studying huntingtons disease aka chorea

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Huntington's disease is also known as chorea, which in Latin is defined as dance (Mendelian 2002). First to coin the term, "chorea", to describe the dance-like, uncoordinated movement disorders that are now known to be symptomatic of HD was Paracelsus, a Renaissance alchemist (1493-1541) (Mendelian 2002). There were three choreas that were described and one in particular was named chorea naturalis, which by definition, is where patients "only felt an involuntary impulse to ally the internal disquietude" (Mendelian 2002).

In 1630, English colonists in Massachusetts, Connecticut, and New York (especially Long Island) used names such as "that disorder" and "Saint Vitus" dance" to describe Huntington's disease (Revkin 1993). In 1686, an English physician by the name of Thomas Sydenham attempted to classify different types of chorea and describe their causes. He found a disease that was related with rheumatic fever but distinct from Huntington's disease which was named after him called Sydenham's chorea. (Mendelian 2002). Another one of the choreas was termed chorea Saint Viti which was originally used for a dancing mania, a form of hysteria common in Europe in the 15th and 16th century (Revkin 1993). The dancing mania became known as chorea magna, and Sydenham's disease as chorea minor - Sydenham's chorea (Mendelian 2002). This mania had greatly declined in Sydenham's time, and it is unlikely that he himself observed the phenomenon.

By 1692, it was well known that the condition had been transmitted from Suffolk, England, to Connecticut in the seventeenth century by way of a single family, known as the Bures family group. Members of the Bures family were frequently accused of witchcraft and were among those convicted of this crime during the Salem Witch Trials (Jourin 2010). Some of the "witches" are now believed to have had the Huntington's disease because of their dance-like movements and odd behavior were seen as possession by the devil (Jourin 2010).

During the 1840's, Huntington's disease was described in the medical literature as "chronic hereditary chorea." For the first time, Physicians in the United States, England, and Norway wrote about people with involuntary movements and mental disorders that were inherited from a similarly affected parent (Jourin 2010).

In 1872, Huntington's disease was concisely defined as an exclusive disease by George Huntington, an American physician. He had wrote a landmark paper entitled "On Chorea" that was published in the April 13, 1872 issue of The Medical and Surgical Reporter in the April 13, 1872, issue (Neylan 2003). In this paper he stated that he Huntington's chorea was a "medical curiosity, and, as such, it may have some interest" (Huntington 1872). Using personal accounts of his father's patients, Huntington provided a classic description of Huntington's disease symptoms and emphasized its hereditary nature. Significant interest in Huntington's disease, especially its genetic component, occurred due to George Huntington's paper.

During the year 1910-1911, an American eugenicist Charles B. Davenport wrote a book titled, "Heredity in Relation to Eugenics", where he used genetic diseases, including Huntington's disease, to argue in support of "necessary sterilization and immigration restriction" for those afflicted with HD (Davenport 1913). Davenport found the Cold Spring Harbor Biological Laboratory and Eugenics Record Office in 1910 to track families with inherited disorders. He produced what was, at the time, the largest study of families with Huntington's disease (Jourin 2010). He had constructed the first field study of HD families on the East Coast of the United States, in which he constructed their pedigrees (Jourin 2010). Davenport utilized this data to record the different ages of onset and assortment of symptoms of Huntington's disease and proposed the assertion that a majority of cases of Huntington's disease in the United States could be tracked back to a few individuals (Davenport 1913). At about the same time researchers first noted the deterioration of the central region of the brains of patients as the disease progressed. They discovered that the caudate nucleus was the central target of brain cell death.

During the 1950's, there was an increase in publications on Huntington's disease research with the growing interest in human genetics. Also contributing to the increase in publications were the 1953 discovery of the DNA structure by Watson and Crick, which was published to the scientific journal Nature on April 25, 1953 (Jourin 2010). In 1955, the Americo Negrette, a Venezuelan newspaper, published a book describing communities in Lake Maracaibo, Venezuela, with abnormally high numbers of individuals affected by Huntington's disease (Jourin 2010).

During the late 1950's, two European scientists, Arvid Carlsson and Oleh Hornykiewicz, made the breakthrough discovery that dopamine pathways are damaged in Parkinson's disease patients (Jourin 2010). Since the symptoms of Parkinson's disease are practically the opposite of those of Huntington's disease, the scientists hypothesized that decreasing Huntington's disease patients' dopamine levels might be a key step in treating the disease. In 1966, Harvard University established the first Department of Neurobiology, Ntinos Myrianthopoulous wrote a review article criticizing the lack of knowledge of Huntington's disease (Jourin 2010). The following year, 1967, famous poet and songwriter Woody Guthrie died of Huntington's disease. Guthrie's wife, Marjorie, created the Committee to Combat Huntington's Disease (CCHD), which now is called the Huntington's Disease Society of America (HDSA), to provide public health outreach on Huntington's disease (Jourin 2010).

In 1972, the International Centennial Symposium on Huntington's disease was held on the one hundredth anniversary of George Huntington's historic publication in 1872 in The Medical and Surgical Reporter (Jourin 2010). The Symposium aimed to assemble all Huntington's disease researchers and evaluated the current state of knowledge at the time. At the same time, Thomas L. Perry, an American researcher found diminished levels of GABA in the brains of HD patients and published this finding in The New England Journal of Medicine (Gusella 1983). In 1974, Milton Wexler, a prominent psychologist, created the Foundation for Research in Hereditary Disease, which later became the Hereditary Disease Foundation (HDF) (Wexler 2004). In 1976, Joseph T. Coyle developed the first rat model of Huntington's disease by using kainic acid and injecting that toxin into the striatal ganglioside (Gusella 1983). The rats demonstrated Huntington's disease-like symptoms such as decreased weight, motor dysfunction, brain atrophy, neuronal inclusions and other cognitive impairments (Gusella 1983).

In 1981, Nancy Wexler, a geneticist, began her fieldwork in the Venezuelan communities around Lake Maracaibo, a hot spot for Huntington's disease. In 1982, Dr. Nancy Wexler led a team of scientists to study Huntington's disease in Lake Maracaibo. Their original goal was to find a Huntington's disease homozygote, but the team also collected blood samples from as many sufferers as they could find and test (Wexler 2004). 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 (Harding 1993). It was during this time that scientists found a gene marker linked to Huntington's disease on the short arm of chromosome 4, which indicated that the Huntington gene was located on chromosome 4 (Wexler 2004). In 1993, the location of the Huntington gene was discovered at the 4p16.3 gene site on chromosome 4. This finding was published in The Cell. (Harding 1993). The gene was found to contain codon C-A-G in varying numbers. An abnormal number of CAG repeats turned out to be a highly reliable way to tell whether someone has the allele for Huntington's disease (Harding 1993).

What is Huntington's disease?

Huntington's disease, which is also known as Huntington's chorea, is a weakening neurological disorder that causes increased degeneration of neurons in the basal ganglia of the brain (Revkin 1993). It is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioral difficulties (Walker 2007). There is no effective treatment or cure for this devastating brain disorder. Huntington's disease gradually lessens an affected individual's ability to talk, walk and reason. Sooner or later the person with Huntington's disease becomes completely dependent on others for his or her care. Huntington's disease greatly affects the lives of families economically, emotionally, and socially.

Huntington's disease is currently recognized as one of the more common hereditary disorders. Over a quarter of a million Americans have this dreadful disorder or are "at risk" of inheriting Huntington's disease from an affected parent (Walker 2007). Huntington's disease has the same prevalence as people diagnosed with cystic fibrosis, muscular dystrophy, and hemophilia (Walker 2007).

Initial symptoms of Huntington's disease can affect mobility, or cognitive ability and include depression, clumsiness, forgetfulness, mood swings, involuntary twitching and lack of coordination (Warita 1999). This also includes the writhing and rhythmic movements that the individual who is affected with this disease cannot control (Revkin 1993).

As Huntington's disease worsens, concentration and short-term memory diminishes and involuntary movements of the head, trunk, and limbs increase. Unfortunately, death may follow from complications such as choking, infection, or even heart failure.

Huntington's disease usually occurs around mid-life between the ages of 30 and 50, though onset may occur as early as the age of 2 years old (Warita 1999). Children who are diagnosed with the juvenile form of this disease hardly ever live to adulthood (Warita 1999).

A child of a parent affected with Huntington's disease has a 50% chance of inheriting the fatal gene. Everyone who carries the gene will develop the disease. In 1993, the Huntington disease gene was isolated and there is now a direct cofirmatory genetic test that has been developed which can accurately determine whether an individual has the Huntington's disease gene (Warita 1999). The mutant protein in Huntington's disease, called huntingtin, results from an expanded CAG codon repeat leading to a polyglutamine strand of variable length at the N-terminus (Walker 2007). However, the genetic test cannot determine when symptoms will begin.

Ever since the Huntington's disease gene was discovered, scientific research has progressively increased and there has been expanded knowledge added to our understanding of Huntington's disease and its effect on different people. Increased time researching the treatment and cure to this disease in clinical research settings will hopefully have some breakthrough in treatment and impending cure.

Clinical Diagnosis

The clinical diagnosis of Huntington's disease is made on the basis of the family history and presence of unexplained characteristic movement disorder, which is usually confirmed by a gene test (Warner 1994). The gene test is very helpful where there is a lack of family history, which would include adoptions, misdiagnosis, early parental death or non-paternity (Margolis 2003). In addition it is also useful to determine if there is a high risk for getting HD when the family history is positive (Margolis 2003). A genetic test is accessible for confirming of the clinical diagnosis. In this test, a minute blood sample is extracted, and DNA from it is studied to establish the CAG repeat number (Warner 1994). An individual with a CAG repeat number of 30 or less will not get Huntington's disease (Warner 1994). A person with a CAG repeat number between 34 and 41 may not develop HD within their normal lifespan (Warner 1994). A person with an unusually high number of repeats such as 65 or above is likely to get the juvenile-onset form of HD (Warner 1994).

Prenatal testing is also available for those who are pregnant. A person at risk for Huntington's disease may get fetal testing without knowing whether she herself carries the gene or not (Margolis 2003). This "nondisclosing" test, also known as a linkage test, investigates the pattern of DNA close to the gene in both parent and fetus, but doesn't examine for the triple repeat itself (Margolis 2003). If the DNA patterns don't match, the fetus can be presumed not to have inherited the Huntington disease gene, even if the parent has it present. A match in pattern indicates the fetus likely has the identical genetic makeup of the at-risk parent. It does not indicate the age of onset or whether the parent (or fetus) actually has the defective gene (Margolis 2003). Approximately 99% of patients with a clinical diagnosis of Huntington's disease have an expanded allele with 36 or more CAG repeats (Margolis 2003).

Other factors to include in assessing the clinical diagnosis of Huntington's disease are abnormalities of involuntary and voluntary movement. This is usually an early symptom of premature Huntington's disease (Creighton 2003). In addition there may be mental disturbances including cognitive decline and psychiatric symptoms such as change in personality (Creighton 2003).

Clinical diagnosis is often difficult and time-consuming because of the highly variable symptoms that are easily confused with those of psychotic disorders (Creighton 2003). Diagnosis must be confirmed by magnetic resonance imaging of the brain and genetic testing (Creighton 2003). If the individual is confirmed to have Huntington disease, the magnetic resonance imaging displays some characteristically affected parts including the caudate nucleus and striatum, which appear shrunken in the course of the disease (Creighton 2003). When there is a family history of the disease, predictive genetic testing is possible but should be considered carefully since the first symptoms appear relatively late in life and, at present, there are no treatments to delay onset or slow progression of the disease (Creighton 2003).

Genetic Diagnosis

The discovery of the Huntington disease (HD) gene has led to the formation of a Huntington's disease genetic test to aid in confirming a diagnosis of the brain disorder (Braude 1998). The first Huntington's disease diagnostic test was developed by David Housman and James Gusella in 1986 (Merrill 2006). Huntington's disease genetic testing has also led to screening for the disease. Screening for Huntington's disease consists of distributing this genetic test to people who do not have symptoms of the disease (Braude 1998). Using a blood sample, the Huntington's disease genetic test analyzes DNA for the Huntington disease mutation by observing the number of CAG repeats in the huntingtin gene (Adam 1993). Individuals who do not have HD usually have 30 or fewer repeats; people with Huntington disease usually have 40 or more repeats (Adam 1993).

Predictive genetic testing before birth or prenatal testing is associated with distinctive concerns. For example, direct mutational analysis that provides a positive result indicates that a parent also carries the mutation (Braude 1998). Nevertheless, in some cases, parents may wish to determine the risk of disease development in the developing fetus, yet may not wish to know their own risk. Although not all testing centers provide such tests, some conduct a form of indirect DNA analysis (restriction fragment length polymorphism or RFLP) in such cases (Braude 1998). To perform this form of testing, fetal DNA samples are acquired by means of amniocentesis or chorionic villus sampling (CVS) (Braude 1998). During amniocentesis, a sample of

amniotic fluid is extracted from the uterus and sent to a laboratory for evaluation. Amniocentesis is done by inserting a thin needle through the abdomen into the uterus and withdrawing a small amount of fluid (Braude 1998). The maternal parent will make more fluid to replace the fluid that is taken out (Braude 1998). The baby will not be hurt during the procedure. Some women feel mild cramping during or after the procedure. Chorionic villus sampling is performed by removing a small sample of the placenta, which is nourishment for the baby, from the uterus (Braude 1998). It is removed with either a catheter or a needle. Local anesthesia is used for this test to reduce pain and discomfort. The sample of placenta may be obtained through the cervix. A catheter is inserted into the vagina and through the cervix and the sample is withdrawn. The sample can also be obtained by inserting a needle into the abdomen and withdrawing some of the placenta. Amniocentesis is usually performed during the 15th week of pregnancy or later (Braude 1998). CVS is usually performed between the 10th and 12th weeks of pregnancy (Braude 1998).

Testing may confirm whether the developing fetus inherited chromosome 4p from the affected grandparent on the side of the family with HD (Adam 1993). If the disease gene was inherited from the affected grandparent, the results indicate that both the developing fetus and the parent have a 100% likeliness of developing the disease as the Huntington disease gene is dominant (Adam 1993). Such testing is considered controversial and raises many ethical concerns which can include whether the parent wants to still have the child or not. It is generally advised that at-risk individuals who are considering having children seek genetic counseling before pregnancy to prevent possibility of miscarriage.

Differential Diagnosis

Diagnostic evaluation may include a sequence of tests to eliminate other disorders with comparable symptoms (Bürger 2002). For instance, certain autosomal dominant neurodegenerative disorders closely mimic HD. These include neuroacanthocytosis and dentatorubropallidoluysian atrophy (Bürger 2002) .

Huntington's disease must also be differentiated from other disorders or conditions associated with chorea, such as Wilson disease; drug-induced tardive dyskinesia; Sydenham's chorea; systemic lupus erythematosus; or senile chorea, a symptom complex primarily characterized by the development of chorea after age 60 (Bürger 2002). Although some patients with senile chorea may have neurodegenerative changes of the caudate nuclei, there is typically no family history of HD (Bürger 2002). Some investigators indicate that the disorder may result from a different genetic mutation than that seen in HD; however, others suspect that it may be a late-onset HD variant.

Approximately 80-90% of Huntington's disease findings based on the characteristic indications and a family history of HD are established by to have the lengthened tri-nucleotide duplicate that causes Huntington's disease. Most of these other disorders are collectively labeled Huntington disease-like (Wild 2007). The cause of most Huntington disease-like diseases is still not known, although those with recognized causes are because of mutations in the prion protein gene (HDL1) and an inherited HTT gene which is recessive, and the gene encoding the TATA box-binding protein (Wild 2007).

Greater than twenty mutations in the prion protein gene (HDL1) have been identified which includes neurodegenerative disorders such as Creutzfeldt-Jakob disease and fatal familial insomnia (Wild 2007). Some HDL1 mutations can also lead to a modification in single amino in the prion protein (Wild 2007). Others insert additional amino acids into the protein or cause an abnormally short protein to be made (Bürger 2002). These mutations cause the cell to make prion proteins with an abnormal structure. The abnormal prion protein can accumulate in the brain and destroy nerve cells, which leads to the mental and behavioral features of prion diseases (Bürger 2002).


Huntington's disease has no cure or drugs that can restore someone's health to normal. However there are treatments which are available to reduce the intensity of a few symptoms associated with it. Many of the Huntington's disease treatments are incomplete to treat symptoms of Huntington's disease specifically. There needs to more scientific test to verify their usefulness in alleviating Huntington's disease symptoms (Bonelli 2006). Unfortunately, as the duration of this disease increases, an individual's ability to take care of himself decreases and caregiving becomes increasingly essential (Bonelli 2006).

Few drugs have been developed specifically to treat the severity of chorea in Huntington's disease (Bonelli 2006). In some non-US countries Germany, France, and Australia, tetrabenazine (Xenazine) has been available for about 35 years (Paleacu 2007).  However, the FDA in the USA requires pre-approval testing that is more stringent than in most countries.  It has been difficult to do testing that is acceptable to the FDA, because good testing requires large numbers of patients (Paleacu 2007).  The disease is sufficiently rare (4 to 10 cases per 100,000 persons), that it is a challenge to get enough patients (Bonelli 2006).  Also, the disease progresses slowly, so there isn't a rapid way to know if the drug is working.

On 15 August, 2008, the FDA announced that tetrabenazine has been approved for the treatment of Huntington's Disease. Tetrabenazine works by inhibiting the action of a protein in the brain, called Vesicular Monoamine Transporter 2 . (VMAT2) (Paleacu 2007).  This is a protein that acts to move chemical messengers inside of nerve cells.  VMAT2 is found mostly in the brain.  There is a similar protein, VMAT1, that is found in the rest of the body (Paleacu 2007). Individuals who take tetrabenazine undergo relative depletion of these chemical messengers, VMAT2 + VMAT1 (Paleacu 2007). The one that is important in Huntington's Disease is dopamine.  It would be nice, perhaps, if we had something that only affected dopamine, but that is not yet the case. Tetrabenazine also reduced the amount of serotonin and noradrenaline (Paleacu 2007).   This lack of selectivity can be expected to cause adverse effects.  Indeed, people who take the drug can get depressed (Paleacu 2007).  Fortunately, there is some indication that the depression caused by tetrabenazine can be treated effectively by using anti-depressants such as MAO inhibitors (Paleacu 2007).  

Eating difficulties and weight loss due to dysphagia and other muscular discoordinations are common, making nutrition balance very important as the disease progresses (Phillips 2008). Agents can be added to liquids to make them feel thicker, as this makes them easier and safer to swallow (Phillips 2008). In extreme cases, if eating becomes too uncomfortable or unsafe, a permanently attached feeding tube must be connected as the abdomen of the stomach (Phillips 2008). This decreases the possibility of not swallowing food and better nutritional management.

Even though there are few studies of therapies that aid in reducing severity of cognitive symptoms of Huntington's disease, there is still some evidence for the effectiveness of physical therapy, speech therapy, and occupational therapy (Phillips 2008). Nevertheless there still needs to be more rigorous studies for health manufacturers to endorse these types of therapy. Counseling would assist these people by improving their knowledge; discarding any false beliefs they may believe and aid them in deciding their potential alternatives and plans (Phillips 2008).


The occurrence of Huntington disease in the U.S. is estimated at about seven per 100,000 or .007% (Conneally 1984). The duration of disease is about 10-20 years from time of diagnosis to time of death. As such, the incidence can be estimated at four cases per million per year or 1,000 new cases in the U.S. per year. It is approximately 10x times more common in North Americans of European descent than in those of pure African or Asian descent or in Native Americans (Conneally 1984). Mixed populations have an intermediate incidence. Similar trends are seen globally, with a significantly lower incidence in Asia and Africa. In isolated areas, such as Lake Maracaibo in Venezuela or Tasmania, a founder's effect can be seen, where an affected early settler can significantly increase the prevalence of Huntington disease in a dense population (Conneally 1984).

Genetic defect responsible for disease

For a great amount of time scientists have worked to develop different model organism systems to mimic Huntington's disease in order to answer important questions such as when does expansion occur? Why does only a specific set of cells in the brain becomes affected and die? Lastly, how do cells escape safeguard mechanisms designed to correct errors in DNA?

It has been known for quite some time now that primary expansion, a modification in a number of repeated segments, in Huntington's disease, occurs in the sex cells of a parent and the abnormal gene is passed to an offspring. Previous studies have indicated that the degree of degeneration of affected brain regions and onset of the disease are dependent on the number of repeated segments in the Huntington disease gene (Benes 2010). Both the inherited expansion and an increase in length that is observed in neurons are known to contribute to toxicity (Benes 2010). The essential mechanism of the expansion process has been a big puzzle for researchers in the field since the genetic defect was originally discovered. Finding a mechanism will most likely help to stop the disease in affected families and lead to a cure. A great effort has been put to answer what pathways in the cells fail to function properly and let the expansion grow (Benes 2010). The integrity of DNA and the fidelity of its synthesis and transfer from parent cell to daughter cell are protected by the sophisticated cellular machinery called DNA repair (Benes 2010). DNA repair machinery recognizes and corrects DNA with various types of damage caused by encounters of DNA with different toxic substances, products of cellular metabolism (Benes 2010).

The quest for the Huntington disease gene

Ever since 1979, the United States & Venezuela Shared Research Project, a group of individuals made up of high ranking international scientists, have been traveling every year to very deprived, rural fishing villages besides the shores of Lake Maracaibo, Venezuela (Venezuela 2008). Every offspring of a parent with Huntington's disease has a probability of one in two of inheriting the identical deadly affliction. It frequently occurs between the ages of thirty to forty, which is during an individuals productive years. A majority of the individuals in the late stages of illness require massive assistance. The afflicted individuals lose the capability to talk, walk, and feed themselves. Nevertheless they are still cognizant, conscious and recognize themselves and their families (Venezuela 2008). It can emerge as young as 2 years of age all the way up to 80 years of age.

Venezuela has the largest concentration of Huntington's disease in the world, predominantly focused in the State of Zulia (Venezuela 2008). The world's largest family diagnosed with HD resides alongside the shores of Lake Maracaibo (Venezuela 2008). The original ancestor of this family resided in the early 19th century and left greater than 18,000 descendants, several who are either afflicted by the illness or have a great possibility for this harmful and unavoidably terminal neurodegenerative disease (Venezuela 2008).

In 1983, the location of the HD gene was discovered on chromosome using the previously-unknown techniques of recombinant DNA technology by the team of scientists led by Nancy Wexler (Venezuela 2008). The efficient illustration that these innovative scientific strategies could be utilized to locate disease genes opened the door for discovering genes causing a variety of disorders, including breast cancer, prostrate cancer, colon cancer and lung cancer (Venezuela 2008).

In the year 1993, the Huntington disease gene was found, which lead to a remarkable reanalysis of the basis of this disease (Venezuela 2008). Huntington's disease was found to be elicited by a section of a gene that expands unusually. The retrieval of the Huntington's disease gene affirmed the existence of a newly found family of diseases all caused by an irregular elongation of a gene. Most of these diseases are fatal and almost all affect the brain. They have a tendency to be of later

onset. The team of scientists led by Nancy Wexler also found that Huntington's disease could start in a family with no preceding history whatsoever, typically as a result of an alteration in the male germ line as there are normally more CAG codons as opposed to the female germ line (Venezuela 2008).

The tissues from these families with Huntington's disease in Venezuela are now situated in international cell banks and are examined by investigators across the world to understand more about human genetics in health and disease (Venezuela 2008).

The analysis of tissues from these families has already led to the discovery of genes for Alzheimer's disease, cancer and dwarfism as well (Venezuela 2008). The Venezuelan Huntington's disease families have been discussed in every modern genetics textbook and have been commonly presented by the United States and Venezuelan media (Venezuela 2008).

Htt Function

Htt, the Huntingtin gene is expressed in all mammalian cells. The maximum concentrations of it are in the testes and brain, with normal amounts in the liver, heart, and lungs (Htt 2008). The purpose of Htt in humans is still uncertain. It works with proteins that are associated in transcription, cell signaling and intracellular exporting (Htt 2008). In genetically modified animals that demonstrate Huntington's disease, numerous functions of Htt have been discovered. In these animals, Htt is significant for embryonic development, as its deficiency is related to the death of an embryo (Htt 2008). It also functions as an anti-apoptotic agent preventing involuntary cell death and manages the assembly of brain-derived neurotrophic factor, a protein that defends neurons and controls their creation during neurogenesis (Persichetti 1996). Htt also functions in vesicle transport and synaptic transmission and facilitates neuronal gene transcription (Persichetti 1996). If the expression of Htt is augmented and more Htt is made, brain cell survival is enhanced and the consequences of Htt are decreased (Persichetti 1996). In humans the interruption of the regular gene does not elicit the disease. It's presently decided that Huntington's disease is not caused by deficient making of Htt, but by an increase of the toxic function of mHtt or mutant Huntingtin (Persichetti 1996).

Throughout the biological process of posttranslational modification of mutant Huntingtin, cleavage of the protein can leave behind small fragments made of parts of the polyglutamine expansion (Persichetti 1996). The nature of the polarity of glutamine causes associations with additional proteins when it is excessively abundant in Huntingtin protein (Persichetti 1996). Therefore, the Htt molecule strands will assemble hydrogen bonds with each another, making a protein mass instead of wrapping into useful proteins (Htt 2008). As time passes, the aggregates build up, eventually interfering with neuron function since these fragments can fold wrongly and come together, in a manner called protein aggregation (Htt 2008). The left over proteins bunch together at the dendrites as well as the axons in neurons, which automatically stops the spread of neurotransmitters because vesicles can no longer migrate through the cytoskeleton


(Persichetti 1996). Eventually less and less neurotransmitters are obtainable for export in stimulating other neurons as the inclusions develop (Persichetti 1996). Inclusion

bodies have been initiated in cytoplasm and nucleus (Persichetti 1996). Inclusion bodies in the neurons of the brain are one of the first detrimental changes to occur, and particular experiments have found that they can be deadly for the cell, but other experiments have revealed that they likely arise due to the defense mechanism of the human body and assist in defending cells (Persichetti 1996).

Quite a few ways which mutant Huntingtin may elicit cell death have been recognized. These include: consequences on chaperone proteins, which assist folded proteins and remove ones in which are misfolded (Persichetti 1996). Interactions with an enzyme called caspase, which plays a position in the process of taking out cells (Htt 2008). The cytotoxic effects of mHtt are greatly improved by associations with Rhes, a protein that functions mostly in the striatum (Htt 2008). Rhes was found to encourage sumoylation of mHtt, which is the process that causes the clumps of protein to disassemble due to the small ubiquitin-related modifier covalently bonding to the protein. (Htt 2008). It was demonstrated in studies of cell cultures that the clumps of protein were much less harmful than the disaggregated forms.

Another theory that clarifies an additional way cell function may be disrupted is by damage to the mitochondria in striatal cells and the interactions of the tainted Huntingtin protein with many proteins in neurons which leads to an increased exposure of glutamine (Persichetti 1996). Glutamine, in great amounts, has been considered to be a toxin (Persichetti 1996). Toxins may cause damage to numerous cellular structures. While glutamine is not found in greatly elevated amounts, it has been postulated that because of the amplified vulnerability, even moderate amounts of glutamine can cause other toxins to be expressed (Persichetti 1996). The Huntingtin protein is cleaved into small pieces by capases (Htt 2008). These aggregates disrupt transcription by intruding with the formation of proteins by moving into the neurons nucleus (Persichetti 1996). Unfortunately, the cellular stress caused by the intrusion causes more Huntingtin to be cleaved up until apoptosis occurs (Htt 2008).

Great changes due to mHtt

Huntington's disease has an effect on specific areas of the brain. The most well-known premature consequences are due to a part of the basal ganglia called the neostriatum, which is made up of the caudate nucleus and putamen (Faideau 2010). Additional areas that are affected include the different layers of the cerebral cortex known as layers 3, 5, and 6, the hippocampus, purkinje fiber cells in the cerebellum and parts of the thalamus (Faideau 2010). These parts are affected due to their composition and the types of brain cells they have. Spiny neurons are the most susceptible, mainly ones with projections approaching the external globus pallidus, through interneurons and spiny cells extending to the internal global pallidum being less affected. Huntington's disease also causes an irregular augmentation in astrocytes (Faideau 2010).

The part that is most affected by Huntington's disease, the basal ganglia, has an significant role in behavior and movement control. Its function is not completely understood, but modern theories suggest that it ispart of the cognitive system and the


motor circuit. The basal ganglia normally prevents a considerable number of circuits that produce specific movements (Faideau 2010). To start a specific motion, the

cortex releases a signal to the basal ganglia that evokes the cessation to be exported (Faideau 2010). Injury to the basal ganglia can produce the exportation or restoration of the inhibitions to be unpredictable and unrestrained, which then results in an discomforted start to motion or movements to be inadvertently started, or a movement to be stopped before, or after, its intended completion (Faideau 2010). The damage to this area causes the distinguishing unpredictable movements linked with Huntington's disease.

There are ways in which the basal ganglia can be injured: directly and indirectly. In the direct pathway, fewer neurotransmitters are sent the internal globus pallidus (IGP), which then comprehends this as a decrease in inhibition, thus releasing a larger amount of the neurotransmitters VMAT2 and VMAT1 (Faideau 2010). The thalamus, which obtains a larger number of neurotransmitters, becomes restricted, consequently transporting fewer neurotransmitters to the motor cortex, which is a section of the cerebral cortex. (Faideau 2010). Eventually, the motor cortex is not stimulated as much and the movements are more delayed. The indirect pathway begins with the globus pallidus obtaining a decreased number of neurotransmitters, and therefore, reacting to this decrease as an indication of less inhibition, exports more neurotransmitters (Faideau 2010). The subthalamic nuclei, also known as STN, which gets the signals from the external globus pallidus, exports fewer neurotransmitters to the internal globus pallidus due to the augmentation of neurotransmitters received (Faideau 2010). The internal globus pallidus is now noticeably inhibited because the job of the subthalamic nuclei is to excite the internal globus pallidus and therefore, the IGP releases fewer neurotransmitters (Faideau 2010). In this circumstance, the response of decreased neurotransmitters is recognized as decreased inhibition. Lastly, the motor cortex obtains additional neurotransmitters and is overly stimulated, causing the erratic movements associated with chorea. The indirect pathway is usually affected initially, which is the reason that chorea is one the first symptoms, but as time progresses, the neurons die and movement is strictly limited (Faideau 2010).


The use of the genetic test for Huntington's disease has numerous ethical issues. The complex concerns about genetic testing include explaining how old an individual should be in order to be considered for testing (Crauford 1986). Also making sure of the privacy of the outcomes, and if employers should be permitted to utilize results of a test for determinations on life insurance, employment status or other financial issues (Craufurd 1986). There was debate in 1910 when Charles Davenport proposed that sterilization and immigration control should be utilized for individuals that have certain diseases, including Huntington's disease, as part of the eugenics movement (Craufurd 1986). In vitro fertilization has some concerns regarding its use of embryos. Some Huntington's disease research has ethical issues because of its involvement in using embryonic stem cells.

The development of a precise genetic test for HD has evoked legal, social and ethical issues about access and use of an individual's results (Craufurd 1986). Several procedures and testing practices have stern actions for acknowledgment and confidentiality to permit people to choose when and how to obtain their results and as to whom the results are made available to (Huggins 1990). Financial establishments and businesses are confronted with the difficulty of whether to utilize genetic test outcomes when evaluating a person for insurance or employment (Huggins 1990). Insurance companies of the United Kingdom have decided that until the year 2014, they will not utilize this information when writing most insurance policies (Huggins 1990).

Along with other terminal genetic conditions that a later diagnosis, it is ethically disputed whether or not to carry out pre-symptomatic testing on an adolescent since there wouldn't be any medical benefit for that child or adolescent (Craufurd 1986). There is an agreement for merely testing individuals who are considered mentally competent, even though there is a counter-argument that the child's legal guardians have a right to declare the choice on their child's behalf (Craufurd 1986). With the need of an efficient treatment, testing a person under age who is not deemed to be competent is acknowledged as unethical in most cases (Craufurd 1986).

Prenatal genetic testing or pre-implantation genetic diagnosis to make sure a child is not born with a known disease has a few ethical burdens as well (Huggins 1990). For instance, prenatal testing brings up the issue of abortion, an option seen as unacceptable by lots of people. Utilizing pre-implantation testing for Huntington's disease needs two times the number of embryos to be utilized for in viwtro fertilization, as about half of them will be affirmed to have Huntington's disease (Huggins 1990). For a dominant allele disease there are also problems in circumstances where a parent refuses to be familiar with their diagnosis, as this would need elements of the process to be hidden from the parent (Huggins 1990).

Research Route's

Investigations into the mechanism of Huntington's disease have focused on looking at the functioning of Htt, how mutant Htt is different or hinders the mechanism, and the pathology of the brain that HD creates (Messer 2006). The majority of research on Huntington's disease is done with animals. Suitable animal models are essential for understanding the underlying mechanisms causing the disease and for aiding the early stages of drug development (Messer 2006). Monkeys and mice that were chemically induced to display Huntington disease-like symptoms were initially used, but they did not mimic the advanced features of the disease (Messer 2006). Ever since the Huntingtin gene was identified in 1993, transgenic animals such as mice, Drosophila fruit flies, and more recently monkeys exhibiting Huntington's disease-like syndromes could be produced by putting a CAG repeat into the gene. Nematode worms also offer an important model when the gene is functional (Messer 2006).

Genetically engineered antibody segments called intrabodies have been shown to stop death throughout the growth phases of Drosophila models (Messer 2006). Their procedure of action was a lessening of mutant Huntingtin (mHtt) aggregation (Thomas 2010). As Huntington's disease has been finally correlated to a single gene, gene silencing is very promising. By utilizing gene knockdown methods in mouse models, researchers have demonstrated that when the influence of mHtt is decreased, symptoms improve (Thomas 2010). Stem cell therapy is the substitution of neurons that are damaged, by inserting stem cells into afflicted areas of the brain (Thomas 2010). Experiments have produced some confirmed results using this method in animal models and first round human clinical trials.

Several drugs have been reported to create advantages in animals, which includes creataine, coenzyme Q10 and minocycline, which is an antibiotic (Thomas 2010). A few of these have been analyzed by humans in experimental trials, and as of 2009 quite a few are at different phases of these clinical trials (Thomas 2010). In 2010, minocycline, unfortunately, was found to be unsuccessful for humans in all the stages of clinical trials (Thomas 2010).