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). Their were three chorea's that were described and one in particular was named chorea naturalis, where 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) use 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 attempts 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 chorea's 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.
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In 1692, it had been 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 had been 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, for the first time, Huntington's disease 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 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 written a landmark paper entitled "On Chorea" that was published in The Medical and Surgical Reporter in the April 13, 1872, issue (Neylan 2003) stating that he Huntington's chorea as 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 diseases symptoms and emphasizes its hereditary nature. Significant interest in Huntington's disease, especially its genetic component, occurs due to George Huntington's paper.
During the year 1910-1911, an American eugenicist Charles B. Davenport written a book titled, "Heredity in Relation to Eugenics", where he uses genetic
diseases, including Huntington's disease, to argue in support of "necessary sterilization and immigration restriction" for those afflicted with Huntington's disease (Davenport 1913). 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 Huntington's disease (Jourin 2010). He had produced the first field study of families with HD in which he constructed their pedigrees, on the East Coast of the United States (Jourin 2010). Davenport used this information to document the variable age of onset and range of symptoms of HD and make the claim that most cases of HD in the USA could be traced back to a handful of individuals (Davenport 1913). At about the same time researchers first note the deterioration to the central region of the brains of patients as the disease progressed. They discover the caudate nucleus as the central target of brain cell death.
During the 1950's, there had been an increase in publications on Huntington's disease research with the growing interest in human genetics and 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, publishes a book describing communities in Lake Maracaibo, Venezuela, with abnormally high numbers of individuals affected by Huntington's disease (Jourin 2010).
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During the late 1950's, two European scientists, Arvid Carlsson and Oleh Hornykiewicz, make the breakthrough discovery that dopamine pathways between
neurons 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 establishes the first Department of Neurobiology in which Ntinos Myrianthopoulous writes a review article criticizing the lack of knowledge of Huntington's disease (Jourin 2010). The following year, 1967, famous poet and songwriter Woody Guthrie dies of Huntington's disease. Guthrie's wife, Marjorie, creates 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). During the 1970's, the Society for Neuroscience (SFN), a nonprofit organization that was dedicated to study of the brain and nervous system had grown from 500 members to more than 36,000. Society of Neuroscience is currently the world's largest organization of scientists devoted to the study of the brain and nervous system.
In 1972, the International Centennial Symposium on Huntington's disease is held on the one hundredth anniversary of George Huntington's historic publication in 1872 in The Medical and Surgical Reporter (Jourin 2010). The Symposium aims to assemble all Huntington's disease researchers and evaluate the current state of knowledge, generating new hopefulness for research. At the same time, Thomas L. Perry, an American researcher finds diminished levels of GABA in the brains of HD patients and publishes it in The New England Journal of Medicine (Gusella 1983). In
1974, Milton Wexler, a prominent psychologist, creates the Foundation for Research in Hereditary Disease, which will later become the Hereditary Disease Foundation (HDF) (Wexler 2004). In 1976, Joseph T. Coyle develops the first rat model of Huntington's disease by using kainic acid (Gusella 1983). The rat's 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, begins 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 an Huntington's disease homozygote, but the team also ended up collecting 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 indicates that the Huntington gene is also located on chromosome 4 (Wexler 2004). Predictive linkage testing is introduced to assess the likelihood of getting Huntington's disease. In 1993, the location of the Huntington gene is discovered at the 4p16.3 gene site on chromosome 4 where it was published in The Cell journal. (Harding 1993). 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 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 completed 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).
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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 includes the writhing and rhythmic movements that mostly are uncontrollable by the individual that is affected with this disease (Revkin 1993).
As Huntington's disease worsens, concentration and short-term memory diminishes and involuntary movements of the head, trunk, and limbs increase. Speaking, walking, and swallowing abilities diminish as well. Ultimately, the affected individual is unable to care for him or herself. 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).
Huntington's disease not biased in who it can affect. It affects males and females equally and crosses all racial and ethnic boundaries. 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 HD gene was isolated and there is now a direct 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 has been 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.
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 negative family history, which would include adoptions, misdiagnosis, early parental death or non-paternity (Margolis 2003). In addition it is also useful when the family history is positive although the symptoms are uncommon (Margolis 2003). A genetic test is available for confirmation of the clinical diagnosis. In this test, a minute blood sample is taken, and DNA from it is analyzed to determine the CAG repeat number (Warner 1994). A person with a CAG repeat number of 30 or below will not develop Huntington's disease (Warner 1994). A person with a CAG repeat number between 35 and 40 may not develop the disease within their normal lifespan (Warner 1994). A person with a very high number of repeats such as 70 or above is likely to develop the juvenile-onset form of Huntington's disease (Warner 1994).
Prenatal testing is available for those who are pregnant as well. A person at risk for Huntington's disease (a child of an affected person) may obtain fetal testing without determining whether she herself carries the gene (Margolis 2003). This "nondisclosing" test, also called a linkage test, examines the pattern of DNA near the gene in both parent and fetus, but does not analyze for the triple repeat itself (Margolis 2003). If the DNA patterns do not match, the fetus can be assumed not to have inherited the HD gene, even if was present in the parent. A pattern match indicates the fetus probably has the same 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 early 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). 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).
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. It is generally advised that at-risk
individuals who are considering having children seek genetic counseling before pregnancy to prevent possibility of miscarriage.
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.
About 90% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of these other disorders are collectively labeled Huntington disease-like (Wild 2007). The cause of most Huntington disease-like diseases is unknown, but those with known causes are due to mutations in the
prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene , and the gene encoding the TATA box-binding protein (Wild 2007).
Greater than twenty mutations in the prion protein gene (HDL1) has 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 accumulates in the brain and destroys 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 treatment 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 more clinical trials to confirm their effectiveness in treating Huntington's disease symptoms (Bonelli 2006). Unfortunately, as the duration of this disease increase, an individuals ability to take care of themselves 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, tetrabenazine (Xenazine) has been available for about 35 years (Paleacu 2007). Â However, the FDA in the USA requires pre-approval testing that is more stringent than in most countries. Â It has been difficult to do testing that is acceptable to the FDA, because good testing requires large numbers of patients (Paleacu 2007). Â The disease is sufficiently rare (4 to 10 cases per 100,000 persons), that it is a challenge to get enough patients (Bonelli 2006). Â 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). Â This is a protein that acts to move chemical messengers inside of nerve cells. Â VMAT2 is found mostly in the brain. Â There is a similar protein, VMAT1, that is found in the rest of the body (Paleacu 2007). Â This is convenient, because we don't want the drug to affect anything outside of the brain. Â People who take tetrabenazine undergo relative depletion of these chemical messengers (Paleacu 2007). The one that is important in Huntington's Disease is dopamine. Â 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). Â This lack of selectivity can be expected to cause adverse effects. Â Indeed, persons who take the drug can get depressed (Paleacu 2007). Â Fortunately, there is some indication that the depression caused by tetrabenazine can be treated effectively (Paleacu 2007). Â
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 more thick as they are easier and safer to swallow (Phillips 2008). In extreme cases, if eating becomes too uncomfortable or unsafe, a permanently attached feeding tube must be connect 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 me more rigorous studies for health manufacturers to endorse them. Genetic counseling benefits these individuals by updating their knowledge, dispelling any myths they may have and helping them consider their future options and plans (Phillips 2008).
The occurrence of Huntington disease in the U.S. is estimated at about seven per 100,000 or .00007% (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. The disease is unbiased and affects men and women equally with the typical onset around 35 to 45 years-of-age with a range of 2 to 80 years of age (Conneally 1984). 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 concentrated 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. Looking for 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
Eve since 1979, the U.S.-Venezuela Collaborative Research Project, a team made up of top international doctors and scientists, have been traveling every year to very deprived, rural fishing villages besides the shores of Lake Maracaibo, Venezuela (Venezuela 2008). They were looking for a cure for a disorder called "Huntington's disease." Huntington's Disease is a dominantly inherited, neurodegenerative disease for which there is no treatment or cure. Each child of a parent with the disorder has a one in two chance of inheriting the same deadly affliction. It frequently strikes between the ages of 30 to 40, in an individual's primary fruitful years. A majority of the individuals in the late stages of illness require massive assistance. The afflicted individuals lose the ability to walk, talk, feed themselves, but are still cognizant, conscious and recognize themselves and their families (Venezuela 2008). It can emerge as young as 2 years of age to as old as 80 years.
Venezuela has the greatest concentration of Huntington's disease in the world, predominantly focused in the State of Zulia (Venezuela 2008). The world's largest family diagnosed with Huntington's disease lives along the shores of Lake Maracaibo (Venezuela 2008). The original progenitor of this family lived in the early 1800's and left more than 18,000 descendants, several of whom are either affected by the illness or at risk for this harmful and unavoidably terminal neurodegenerative disease (Venezuela 2008).
In 1983, the position of the Huntington's disease gene on chromosome 4 was discovered using previously-unknown techniques of recombinant DNA technology by the team of scientists led by Nancy Wexler (Venezuela 2008). The successful demonstration that these new scientific strategies could be used to find disease genes opened the door for discovering genes causing all distinctive kinds of disorders, including cancer - breast, prostrate, colon and lung - heart disease, arthritis, psychiatric disorders and many more (Venezuela 2008).
In 1993, the gene for Huntington's disease itself was discovered, leading to a dramatic re-assessment of the nature of this disease (Venezuela 2008). Huntington's disease was found to be caused by a piece of a gene that expands abnormally. The capture of the Huntington's disease gene confirmed the presence of a newly discovered
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 consequence of a mutation 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 studied by investigators worldwide to understand more about human genetics in health and disease (Venezuela 2008).
The study of tissues from these families has already led to the finding of genes for Alzheimer's disease, dwarfism and cancer as well (Venezuela 2008). The Venezuelan Huntington's disease families have been described in every recent genetics textbook and have been frequently presented by the United States and Venezuelan media (Venezuela 2008).
Htt, the Huntingtin gene is expressed in all mammalian cells. The maximum concentrations of it are found 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 involved in transcription, cell signaling and intracellular transporting (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 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 normal gene does not cause the disease. It is currently concluded that the disease is not caused by insufficient production 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 other proteins when it is overabundant in Htt proteins (Persichetti 1996). Therefore, the Htt molecule strands will assemble hydrogen bonds with one another, making a protein aggregate instead of folding into functional proteins (Htt 2008). As time passes, the aggregates build up, eventually interfering with neuron function since these fragments can then misfold and come together, in a manner called protein aggregation (Htt 2008). The left over proteins clump together at axons and dendrites 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 release in signaling other neurons as the neuronal inclusions grow (Persichetti 1996). Inclusion
bodies have been initiated in cytoplasm and nucleus (Persichetti 1996). Inclusion bodies in cells of the brain are one of the first pathological changes, and particular experiments have found that they can be deadly for the cell, but other experiments have revealed that they may form as part of the body's defense mechanism and help defend cells (Persichetti 1996).
Quite a few pathways by which mHtt may cause 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 interactions with a protein called Rhes, which is expressed mainly 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, which, in large amounts, has been found 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 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 "slipping" into the nucleus of the neuron (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 effects are in 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 layers 3, 5 and 6 of the cerebral cortex, the hippocampus, purkinje 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, with 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 movement, the
cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released (Faideau 2010). Injury to the basal ganglia can produce the release or reinstatement of the inhibitions to be unpredictable and unrestrained, which results in an ackward start to motion or motions to be inadvertently initiated, or a motion to be halted before, or further than, 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 neurotransmitters than usual (Faideau 2010). The thalamus, which receives a greater number of neurotransmitters, becomes inhibited, thus sending less neurotransmitters to the motor cortex (Faideau 2010). Eventually, the motor cortex is understimulated and movements are slower than normal. The indirect pathway begins with the external globus pallidus receiving a lower number of neurotransmitters, and in turn, responding to this decrease as a signal of less inhibition, releases a more neurotransmitters (Faideau 2010). The subthalamic nuclei (STN), which receives the signals from the external globus pallidus, releases fewer neurotransmitters to the internal globus pallidus in response to the increase 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
reception of less neurotransmitters by the thalamus is perceived as less inhibition. Finally, the motor cortex receives more neurotransmitters and is overstimulated, causing the erratic movements usual in chorea. The indirect pathway is usually affected first, which is why chorea is among the first symptoms, but as time progresses, both types of neurons die off and movement is severely limited (Faideau 2010).
The use of the genetic test for Huntington's disease has gotten numerous several ethical issues. The complex concerns for genetic testing include explaining how developed an individual should be prior to being considered appropriate for testing, making sure of the confidentiality of the results, and whether companies should be permitted to utilize test results for decisions on employment, life insurance or other financial issues (Craufurd 1986). There was debate in 1910 when Charles Davenport proposed that sterilization and immigration control should be used for people with 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 diagnostic test for Huntington's disease has caused social, legal, and ethical issues over access to and use of a person's results (Craufurd 1986). Several guidelines and testing procedures have strict procedures for
disclosure and confidentiality to permit individuals to decide when and how to receive their results and also to who the results are made available to (Huggins 1990). Financial institutions and businesses are faced with the difficulty of whether to utilize genetic test results when assessing an individual, such as for life insurance or employment (Huggins 1990). The United Kingdom's insurance companies have agreed that until 2014 they will not utilize this information when writing most insurance policies (Huggins 1990).
As with other untreatable genetic conditions with a later diagnosis, it is ethically disputed to perform pre-symptomatic testing on a child or adolescent as there would be no medical benefit for that individual (Craufurd 1986). There is an agreement for only testing individuals who are considered cognitively developed, although there is a counter-argument that parents have a right to make the choice on their child's behalf (Craufurd 1986). With the need of an efficient treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases (Craufurd 1986).
Prenatal genetic testing or pre-implantation genetic diagnosis to ensure a child is not born with a given disease has some ethical concerns as well (Huggins 1990). For example, prenatal testing raises the issue of selective abortion, a choice considered intolerable by many. Utilizing pre-implantation testing for Huntington's disease needs
twice as many embryos to be used for in vitro fertilization, as half of them will be positive for Huntington's disease (Huggins 1990). For a dominant disease there are also difficulties in situations in which a parent refuses to know his or her own
diagnosis, as this would require parts of the process to be kept secret from the parent (Huggins 1990).
Investigations into the mechanism of Huntington's disease have focused on looking at the functioning of Htt, how mutant Htt or mHtt differs or interferes with it, and the brain pathology that the disease produces (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 premature 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 inserting a CAG repeat expansion into the gene. Nematode worms also offer a valuable model when the gene is expressed (Messer 2006).
Genetically engineered antibody fragments called intrabodies have been shown to stop mortality during the development stages of Drosophila models (Messer 2006).
Their mechanism of action was an inhibition of mHtt aggregation (Thomas 2004). As Huntington's disease has been finally linked to a single gene, gene silencing is potentially promising and by using gene knockdown in mouse models, researchers have demonstrated that when the influence of mHtt is decreased, symptoms improve (Thomas 2004). Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain (Thomas 2004). Experiments have yielded some positive results using this technique in animal models and first round human clinical trials.
Several drugs have been reported to create benefits in animals, including creatine, coenzyme Q10 and the antibiotic minocycline (Thomas 2004). Some of these have then been tested by humans in clinical trials, and as of 2009 several are at different stages of these trials (Thomas 2004). In 2010, minocycline, unfortunately, was found to be ineffective for humans in a multi-center trial (Thomas 2004).