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.
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).
- Changes in coordination
- Some involuntary movement (such as irregular, sudden jerks of limbs)
- Restlessness, desire to move about
- Twitching, muscle spasms, tics
- Less control over handwriting
- Facial grimaces
- Difficulty with coordinated activities, such as driving
- Some rigidity
- 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
- 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.
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.
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.
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.
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).
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.
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.
For further reading^
- 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.
- 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.
- 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.
- 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.
- Emedicine.com. “Huntington disease dementia.” http://www.emedicine.com/me d/topic3111.htm
Brief review of motor symptoms associated with HD.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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