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= __Huntington's Disease__ = = = toc

Description
Huntington's disease (chorea) is a neurodegenerative disease. Though the disease has a known inheritance pattern different than other neurodegenerative diseases it is usually lumped together with Parkinson's disease because of the similar effects the diseases have on an individual. Once the disorder appears, generally later in an individuals life, the disease will be get progressively worse causing a decline in cognitive function, a decrease in mobility and worsening dementia. The disease is found to be more prevalent in individuals with a Western European decent than individuals that descend from Africa or Asia. The disease affects five to ten people in every one thousand individuals (Zhang) . As of the recently, the disease is beginning to have more appearances in the public eye to help raise an awareness and understanding about the disorder. An example of the disease being portrayed to the public eye would be the diagnosis of Dr. Remy Hadley, played by Olivia Wilde, in the popular Fox TV show House.

History
George Huntington first documented Huntington's disease, and the disease now bears his name. The first paper that George Huntington had worked on, that of the disease which we now know as Huntington's lasted the entirety of his career (Harper, 1991). He spent seventy-eight years, the length of his career studying the family and documenting the symptoms, progression, and how the disease was inherited (Harper, 1991). Little did Huntington know that the inheritance pattern he was observing was a textbook case of an autosomal dominant disorder, that it appeared in every generation for instance. Finally, by 1872, George Huntington had shown that Huntington's Disease was its own entity as a serious disease, though earlier reports had depicted similar symptoms and progression (Harper, 1991).

Symptoms
There are many forms of symptoms for Huntington disease appearing in behavior, movement, dementia and additional symptoms as well (Sheth, 2011). The symptoms for the disease generally appear during the individual's middle ages, but symptoms can appear at any age (Zhang). Behavioral problems include the following symptoms: behavioral disturbances, hallucinations, irritability, moodiness, restlessness or fidgeting, paranoia, and psychosis. Abnormal and unusual movements can include facial movements-including grimaces, head turning to shift eye position, slow and uncontrolled movements, quick and sudden jerking movements in the limbs and other body parts, and an unsteady gait. The symptoms involved in dementia are: personality changes, disorientation or confusion, loss or judgment and memory, and speech changes (Sheth, 2011). There are also symptoms of the disease that do not all under any of the major categories above, these include: anxiety, tension, stress, speech impairment and difficulty swallowing. Finally, there are specific symptoms that only appear in the childhood onset of Huntington's disease which include a tremor, rigidity, or slow movements (Sheth, 2011).

Tests
Since many of the symptoms are also seen in other diseases there are tests to tell whether or not the patient is really suffering from Huntington's disease. A doctor may use a head CT scan, a head MRI scan, or a PET (isotope) scan of the brain. The CT involves the patient drinking a dye that will have the scan able to register the detail in each of the organs, an MRI shows the nearly the same image as a CT scan, but instead of the dye, everything is registered by strong magnets that circulate around the individual, and finally, a PET scan has the patient ingest a radioactive isotope before entering the scan inorder for the machine to register the images. The PET scan can either be viewed as a black and white image or it will also be shown in varying colors, for example cancer would be shown as glowing white. All the scans provide the same type of images including sections from top to bottom, left to right, and front to back, each cut only a fraction of an inch thick. A CT scan would be the individual's best option because is able to show loss of brain tissue deep within the brain (Sheth, 2011). There are also genetics tests that are able to tell if the individual possess an allele for Huntington's disease (Sheth, 2011). The image to the left shows a diagnosis from the neurology case of the month (De Guzman, 2002).

Treatment
The current state of treatment for Huntington's disease has not yet found a way to cure Huntington's disease (Mestre et al, 2009). However, there are ways to make the disease easier to live with depending on the symptoms the individual experiences. There are different medications used to treat particular symptoms whether they fall under behavioral symptoms or under another category. If the individual is experiencing symptoms such as abnormal behavior or abnormal movements, the patient could use dopamine blockers to reduce the effects of these symptoms. Other medications that can be used for movement the therapeutic drugs of amantadine or tetrabenazine (Sheth, 2011). Once science reaches the conclusion of how the abnormal Huntingtin protein affects the brain's ability to function, they will be able to develop proper care for treating or prolonging the disease. Clinical tests were conducted for the tetrabenazine drug to see if it would be able to controlling the symptoms of Huntington's disease. A total of twenty-two trials were done including 1245 Huntington's disease patients (Mestre et al, 2009). After all of the trials the scientists found that though the drug was not able to control all the symptoms of Huntington's, it was able to relieve much of the abnormal movements that patients experience (Mestre et al, 2009). The diagnosis of Huntington's disease can be a difficult fo many affected individuals. With the knowledge that the disease will get progressively worse, and that there has not yet been discovered a way to prolong the onset of the symptoms nor a way to cure the disease, makes depression and suicide common in individuals diagnosed with Huntington's (Sheth, 2011). Knowing that these feelings are common there are many support groups that are available to individuals with Huntington's, and the individual's should be watched for any behavior that may hint at depression or suicide after diagnosis (Sheth, 2011).

Inheritance
The inheritance pattern displayed by Huntington's disease is an autosomal dominant disorder pattern (Mestre et al, 2009). Autosomal is classified as both males and females having the same likelihood to inherit the disease from their parents. The classification dominant means that the dominant allele, if present, will mask the phenotype of the recessive allele to display only the phenotype of the dominant in heterozygous individuals. For example, if a couple is planning on having children and the father does not carry any allele for Huntington's disease but the mother is heterozygous, their children will have a fifty percent chance of inheriting the disease. If both parents are heterozygous, their children have a seventy-five percent chance of inheriting the disease. Lastly, if one parent is homozygous for Huntington's disease, regardless of the other parent's genotype, their children have a one hundred percent chance of inheriting Huntington's disease.

Molecular Basis
To begin the discussion on the molecular basis of Huntington's disease, which has the majority of the abnormalities occurring from a faulty Huntingtin protein, one must first know the typical function of a Huntingtin protein. The wild type protein of Huntingtin can be found in every cell of mammals, but the highest concentrations are found within the cells of a mammal's brain and testes (Zhang). The protein can be found in both the cytoplasm and within the cell's nucleus, performing a function that science today is still unsure about. There is research that shows operations that the Huntingtin protein may participate in including: gene expression, intracellular transport, intracellular signaling, apoptosis, mitochondrial function, and may even take part in shuffling transcription factors between the cytoplasm and the nucleus. (Zhang). Though the exact function of Huntingtin protein is not known, it is very clear that it plays a major role within the adult mind because the absence of the protein, as seen in Huntington's disease, leads to neurodegeneration (Zhang). In hearing some of the functions that the Huntingtin protein is involved in, it is better understood the importance of the protein's presence within the brain cells. Although Huntington's disease has one known genetic cause, it is an extremely complex disease that affects many of the cell processes (Skaper and Giusti, 2010). Though, much like the protein's function, the molecular pathway that leads to the disease is not entirely known as of yet. Scientists do know that the abnormal protein is produced in two different steps. In the first step proteolysis, a process that digests proteins by either using enzymes (proteases) or in intramolecular digestion occurs to form N-terminus pieces that contain the polyglutamine stretch (Zhang). The polyglutamine stretch refers to a repeat of the codon CAG that causes the amino acid glutamine to be repeated within the primary structure of the Huntingtin protein causing trouble in the protein folding of the secondary structure. The elongated Huntingtin protein repositions to the nucleus in the second step (Zhang). The abnormal CAG repeat causes a gain of function mutation in the Huntingtin protein (Giorgini and Muchowski, 2009). The polyglutamine stretch found in a defective HD gene and the amount of CAG codon repeats within the gene play a pivotal role in the expression of Huntington's disease. In every HD gene, either normal or defective, there are CAG repeats displayed in the genetic code. However, the amount of repeats is what determines whether or not the individual will have Huntington's. In the average HD gene, an individual will have between ten and twenty-eight CAG repeats (Sheth, 2011). In contrast, an individual with Huntington's disease will have anywhere between thirty-six and one hundred and twenty CAG repeats (Sheth, 2011). There has also been an inverse correlation found between the amount of CAG repeats on the HD gene of the individual and the age that the symptoms begin to develop, meaning that the more CAG repeats the person has, the younger he will be when the symptoms begin to appear (Sheth, 2011).

Research
Much of the research done on Huntington's disease has been used on two different model organisms, mice and yeast. Yeast is a single-celled eukaryotic organism that is mostly used as a model organism when scientists want to gather information on cell division. They have been beneficial in the study of Huntington's because their genome is easy to manipulate and they have a quick reproductive cycle. Scientists choose to use mice as model organisms because of their genome be similar to that of humans. With the similar genome, many genes affect mice in a way that is very similar to the way it affects humans, as seen with the studies on Huntington's disease.

First, let us discuss some of the findings that have occurred in using the mice model organisms. The biggest finding done by the experiments is that, when the Huntington's disease mice were examined after the disease had taken effect, scientists found that Huntington's disease does not only damage the cells in the central nervous system, but it also deteriorates the cells in the skeletal system as well (Sassone et al, 2009). In looking more closely at the mice being observed they found cell death in many different tissues, including those of the muscles, testes, liver, kidneys and spleen (Sassone et al, 2009). The decrease in the size of the organs of Huntington's patients could have serious consequences in the heart and liver (Sassone et al, 2009). The studies done in the mice have also shown several different pathways to the death of many different tissue's cells in Huntington's patients. The first pathway is related to the mitochondrial process of apoptosis. Apoptosis is a process within the cell that programs for cell death in order to relieve the cell of old cells, cells that are unnecessary, and sickly cells (Medterms, 2011). It also kills the cells without releasing the freeing any harmful debris into the surrounding area (Medterms, 2011). The reason that apoptosis is suspected is that it causes issues in other disorders similar to Huntington's when the process work too well (Sassone et al, 2009). The second possible pathway has to do with process of autophagy. This is another cellular process that involves degeneration, except this process is generally done with a large number of proteins, protein complexes and organelles that have lived past their function (Sassone et al, 2009). They are terminated by having a part of the cytosol encompassed by structures known as atuophagosomes or autophagic vacuoles (Sassone et al, 2009). Though the process is generally used by the cell to remove macromolecules in a time of stress (Medterms, 2011), it is found that in the neurodegenerative diseases, like Huntington's disease, the size and amount of vacuoles resembled that of the amount of CAG repeats in the patient (Sassone et al, 2009). These vacuoles were found to have the markers for a lysosome, those of cathepsin-B and cathepsin-D, meaning that the vacuoles could be classified as autophagesomes; similar vacuoles were found in deceased Huntington's patients, though they had never been found with the markers as in the live patients (Sassone et al, 2009). Using the mouse models in research has shown a few possible pathways that lead to the degeneration of different cells from the defective Huntingtin protein. The key to finding a possible cure is to figure out where in the cell's cycle, did these two processes go out of sync, or into overdrive, in order to find a possible prolonging of symptoms, and perhaps even a cure for the disease. However, there is even more to be learned by using different model organisms affected with the abnormal HD gene CAG repeat. Another model organism that has been used to study the effects of the abnormal HD gene is yeast, in a study done by Flaviano Giorgini and his partner Paul J. Muchowski. It is without a doubt that yeast is used in the Huntingtin protein research because of its ability to act as a "living test tube," and it's ability to show mechanism within the cellular processes (Giorgingi and Muchowski, 2009). The yeast in his experiments were used to view the protein misfolding to provide information for both genetic and pharmacological screens to reach therapies without the cost or time needed with other model organisms (Giorgini and Muchowski, 2009). They discovered gene deletions that other increased or decreased the abnormal Huntingtin protein toxicity in the yeast, using this as a grounds to find different therapeutic regimes, and finding done later in fruit flies and mammal cells showed similar results (Giorgini and Muchowski, 2009). Though their finding in the role the mutant Huntingtin protein plays in the toxicity of the yeast's environment, there have only been tests in yeast of nonessentials genes in the loss of function screenings, and in order to find therapies for Huntington's disease, scientists need to identify the essential modifier genes present in the yeast cells (Giorgini and Muchowski, 2009). There has been much progress made in understanding the molecular basis of Huntington's disease, but not much has worked in furthering medicine's ability to treat or halt the disease's progression because of the lack of understanding about the cellular processes that cause the death of the neurons that the disease is affecting (Skaper and Giusti, 2010). In the last experiment discussed in this section, there were no model organisms used. Instead, the researchers used human Huntington's patients and measured their leptin secretion every twenty minutes and their adiponectin and resistin were measured every hour (Aziz et al, 2010). Leptin is a hormone that controls the fat metabolism, adiponectin is a hormone that plays a role in controlling an individual's appetite, and resistin is a hormone that affects the tissues ability to react to insulin secretions (Medterms, 2011). They found after their trials that the levels of leptin and adiponectin levels increased with a greater amount of motor and functional impairment (Aziz et al, 2010). Basically, what they found in their experiment is that the greater amounts of CAG repeats affects these hormone levels and may be the cause of weight loss in Huntington's patients (Aziz et al, 2010).