to the discovery of the Huntington gene (see Lake Maracaibo, Venezuela) and has since helped other researchers map genes responsible for Alzheimer´s disease, kidney cancer, manic depression, and other disorders. She served as the Hereditary Disease Foundation´s president, and is currently a Professor of Neuropsychology at Columbia University.

Alice Wexler, a teacher, writer, and historian, chronicled her family´s journey in the insightful book Mapping Fate: A Memoir of Family, Risk, and Genetic Research.

Fig R-16: Scene 35

Huntington’s disease in Lake Maracaibo, Venezuela

In the early 1950s, Dr. Amerigo Negrette first diagnosed Huntington´s disease in Lake Maracaibo, Venezuela. Working as a rural physician, Negrette was perplexed by the fact that many townspeople often appeared drunk, staggering and weaving at all hours of the day. He learned from locals that these people were not drunk, but instead suffered from a disease referred to as el mal de San Vito, or the sickness of Saint Vitus. After visiting many people with the sickness, Negrette diagnosed the disease as HD. He discovered that HD ran deep in the community; people with the illness were interrelated and had common ancestry. In 1963, he published a book entitled Corea de Huntington: Estudio de una Sola Familia a Traves de Varias Genereaciones describing HD in his community. The world learned of this tragic occurrence when Negrette´s work was presented at the 1972 Centennial Symposium.

In 1981, Dr. Nancy Wexler led a team of scientists to study HD in Lake Maracaibo. Their original goal was to find an HD homozygote (an individual who has inherited two copies of the HD allele), but the team also ended up collecting blood samples from as many HD sufferers as they could find and test. These samples played a key role in the discovery of a genetic marker for HD in 1983 and led to the creation of a community pedigree, the largest of its kind in the world.

-S.Jourin, 4-05-05
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Juvenile Huntington's Disease (Text and Audio)

Click on the link below to hear an audio recording of this article:

Juvenile Huntington’s Disease

Juvenile HD is a form of Huntington’s disease that affects children and teenagers. Like the adult form of the disease, juvenile HD is hereditary in nature. Because of its hereditary character and early age of onset, a child with juvenile HD may also have a parent or other close family member who is affected by adult-onset HD at the same time. This tendency to affect multiple generations simultaneously places an even greater strain upon families who are affected by juvenile HD.

What is juvenile HD?^

About 10 percent of HD cases occur in individuals under the age of 20 years. This form of HD is called juvenile Huntington?s Disease, or early-onset HD, and it has an age of onset anywhere between infancy and 20 years of age. Although juvenile HD and adult-onset HD both result from an altered form of the same gene (the Huntington gene), the symptoms of juvenile HD are very different from those of adult-onset HD. Individuals with juvenile HD often become stiff or rigid in their movements (instead of having chorea), and about one third of them have recurrent seizures. As with adult-onset HD, individual cases of juvenile HD vary greatly, and different children often have different symptoms. As a result, cases of HD are classified as the juvenile or adult form based upon age of onset, and not by symptom. Any case of HD where the onset occurs before the age of 20 is considered to be of the juvenile form, regardless of the symptoms present.

Although the number of CAG codon repeats in a particular segment of the Huntington gene does not accurately predict the age of onset, generally more repeats correspond to an earlier age of onset. This tendency is especially true in cases of juvenile HD, where most individuals have between 80 and 100 CAG repeats. The earlier the onset of juvenile HD, the faster it usually progresses. In general, progression of the disease is more rapid than in adult-onset HD. Often, death from juvenile HD occurs within 10 years of onset, as opposed to 10-25 years in adult-onset HD.

What causes the large CAG repeat numbers seen in juvenile HD cases?^

Children with juvenile HD usually have a larger number of CAG repeats in a particular segment of the Huntington gene than do individuals with adult-onset HD. In many cases, these children also have many more CAG repeats compared to the parents from whom they inherited the HD allele. The exact cause of repeat expansion is still unclear. At one point, it was thought that the DNA from the unaffected parent might somehow contribute to the development of juvenile HD. A non-HD allele from the unaffected parent could potentially “aggravate” the Huntington gene and somehow cause the large increase in repeat numbers characteristic of juvenile HD. Given that juvenile HD is so rare, if there existed an allele that aggravated the disease, it would necessarily be rare as well. A case study in the 1960’s showed a man with adult-onset HD who had affected children with two different women. In order for this to occur, both of the mothers must have had the rare “aggravating allele,” a highly improbable occurrence. This finding made it seem unlikely that DNA from the unaffected parent was contributing to the expanded repeats.

Alternately, it is possible that repeat expansion is caused by DNA copying inaccuracies during cell division. Each time a cell divides, its DNA must be copied, or replicated, so that the new cell has a duplicate copy of the original DNA. (For more information on DNA, click here.) Along with this process comes the possibility that a mistake is made somewhere during the copying procedure. Such “mistakes” are very common during DNA replication. One such mistake might cause the number of codon repeats to increase. Since the formation of sperm involves millions of cell divisions more than the formation of eggs, the number of opportunities for triplet expansion during DNA replication is much larger in males than in females. Hence, it is possible that adult males are more likely to pass alleles with expanded repeat numbers to their children. We will call this the “paternal triplet expansion hypothesis.” This hypothesis could explain why in most cases (about 70-90% of them), individuals with juvenile HD have inherited the HD allele from their fathers rather than their mothers.

How are large repeat numbers related to the increased severity of juvenile HD?^

Individuals with early-onset HD usually have a number of CAG repeats in a particular segment of the Huntington gene that is much larger than the number of repeats seen in adult-onset HD. The largest number of CAG repeats seen thus far is around 250, but most individuals with juvenile HD have between 80 and 100 repeats.

Many studies have shown a correlation between the number of repeats and the age of onset. Usually, the more repeats, the younger the age of onset. This correlation, however, does not prove that the large repeat numbers actually cause the earlier onset. It merely suggests that the two events – large repeat numbers and early age of onset – usually occur together. (For another example of correlation and causation click here.)

Most individuals with juvenile HD experience an age of onset that is much younger than that of their affected parents. They also often face a much more rapid progression of the disease. This occurrence is described as genetic anticipation, where a disease increases in severity in successive generations, and a parent can produce a child with a more severe form of a disease. In the case of HD, the expanded section of triplet repeats provides a possible (though still unconfirmed) explanation for the pattern of anticipation seen in HD inheritance. As the number of repeats grows between generations, the severity of the disease increases, and individuals experience an earlier age of onset and a more rapid development of the disease.

How is juvenile HD inherited?^

Juvenile HD is caused by the same gene that causes adult-onset HD. The version of the Huntington allele causing early-onset HD usually has, however, a greater number of CAG repeats. Because the early-onset and late-onset forms depend upon the same gene, early-onset HD is inherited in the same manner as adult-onset HD. (To read about how the HD allele is inherited, click here.)

An individual with juvenile HD inherited the HD allele from one of his or her parents. In most cases, this allele seems to be paternally inherited, following the “paternal triplet expansion hypothesis” discussed previously. Usually, it is not maternally inherited unless the mother herself had juvenile HD (since in this case the mother would already have a number of repeats on the order of those seen in juvenile HD).

Due to the rapid progression of the disease, most individuals with juvenile HD do not survive to bear children of their own. For those who do, however, their children have the same 50% risk of inheriting the HD allele as the children of individuals with adult-onset HD. The number of CAG repeats in the Huntington gene of an individual with juvenile HD is normally very high (even compared to that of individuals with adult-onset HD). Since repeat numbers tend to increase rather than decrease in successive generations, it is likely that the child of such an individual will have a similar or larger number of repeats if he or she inherits the altered allele. Given the correlation between repeat number and age of onset (discussed in the previous section), it is very likely that the child will also develop juvenile HD. In short, the child of an individual with juvenile HD has a 50% chance of inheriting the HD allele. If the child does inherit the altered allele, he or she is very likely to develop juvenile HD.

What are the early signs of juvenile HD?^

Although by definition juvenile HD begins at an early age, most children are able to walk and talk at a normal age before symptoms start to appear. The signs of juvenile HD are often subtle and difficult to distinguish from the normal “growing pains” that children experience. A major sign of onset is a continuing decline in school performance. Other indications include subtle changes in handwriting, difficulty learning new things, and small problems with movement. Some common movement problems include slowness, clumsiness, rigidity, tremor, and muscular twitching, or myoclonus. Parents often notice that their children fall more often and are less coordinated than they used to be.

Every case of juvenile HD is unique, and it is possible that individuals experience different symptoms depending on the age of onset and exact number of CAG repeats. However, many parents of children with HD have said that the most noticeable aspect of onset is change. Parents might notice personality changes, new problems with coordination, behavioral changes, new speech difficulties, and changes of pace in learning. For example, a child who was once very good at sports has become clumsy in recent months, or a previously well-behaved student is suddenly causing trouble at school. A mother of two children with HD described her perception of the changes within her family members:

“Following the diagnosis of HD in the first child, I began, of course, to observe the other family members very closely – ever vigilant for signs of HD. Some things, such as moodiness, speech problems, or hyperactivity could have been interpreted as early symptoms of HD. It became apparent that the clue seemed not to be the action itself, but rather, whether or not those things had always been present or if they represented a definite change.”

What symptoms are common to both juvenile HD and adult-onset HD?^

Both the early- and adult-onset forms of HD are characterized by what is called dementia, a progressive loss of mental function. Many individuals also seem to undergo personality changes. Some changes, such as increased irritability and bad temper outbursts, are sometimes due to the difficulties of dealing with the disease rather than actual clinical symptoms. Often, people with HD experience frustration when realizing that they can no longer do things they once could. Sometimes, however, these personality changes are a more direct result of the disease. Such symptoms may be alleviated with medication.

Both juvenile and adult forms of the disease result in neurological damage that causes severe movement disorders, although the movement problems vary greatly between the two forms. Individuals with either form experience difficulties with swallowing and speaking. However, adult-onset HD is normally characterized by dance-like chorea, while juvenile HD more often results in rigidity and stiffness of muscles.

For an explanation of these differences click here.

How are the symptoms of juvenile HD different from those of adult-onset HD?^

The most notable symptomatic distinction between the two forms of HD is that many individuals with juvenile HD do not experience the chorea that is so commonly associated with the adult-onset form. Instead of exhibiting the dance-like movements of chorea, affected children are often rigid and stiff. Generally, children with a younger age of onset are less likely to experience chorea. Chorea is more likely to be present in individuals who have an age of onset from 15-18 years. It seems that individuals with juvenile HD who have a later age of onset are more likely to experience symptoms that resemble those of adult-onset HD.

About 25-30% of individuals with early-onset HD also experience recurring seizures, a symptom that is uncommon in the adult-onset form. Seizures experienced by children with HD are usually generalized, meaning that they are caused by electrical discharges that affect both sides of the brain and often involve a loss of consciousness. However, some children also develop partial seizures, which involve discharges in just one part of the brain and may or may not involve a loss of consciousness.

The generalized seizures experienced by HD children are usually what are called tonic-clonic seizures. Generalized tonic-clonic seizures (or grand mal seizures) consist of both tonic and clonic phases. During the tonic phase the body is rigid, and often the child falls to the ground. The clonic phase follows the tonic phase and is usually associated with convulsive movements or rhythmic jerking motions. The child typically loses consciousness for a variable period of time.

Some children also develop myoclonic seizures, which involve sudden, brief jerking movements, or myoclonus. These seizures vary greatly in their severity and frequency. Myoclonus should not be mistaken for seizures – the term myoclonus refers to the jerking symptom itself, which can have many causes. It is only when myoclonus is caused by abnormal brain activity that it is properly called myoclonic seizure. Many children with HD experience myoclonus that is not related to seizures.

What parts of the brain are affected in juvenile HD?^

Fig E-1: Caudate, Putamen, & Globus Pallidus

At autopsy, individuals who have died from juvenile HD show an even more widespread pattern of brain degeneration than that seen in adult-onset HD. As in the adult form, there is severe degeneration of the caudate and putamen. (See Figure D-4.) The caudate and the putamen are responsible for regulating voluntary movement, and it is thought that damage to these parts of the brain is responsible for many of the movement problems — especially the chorea — that individuals with HD experience. (See Figure E-1.)

Fig E-2: Spider Cells

A characteristic that is seen more often in the juvenile form than in the adult form is extreme gliosis of the globus pallidus (Figure E-1). Gliosis is excess growth of what are called spider cells (see Figure E-2) — cells that normally provide supporting and protective tissue for nerve cells. Some individuals with adult-onset HD experience rigidity (instead of chorea), and case studies of several of these individuals have also shown damage to the globus pallidus. Hence, it is thought that abnormality of the globus pallidus may be responsible for the rigidity seen in juvenile HD.

Analysis of juvenile HD brains shows damage to many areas, but the pattern of damage is not consistent between individuals. Loss of neurons in the Purkinje cells and granule cells of the cerebellum is often seen in the juvenile but not the adult form. Other areas of damage sometimes include the dentate nucleus, hippocampus, and neocortex. The dentate nucleus is responsible for rapid movements, and the hippocampus deals with the transfer of information from short-term to long-term memory. The neocortex constitutes about 85% of the brain’s total mass, and it is believed to be responsible for higher cognitive functions, such as language and memories. It is currently not known how damage to these areas of the brain manifests itself as symptoms in people with juvenile HD.

What treatments are recommended specifically for juvenile HD?^

Anticonvulsant drugs are usually prescribed to help prevent and control the seizures that occur in children with juvenile HD. Finding the right combination and amount of drugs is not an easy process, and often the optimal treatment varies over time and between individuals. In many cases, caregivers know the most about the child’s reactions to specific drugs, making it very important for the doctor and caregivers to communicate frequently about which drugs and doses are working and which are not.

Usually, physicians attempt to minimize the number of generalized tonic-clonic seizures. Carbamazepine (Tegretol), phenobarbital and phenytoin (Dilantin), and other medications commonly prescribed to control non-HD seizures are not effective in many individuals with HD. Many individuals with juvenile HD have responded more favorably to other seizure drugs, such as valproic acid and benzodiazepines like clonazepam. Myoclonus and jerking motions are usually not treated unless they are very severe (for example, if they cause the child to fall frequently or reduce the child’s ability to take in food). Antimyoclonic drugs such as valproate are sometimes prescribed to treat myoclonic jerks.

Side effects of seizure drugs can include drooling, sleepiness, and a general sense of confusion. However, the most significant concern of seizure medications is their potential to aggravate other juvenile HD symptoms. Some drugs may cause increased swallowing problems, drowsiness, and coordination difficulties. Many children with HD also have a poor tolerance of anticonvulsant drugs. Generally, physicians attempt to minimize the seizures as much as they can without lowering the quality of life in other areas. Achieving this ideal balance often requires trying many different drugs and prescribing less than the maximum dosage of each particular drug. Although the children may still have occasional seizures, many parents consider this treatment more acceptable than the alternative: prescribing a higher dosage to eliminate seizures but worsening the child’s other symptoms.

Physical therapy is recommended to ease rigidity and to prevent degeneration (atrophy) of unused muscle. For some individuals, pool therapy especially helps to loosen tight muscles. Pool therapy involves exercises that are done while the individual is submerged in warm water. The warm temperature is soothing for muscles, and the buoyancy of the water makes motion require less effort, enabling patients to strengthen muscles gradually.

Drugs are sometimes prescribed to control other symptoms, such as rigidity and difficulty sleeping. Counseling and medication sometimes help with behavioral and psychological symptoms. Many times individuals with juvenile HD respond poorly to drugs that are commonly prescribed for adult-onset HD. Hence, with each new drug or dosage, the child should be monitored carefully for side effects, such as increased drowsiness or poorer performance in school. The most effective combination of treatments is different for every individual with juvenile HD, and this optimal care can be achieved only when the doctor and caregivers work together to discover what is best for the child.

Table E-1 gives an abbreviated summary of juvenile HD.

Tbl E-1: Juvenile HD Quick Facts

For further reading^

  1. “Juvenile Huntington Disease,” Huntington Society of Canada. Online.
    An excellent resource for juvenile HD; one of the few souces that focuses only on juvenile HD.
  2. Byers, R. K., and J. A. Dodge (1967) “Huntington’s chorea in children. Report of four cases.” Neurology 17: 587-96.
    A paper describing the symptoms, treatment, and diagnoses of four children with juvenile HD.
  3. Byers, R. K., F. H. Gilles, and C. Fung (1973) “Huntington’s disease in children. Neuropathologic study of four cases.” Neurology 23: 561-9.
    A very detailed paper that analyzes the brains of four individuals who died from juvenile HD and compares them to similar neuropathologic studies.
  4. “Case 117 — Progressive Movement Disorder,” University of Pittsburgh School of Medicine, Department of Pathology. Online.
    A case study of the diagnosis of a girl with juvenile HD.

A. Hsu, 2-25-02

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Introduction à la Maladie de Huntington

La première apparition de la maladie de Huntington (souvent appelée “MH”) dans la littérature médicale est due au docteur George Huntington, un médecin de Long Island à New York. Cette maladie atteint aussi bien les hommes que les femmes, touchant environ une personne sur 10 000 dans la plupart des pays occidentaux. Comme les personnes atteintes de MH ont besoin de soins constants et du support de leurs proches, cette maladie fait partie de la vie de beaucoup plus de gens encore.

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La maladie de Huntington se déclare normalement assez tardivement, quand la personne a entre 30 et 50 ans; cependant, il existe une forme de MH qui touche les enfants et les adolescents. Les personnes atteintes de MH montrent une grande variété de symptômes, que les médecins classifient habituellement en trois catégories: les symptômes moteurs, cognitifs et psychiatriques.

  • Parmi les symptômes moteurs de la MH, on peut observer spasmes musculaires, tics, rigidité, chutes, difficultés physiques à parler, et dans un état plus avancé de la maladie, difficultés à avaler (ce qui peut mener à une perte de poids significative). Des mouvements incontrôlés de torsion et de contorsion sont aussi un symptôme relativement courant de la MH. Les médecins appellent ces mouvements incontrôlés “chorée”.

  • Le principal symptôme cognitif de la MH est une modification de l’organisation des informations dans le cerveau, et en général un ralentissement du traitement de ces informations. Ces symptômes peuvent entraîner des difficultés pour apprendre des choses nouvelles, des difficultés pour s’organiser et fixer des priorités, une maladresse dans la perception de l’espace (où l’on se trouve par rapport à une table, aux murs…) et des difficultés pour porter son attention sur plusieurs choses à la fois. Il est fréquent que ces personnes se rattachent à des tâches de routine parce qu’elles leur sont plus faciles à accomplir. Enfin, à cause de troubles à organiser les mots reçus et les mots émis dans leur cerveau, beaucoup de personnes atteintes de MH ont des difficultés à communiquer avec d’autres personnes.

  • Le plus commun des symptômes psychiatriques de la MH est la dépression. Mais on peut aussi observer des troubles de personnalité, l’apathie, l’anxiété, l’irritabilité, l’obsession pour certaines activités (telles que d’aller se laver les mains), le délire et la manie. Le refus de reconnaître que l’on est atteint de MH est aussi un symptôme courant.

Malheureusement, généralement entre 10 et 25 ans après que la maladie se soit déclarée, MH a fait tellement de ravages chez la personne qu’elle en meurt, de pneumonie, crise cardiaque ou autres complications.

MH cause des détèriorations des cellules nerveuses du cerveau, entraînant des changements significatifs dans les capacités à réfléchir, ressentir et se déplacer. La cause de ces symptômes est demeurée un mystère pendant assez longtemps, jusqu’à ce que des docteurs remarquent que la maladie se retrouvait plus fréquemment dans certaines familles, et qu’ils suspectent des causes héréditaires. On sait maintenant que la transmission de la MH, comme celle d’autres traits héréditaires dépend d’informations “codées chimiquement” dans une substance appelée “acide déoxyribonucléique” ou ADN, qui existe dans les cellules vivantes. Comprendre un petit peu comment fonctionne ce code chimique permet de mieux saisir les causes de MH, et les traitements qui pourront peut-être un jour conduire à soigner la maladie.

Fig A-1: La Langue de l'ADN

Le code chimique de l’ADN est très similaire à la langue française: tous les deux utilisent certaines lettres dans un certain ordre pour faire passer certains messages. Mais alors que le Français a 26 lettres, l’ADN n’en a que 4: A, C, G et T (qui sont les initiales des quatre substances chimiques qui forment l’ADN). De plus, alors que la taille des mots varie beaucoup en françs, les “mots” de l’ADN sont toujours longs de trois “lettres”. Les gens qui étudient la génétique appellent ces mots des codons. Judicieusement, car les codons codent les futurs objets construits dans la cellule nerveuse. Ils sont un peu les plans, les schémas de montage. Prenons un exemple: quand un passage contient le mot anglais C-A-T (chat), vous vous représentez l’image de votre animal domestique préféré. De façon similaire, quand le code ADN contient les lettres G-G-C, il dit à la cellule de produire de la proline, un acide aminé. Pour en apprendre plus sur l’ADN, cliquer sur:

Si les codons forment les schémas de montage, alors nous pouvons voir les acide aminés qui en résultent comme des briques. Quand ces briques sont assemblées chimiquement elles forment une structure appelée protéine. Et comme dans des immeubles dans notre société, c’est dans les protéines que le travail des cellules nerveuses est effectué. Les protéines peuvent jouer des rôles très différents: elles aident la cellule à maintenir sa structure, produire de l’énergie et communiquer avec d’autres cellules.Sans les millions de protéines de notre corps; la vie telle que nous la connaissons ne pourrait pas exister.

Fig A-2: La Forme des Protéines

Le comportement particulier d’une protéine est déterminé par sa forme unique dans l’espace. Cette forme contrôle comment la protéine s’imbrique et intéragit avec d’autres parties de la cellule. La forme est elle-même déterminée par les acides aminés qui composent la protéine, et par leur ordre. Et c’est comme ça qu’à la manière d’un immeuble bien conçu qui a ses origines dans les plans de l’architecte, une protéine qui fonctionne avec succès a pour origine les codons de l’ADN.

Tous les êtres humains possèdent une protéine appelée huntingtine dans leurs cellules nerveuses. (Remarquez que, bien que la “maladie d’Huntington” s’écrit avec un “o”, l’orthographe correcte de la protéine impliquée est huntingtine avec un “i”.) Les scientifiques n’ont pas encore déterminé la fonction exacte de l’huntingtine, mais elle joue visiblement un rôle critique dans les événements qui permettent aux cellules de fonctionner efficacement. Comme beaucoup d’autres protéines, l’huntingtine contient l’acide aminé glutamine. Chez les personnes atteintes de MH pourtant, il y a un nombre excessif de glutamines dans un segment de la protéine en particulier. Ces glutamines supplémentaires sont dues à un trop grand nombre de copies du codon correspondant (celui qui code “glutamine”) dans le code de l’ADN. Ce codon est le mot de trois lettres C-A-G. Il est donc exact de dire que la MH est le résultat d’un trop grand nombre de copies de C-A-G dans l’ADN qui code la protéine huntingtine. C’est pourquoi on appelle souvent la MH un “désordre de répétition trinucléotide” (“trinucléotide” est un mot savant pour “codon”.)

Tbl A-1: Nombre de Copies du Codon CAG

Combien de copies du codon C-A-G sont trop de copies? Beaucoup de recherche a été faite dans ce domaine et il y a de nombreuses réponses différentes à cette question dans la littérature scientifique. Voici une estimation grossière: les gens qui ont entre 10 et 35 copies du codon C-A-G ont une protéine huntingtine normale. Ceux qui en ont 40 ou plus, en revanche, ont une protéine huntingtine défectueuse et développeront les symptômes de la MH. En ce qui concerne les personnes qui ont entre 36 et 39 copies les choses sont moins certaines. Certains verront apparaître les symtômes alors que d’autres en seront exempts. Pour en savoir plus sur la façon dont la MH est transmise d’une génération à la suivante, cliquer ici;

Pour résumer tout ce que l’on vient de dire, la maladie de Huntington est causée par un nombre excessif de copies du codon C-A-G dans l’ADN humain, ce qui entraîne la présence de trop de glutamine dans la protéine huntingtine. Mais pourquoi l’huntingtine ainsi modifiée est-elle nuisible ? Malheureusement, et malgré les efforts vaillants des chercheurs, nous n’avons pas encore de réponse finale à cette question. Etant donné que la forme d’une protéine détermine ses interactions avec les autres parties de la cellule (comme nous l’avons appris plus haut), une importante part de la recherche sur ce point tente de comprendre exactement comment une modification de sa forme affecte les interactions de la protéine hintingtine avec les autres composants de la cellule. Une étude suggère qu’une trop grande abondance de glutamines dans la protéine huntingtine cause la formation d’agglomérats rigides de protéines. Et comme les autres composants de la cellule sont conçus pour travailler dans un environnement plus souple, ils ne peuvent plus travailler dans cette encombrement accru. Le résultat final est la mort anticipée de la cellule nerveuse (appelée apoptose). Une autre étude récente suggère que la protéine huntingtine modifiée (et plus grande qu’à la normale) “kidnape” les protéines plus petites de la cellule nerveuse, les empèchant de faire leur travail. C’est ainsi que la protéine huntingtine pourrait endommager la cellule nerveuse directement. (Pour en savoir plus sur la protéine huntigtine modifiée, click ici.)

Fig A-3: Une Cellule est Comme une Ville

Tandis que les scientifiques continuent à explorer les points de détail de la MH, le mécanisme de base est clair. Si nous prolongeons notre analogie avec la construction d’immeubles, ce qui se passe quand la protéine huntingtine est modifiée est que l’immeuble (la protéine) n’a ni la taille, ni la forme désirée et ne peut donc pas fonctionner correctement dans la métropole qu’est la cellule nerveuse. Et comme elle ne peut pas fonctionner correctement, elle empêche les autres protéines dont le travail dépendait du sien de fonctionner correctement. Le résultat final est un effet boule-de-neige, où les problèmes se cumulent continuellement et la cellule nerveuse devient de plus en plus endommagée. Jusqu’à ce qu’après suffisament de dommages, la cellule nerveuse en meure. Et quand ce phénomène se produit à l’échelle de nombreuses cellules nerveuses, les problèmes de réflexion, de sensation et de gestes associés à la MH peuvent être observés. Pour en savoir plus sur les cellules nerveuses et comment leur mort est liée aux symptômes de la MH, cliquer ici:


Pour en apprendre plus sur l’ADN et la MH, un grand nombre de documents sont disponibles sur le Web (ces liens pointent vers des pages anglophones, mais il existe aussi de nombreuses pages francophones) :
  1. Visitez Khan Academy pour un bon tutorial.
  2. Le site Australien “Cooperative Research Centre for Discovery of Genes for Common Human Diseases” (Gene CRC) a quelques explications fabuleuses à différents niveaux de complexité.
  3. Cummings, C. J and Zoghbi, H.Y. “Trinucleotide Repeats: Mechanisms and Pathophysiology.” Annu. Rev. Genomics Hum. Genet. 2000. 1:281-328.Cet article assez technique explique les symptômes de la MH, et commente le nombre de répétitions du codon C-A-G chez les personnes atteintes ou non de la maladie. Il présente aussi des théories sur le rôle de la protéine huntingtine modifiée.
  4. Falush D, et al. “Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial under ascertainment of late-onset cases.” Am J Hum Genet 68 (2) 2001 Feb: 373-385.Une analyse technique du nombre de C-A-G au delà duquel une personne developpera les symptômes de la MH.
  5. “Huntington’s Disease”. Online Mendelian Inheritance in Man. Une collection de résumés d’une multitude d’études différentes sur la MH. Cela va des études de cas sur la transmission héréditaire de la maladie aux nouvelles méthodes pour la diagnostiquer. C’est un excellent site pour se tenir au courant des différentes études et recherches menées sur la MH aujourd’hui.
  6. “Huntington’s Disease”. Web MD. Une présentation générale de la MH très facile à lire.
  7. Li SH, Lam S, Cheng AL, Li XJ. “Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis.” Human Molecular Genetics, 2000, Vol. 9, No. 19: 2859-2867. Un papier très technique expliquant comment les protéines huntingtines modifiées pourraient anticiper la mort de la cellule nerveuse (apoptose).
  8. Nucifora, Frederick C. Jr., et al. “Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis.” Human Molecular Genetics, 2000, Vol. 9, No. 19: 2859-2867.Un autre papier très technique expliquant comment les protéines huntingtines modifiées pourraient anticiper la mort de la cellule nerveuse (apoptose).
-M. Stenerson, 07/15/03; traduit par J.G. Morard, 11/12/04
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Los Elementos Básicos de la Enfermedad de Huntington

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Los Elementos Básicos de la Enfermedad de Huntington

La enfermedad de Huntington (abreviada frecuentemente “EH”) fue decrita originalmente en la literatura médica en 1872 por George Huntington, un médico de Long Island, Nueva York. La enfermedad afecta a hombres y mujeres por igual, con una incidencia de aproximadamente uno en cada 10.000 personas en la mayoría de los países occidentales. Personas con EH necesitan de cuidado especializado y el apoyo de sus familias, lo cual aumenta el número de vidas afectadas directa o indirectamente por la enfermedad.

EH es una enfermedad cerebral, degenerativa, progresiva, y hereditaria. Normalmente la edad del inicio de la enfermedad es entre 30 y 50 años, aunque hay una forma de EH que afecta a niños y adolescentes. Personas con EH pueden demostrar una gran variedad de síntomas, que los médicos agrupan usualmente en tres categorías: síntomas de movimiento, cognositivos, y psiquiátricos.

  • Algunos de los síntomas de movimiento de la EH incluyen los espasmos de los músculos, los tics, la rigidez, caídas, la dificultad para producir fisicamente el habla, y, en las fases avanzadas de la enfermedad, la dificultad para tragar (que puede causar mucha perdida de peso). También incluye movimientos ingobernables, por ejemplo torcer y retorcer el cuerpo, son síntomas ordinarios de la EH. A veces los médicos se refieren a estos movimientos ingobernables como “corea” (palabra griega que significa “baile”).

  • Los síntomas cognositivos más significativos de la EH son la organización alterada y el procesamiento lento de la información en el cerebro. Estos síntomas pueden resultar en dificultad para aprender cosas nuevas, dificultad en la planificación y toma de decisiones, el deterioro de la percepción del espacio (donde está uno en relación con las mesas, paredes, etc.), y la dificultad en hacer varias cosas simultáneamente. Las personas se adhieren frecuentemente a las rutinas ordinarias porque estas rutinas son las más faciles de aprender. Finalmente, dado que las personas con EH tienen problemas para organizar las palabras (que entran y salen) en sus cerebros, muchas personas tienen dificultad para comunicarse con otras personas a su alrededor.

  • La depresión es el síntoma más ordinario de los síntomas psiquiátricos de la EH. Otros síntomas incluyen los cambios del carácter, la apatía, la zozobra, la irritabilidad, la obsesión con ciertas actividades (como lavarse las manos), el delirio, y la manía. El rechazo a la posibilidad de tener EH es también un síntoma ordinario de la enfermedad.

Tristemente, la EH puede tomar entre 10 y 25 años después del inicio de los síntomas, en desmejorar a las personas que generalmente mueren de neumonía, insuficiencia del corazón, u otras complicaciones.

EH causa el deterioro de las células nerviosas en el cerebro (miembros de una clase de células, responsables de la señalización y funcionamiento del sistema nervioso; éstas son únicas respecto a otras células porque tienen la capacidad para comunicarse rápidamente con otras por distancias largas y con mucha precision. A veces nos referimos a las células nerviosas como neuronas.) El deterioro de estas células determina los cambios importantes que los pacientes con EH experimentan en la capacidad para pensar, sentir, y moverse. La causa de estos síntomas fue un misterio por muchos años hasta que unos médicos observaron que la enfermedad tenía “una tendencia familiar” y sospecharon así una base hereditaria (es decir, algo que es pasado genéticamente a través de varias generaciones. La herencia de EH como una enfermedad hereditaria depende en los genes que el niño recibe de sus padres.) Ahora se sabe que la herencia de la EH (así como otros rasgos hereditarios) depende en un “código químico” de información contenido en una substancia que se llama ácido desoxirribonucleico, mas conocido como ADN (la molécula de herencia; se compone de muchos subconjuntos nucleótidos arreglados en una larga cadena), que existen dentro de las células vivas. Entendiendo un poco sobre este código químico ayuda a entender mejor las causas de la EH y los tratamientos que, algún día, pueden llevar a la cura.

Fig A-1: El Idoma del ADN

El código químico del ADN es semejante al idioma español: los dos usan letras específicas en un orden específico para comunicar cosas específicas. Pero mientras el idioma español tiene 29 letras, el código ADN sólo tiene cuatro A,C, G, y T (que representan los subconjuntos del ADN). Además, mientras las palabras en español pueden estar formadas por una o muchas letras, las “palabras” del ADN siempre consisten de tres letras. En la genética (que es el estudio de la herencia y de como los rasgos pasan de una generación a otra), estas “palabras” de tres letras se llaman codones. Propiamente, los codones codifican la construcción que ocurrirá en las células nerviosas. Esto es un poco semejante a los anteproyectos. Por ejemplo, cuando unpárrafo contiene las letras G-A-T-O, este pinta una figura de nuestro animal de compañía favorito. De manera semejante, cuando el código del ADN contiene las letras G-G-C, este le dice a las células que construya con prolina, uno de los veinte aminoácidos (moléculas pequeñas que son los bloques de fundación de proteínas). Para más sobre el ADN, haga clic aquí.

Si los codones son como anteproyectos, entonces podemos pensar que los aminoácidos que resultan de ellos son como unos bloques de fundación únicos. Cuando estos bloques se juntan químicamente, ellos crean la estructura de una proteína (un tipo de molécula importante en el cuerpo humano que está formado por una serie de aminoácidos. La forma de una proteína depende del número y secuencia de sus aminoácidos.). Como los edificios en una sociedad moderna, las proteínas son los sitios del trabajo de la célula nerviosa. Las proteínas tienen muchos trabajos: ellos ayudan a mantener la estructura de la célula, producir la energía, y comunicarse con otras células. Sin los millones de proteínas que tenemos en el cuerpo, la vida no podría ocurrir.

Fig A-2: La Forma de una Proteína

Las acciones específicas de una proteína son determinadas por su forma única de tres dimensiones. Esta forma regula como la proteína puede “encuadrar” y interactuar con otras partes de la célula. La forma es determinada por la clase de aminoácidos que compone la proteína, tanto como por su orden específico. Así como cualquier edificio que es bien construído, una proteína que funciona con buen suceso empieza con los “anteproyectos” (los codones).

Todos los humanos tienen una proteína que se llama huntingtin en sus células nerviosas. (Por favor, note que aunque “la enfermedad de Huntington” es deletreada con la letra “o”, el deletreo correcto de la proteína implicada es “huntingtin” con la letra “i”.) Aunque científicos no han determinado la funcíon exacta de huntingtin, la proteína parece desempeñar un papel crítico en los acontecimientos que ayudan a las células nerviosas a funcionar efectivamente. Como muchas otras proteínas, huntingtin contiene el aminoácido glutamina (el aminoácido clave en la EH). En las personas con EH, sin embargo, hay demasiadas glutaminas en un segmento particular de la proteína. Estas glutaminas adicionales resultan cuando una persona tiene demasiadas copias del codón correspondiente (el codón que codifica como glutamina) en el código químico del ADN. Ese codón tiene las letras C-A-G. En realidad, la EH resulta cuando una persona tiene demasiadas copias de C-A-G en el ADN que codifica como la proteína huntingtin. Por este razón, aludimos a EH como una enfermedad de la repetición de trinucleótidos (“trinucleótidos” es una palabra usada en vez de codones). Otras enfermedades de la repetición de trinucleótidos incluyen el síndrome frágil de X y la atrofia espinobulbar muscular.

Tbl A-1: Número de Repeticiones de CAG

¿Pero cuantas copias de C-A-G son demasiadas? Se ha realizado abundante investigación en esta área y en la literatura científica encontramos variadas opiniones en respuesta a esta pregunta. Estimaciones preliminares indican que: Personas con 10-35 copias de C-A-G tienen una forma de la proteína huntingtin que funciona normalmente. Aquellos con 40 o más copias tienen el huntingtin alterado y desarrollarán finalmente los síntomas de EH. Sin embargo, para las personas con 36-39 copias de C-A-G, el resultado no es claro. Algunas personas desarrollarán los síntomas de la EH y algunas no los desarrollarán. Para aprender más sobre la herencia de la EH, haga clic aquí.

Para resumir lo anterior, la enfermedad de Huntington es causada por demasiadas copias del codón C-A-G en el ADN, que incluye demasiadas copias de la glutamina en la proteína huntingtin. ¿Pero exactamente porque es una alteración del huntingtin perjudicial? Desafortunadamente, a pesar de los esfuerzos valientes de los científicos, nadie posee una respuesta definitiva a esta pregunta. Dado que la forma de la proteína determina sus interacciones con otras partes de la célula (tal y como fue expuesto anteriormente), mucho de la investigación a la fecha ha buscado comprender exactamente como una alteración afecta las interacciones del huntingtin con otros componentes de la célula. Un estudio indica que la superabundancia de glutaminas en el huntingtin es la causa de las agrupaciones rígidas de las proteínas. Dado que los componentes de la célula nerviosa están acostumbrados a un ambiente más flexible, no pueden funcionar con la rigidez de la proteína. Básicamente el resultado final es la muerte temprana de la célula nerviosa (a esto se le denomina apoptosis). Otro estudio reciente indica que el huntingtin alterado (y más grande que lo normal) “rapta” las proteínas menores en la célula nerviosa, previniendo su funcionamiento. De esta manera, el huntingtin alterado puede lastimar indirectamente la célula nerviosa. (Para más información sobre la proteína huntingtin alterada, haga clic aquí.)

Fig A-3: Célula & la Ciudad

Mientras los científicos continuan desarrollando los detalles que caracterizan la EH, el mecanismo básico es claro. Continuando con nuestra analogía de construcción del edificio, lo que pasa cuando el huntingtin está hecho en la forma alterada es que el “edificio” (la proteína) no tiene la proporción y la forma específica correcta, por lo que no puede funcionar correctamente en la “metrópoli” que es la célula nerviosa. Cuando la proteína no funciona correctamente, impide la acción de otras proteínas que dependen de la función correcta teniendo como resultado final el efecto de bola de nieve, donde los problemas que generan las proteínas continuamente danan a las células nerviosas. Finalmente, después de mucho daño, la célula nerviosa muere. Cuando muchas otras células nerviosas siguen el ejemplo, se observan los problemas de pensar, sentir, y moverse asociados con las personas que padecen EH. Para más información sobre las células nerviosas y los síntomas de EH, haga clic aquí.

Para aprender más sobre el ADN, existen muchos recursos en la red:

  1. Un sitio web de Australia, “Cooperative Research Centre for Discovery of Genes for Common Human Diseases” (Gene CRC) tiene excelentes guías didácticas para diferentes niveles de comprensión.
  2. Cummings, C. J and Zoghbi, H.Y. “Trinucleotide Repeats: Mechanisms and Pathophysiology.” Annu. Rev. Genomics Hum. Genet. 2000. 1:281-328.
    Un capítulo medianamente técnico que explica los síntomas de la EH, y un desglose del número de repeticiones de CAG en las personas con y sin la enfermedad. Además, este capítulo discute las teorías con relación a la función del huntingtin alterado.
  3. Falush D, et al. “Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial under ascertainment of late-onset cases.” Am J Hum Genet 68 (2) 2001 Feb: 373-385.
    Un análisis técnico del número de repeticiones de CAG que puede determinar si una persona desarrollará los síntomas de EH.
  4. “Huntington’s Disease”. Online Mendelian Inheritance in Man.
    Una compilación de abstractos de una gran número de estudios de la EH. Este es un sitio excelente para toda clase de investigación de la EH. Incluye estudios de casos sobre la herencia y métodos nuevos de diagnosticar la EH.
  5. “Huntington’s Disease”. Web MD.
    Información general sobre la EH, amistosa para los lectores. Explica generalmente la historia, los síntomas, y el tratamiento de la enfermedad.
  6. Li SH, Lam S, Cheng AL, Li XJ. “Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis.” Human Molecular Genetics, 2000, Vol. 9, No. 19: 2859-2867.
    Una ponencia técnica sobre la manera en que el huntingtin alterado puede causar la muerte temprana (apoptosis) de la célula nerviosa.
-M. Stenerson, 07/15/03; translated by T. Altman, 11/20/04; recorded by B. Tatum 08/21/12
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