Huntington's chorea

Medical Encyclopedia: Huntington Disease

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Definition

Huntington disease is a progressive, neurodegenerative disease causing uncontrolled physical movements and mental deterioration. The disease was discovered by George Huntington of Pomeroy, Ohio, who first described a hereditary movement disorder.

Description

Huntington disease is also called Huntington chorea, from the Greek word for "dance," referring to the involuntary movements that develop as the disease progresses. It is occasionally referred to as "Woody Guthrie disease" for the American folk singer who died from it. Huntington disease (HD) causes progressive loss of cells in areas of the brain responsible for some aspects of movement control and mental abilities. A person with HD gradually develops abnormal movements and changes in cognition (thinking), behavior and personality.

The onset of symptoms of HD is usually between the ages of 30 and 50; although in 10% of cases, onset is in late childhood or early adolescence. Approximately 30,000 people in the United States are affected by HD, with another 150,000 at risk for developing this disorder. The frequency of HD is four to seven per 100,000 persons.

Causes and symptoms

Huntington disease is caused by a defect in the gene (an inherited unit which contains a code for a protein) of unknown function called huntingtin. The nucleotide codes (building blocks of genes arranged in a specific code which chemically forms into proteins), contain CAG repeats (40 or more of these repeat sequences). The extra building blocks in the huntingtin gene cause the protein that is made from it to contain an extra section as well. It is currently thought that this extra protein section, or portion, interacts with other proteins in brain cells where it occurs, and that this interaction ultimately leads to cell death.

The HD gene is a dominant gene, meaning that only one copy of it is needed to develop the disease. HD affects both males and females. The gene may be inherited from either parent, who will also be affected by the disease. A parent with the HD gene has a 50% chance of passing it on to each offspring. The chances of passing on the HD gene are not affected by the results of previous pregnancies.

The symptoms of HD fall into three categories: motor or movement symptoms, personality and behavioral changes and cognitive decline. The severity and rate of progression of each type of symptom can vary from person to person.

Early motor symptoms include restlessness, twitching and a desire to move about. Handwriting may become less controlled, and coordination may decline. Later symptoms include:

dystonia, or sustained abnormal postures, including facial grimaces, a twisted neck, or an arched back
chorea, in which involuntary jerking, twisting or writhing motions become pronounced
slowness of voluntary movements, inability to regulate the speed or force of movements, inability to initiate movement and slowed reactions
difficulty speaking and swallowing due to involvement of the throat muscles
localized or generalized weakness and impaired balance ability
rigidity, especially in late-stage disease

Personality and behavioral changes include depression, irritability, anxiety and apathy. The person with HD may become impulsive, aggressive or socially withdrawn.

Cognitive changes include loss of ability to plan and execute routine tasks, slowed thought, and impaired or inappropriate judgment. Short-term memory loss usually occurs, although long-term memory is usually not affected. The person with late-stage HD usually retains knowledge of his environment and recognizes family members or other loved ones, despite severe cognitive decline.

— Laith Gulli, MD

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Dictionary: Hun·ting·ton's chorea (hŭn'tĭng-tənz) pronunciation

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A rare inherited disease of the central nervous system characterized by progressive dementia, abnormal posture, and involuntary movements. The typical age of onset is between 30 and 50 years. Also called Huntington's disease.

[After George Huntington (1851?–1916), American physician.]

Neurological Disorder:

Huntington disease

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Definition

First described by Dr. George Huntington in 1872, Huntington disease (HD) is a relatively common hereditary neurological condition that most commonly affects people in their adult years. HD is a progressive disorder that often involves thinking and learning problems, psychological disturbances, and abnormal movements. HD has been well studied and documented in family histories across the world. This ultimately led to the discovery of the HD gene, now known to be responsible for the disorder.

Description

Huntington disease is also known by the name Huntington (or Huntington's) chorea; "chorea" refers to neurological diseases that are characterized by spasmodic movements of the limbs and facial muscles. This is because about 90% of people with HD have chorea. These movements may be mild at first, but can worsen and become more involuntary with time.

About two-thirds of people with HD first present with neurological signs, while others first have psychiatric changes. Other neurological signs include various abnormal movements, changes in eye movements, difficulty speaking, difficulty swallowing, and increased reflexes.

A general decline in thinking skills occurs in essentially everyone with HD. This may begin as general forgetfulness and progress to difficulty gathering thoughts or keeping and using new knowledge. People with HD often also have psychiatric changes, including significant personality and behavior changes.

The majority of those with HD first develops symptoms between the ages of 35 and 50 years. Symptoms vary considerably between people and sometimes within families, so it is difficult to predict an individual's exact experience with HD if he or she is diagnosed with the condition. Disease progression occurs in everyone, with death usually seen 10–30 years after its onset.

Demographics

HD is estimated to occur in the United States and most of Europe at a rate of about five cases per 100,000 people. Pockets of populations exist where the prevalence may be a bit higher, such as those with western European ancestors. Conversely, HD is estimated to have a much lower prevalence in Japan, China, Finland, and Africa. For example, the frequency of HD in Japan has been estimated at between 0.1 and 0.38 per 100,000 people.

Symptoms of HD typically begin after about age 35 years. However, in some families a juvenile form of HD has been seen with an onset of symptoms in the first or second decades of life. About a quarter of people with the condition are diagnosed past the age of 50 years. HD is a disease that affects males and females equally.

Currently, genetic testing is widely available to identify a well-documented mutation in the HD gene. Testing is available for confirmation of a clinical diagnosis, or for those at risk but who, as yet, have no symptoms. Predictive genetic testing (for those who are asymptomatic) typically involves a specialized protocol with pretest and post-test counseling, requiring coordinated care with various medical professionals.

Causes and symptoms

Some neurological changes have been seen in HD. However, the connection of many of these changes to the disease's symptoms is still not understood. Atrophy of the basal ganglia and corpus striatum are common neurological findings in HD, which may worsen over time. Cortical atrophy is often present, and this may be seen with magnetic resonance imaging (MRI) or computed tomography (CT) scans. From pathology studies after death, brain atrophy is most prominent in the caudate, putamen, and cerebral cortex in people with HD. Total brain weight may be reduced by as much as 25–30% in people who have advanced cases of HD.

A specific mutation in the HD gene called a triplet expansion causes symptoms of the condition to occur. The four different deoxyribonucleic acid (DNA) bases that make up genes are abbreviated as A, C, T, and G. Three DNA bases, CAG, are naturally repeated in the HD gene; a certain number of repeats is considered normal. People with symptoms of HD have a higher number of repeats than the usual range. Unfortunately, the number of CAG repeats can increase (or expand) from generation to generation, and this usually occurs in men. This genetic process is called anticipation; it cannot be predicted when and how the CAG repeats will expand in someone when they have children. A larger CAG repeat size is generally associated with developing symptoms at a younger age.

HD is inherited in an autosomal dominant manner, which means that an affected individual has a one in two chance to pass the disease-causing mutation to his or her children, regardless of the gender. Children who inherit a disease-causing mutation will develop signs of HD at some point in their lives. On the other side of that, children who do not inherit the mutation should not develop the disease. Strong family histories of HD have been well documented and studied across the globe.

HD is usually first suspected with the observation or progression of abnormal movements. The initial reasons for seeking medical attention are often clumsiness, tremor, balance trouble, or jerkiness. Chorea is a frequent symptom.

The areas of the body most commonly affected by chorea are the face, limbs, and trunk. As the chorea progresses, breathing, swallowing, and the mouth and nasal muscles may become involved. Muscles may become extremely rigid and gait may show signs of ataxia. Chorea may also be mixed with other movement disorders such as dystonia. Visual muscles may also be affected, and this can eventually lead to difficulties with vision, speech, swallowing, and breathing.

Weight loss is a common symptom in HD, which may occur despite a proper intake of calories and nutrients. Because people with HD are frequently moving, it is thought this continual activity increases metabolic rates and may explain the weight loss. However, the exact cause for weight loss in HD is still not well understood.

Mental impairment is an eventual sign of HD. This may begin at about the same time as movement abnormalities. If a diagnosis of HD is made, cognitive decline may have actually begun earlier, but might have gone unnoticed until other symptoms of the condition began to develop.

General forgetfulness, loss of mental flexibility, difficulty with mental planning, and organization of sequential activities may be early signs of HD. Reduced attention and concentration spans are common, and this may lead to one being quite distractible. Aphasia and agnosia are less evident than in Alzheimer's disease, but overall cognitive speed and efficiency are usually affected. The ability to speak is usually maintained, but people with HD may eventually have difficulty with complex words or finding the correct words to express their thoughts. Late-stage symptoms may include difficulty with visual and spatial relations.

The last category of symptoms in HD is that involving psychological disturbances. Irritability and depression are common early signs of HD. People may initially be incorrectly diagnosed with psychiatric diseases like schizophrenia and delusional disorder, particularly if they have no other symptoms of HD. This is probably because a large percentage of people with HD have significant personality changes or affective psychosis. Behavioral issues can include intermittent explosiveness, apathy, aggression, alcohol abuse, sexual problems and deviations, paranoid delusions, and an increased appetite.

Suicide occurs in 5–12% of people with HD. Late-stage disease is often quite significant and can be disabling. Weight loss, sleep problems, and incontinence are common signs of advanced HD.

Juvenile HD occurs when someone develops symptoms in the first two decades of life; this occurs in about 5–10% of all HD cases. Symptoms are distinct from those associated with adult-onset forms of HD. For example, chorea rarely occurs in people who develop HD in their first decade of life. However, dystonia and rigidity can be very significant for those individuals. Common characteristics of people with juvenile HD diagnosed before age 10 include declining performance in school, mouth muscle abnormalities, rigidity, and problems with their gait. Seizures are also a somewhat unique characteristic of juvenile HD.

Complications related to immobility are often the cause of death in people with HD. Abnormal muscular movements, particularly those related to swallowing and breathing, may cause someone to die from aspiration pneumonia and other infections; such a cause of death occurs years after the onset of the disease.

People with juvenile HD diagnosed between the age of 10 and 20 may have symptoms similar to adult-onset HD. Others may have more severe behavioral and psychiatric problems noticed before anything else. Common among people with juvenile HD is a father with adult-onset HD.

Diagnosis

Until the discovery of the HD gene on chromosome 4 in 1993, the diagnosis of the condition was made purely on a clinical basis. This can be somewhat challenging because of similarities with other hereditary and non-hereditary conditions involving chorea.

A careful neurological examination and documentation of abnormal movements are important to diagnose HD. Sydenham's chorea is a nonhereditary, infectious cause of chorea. It most often occurs in children and adolescents following a streptococcal infection, and the chorea associated is slightly different than that with HD. About 30% of people with rheumatic fever or polyarthritis develop Sydenham's chorea two to three months later. Symptoms may even come back in pregnancy, or in people taking oral contraceptives. The chorea in Sydenham's chorea is brisk and abrupt, but it is more flowing and somewhat slower in HD. Treatment for Sydenham's chorea usually involves bed rest, sedation, and antibiotic therapy with medications like penicillin.

Movements with characteristics of dystonia and athetosis, called choreoathetosis, are also common in HD. People with HD may be able to more easily mask their movements at first, because they are not that intrusive in the early stages. Tardive dyskinesia is a nonhereditary cause of chorea that may be mistaken for HD in an individual on antipsychotic medications.

Chorea occurs in 1–7% of people with lupus, and in a proportion of people with drug-related problems. It is important to rule out nonhereditary causes of chorea because treatments may exist for them, which may increase quality of life for the affected person.

Although very useful for many other neurological conditions, looking at the brain with techniques like magnetic resonance imaging (MRI) or computed tomography (CT) scans currently are not as helpful in diagnosing HD. These techniques may help find some typical brain changes in HD. For example, caudate atrophy is typically associated with advanced HD. Studies have shown that serial CT scans of the basal ganglia in at-risk individuals without symptoms may show signs of caudate atrophy before the disease even shows symptoms. These types of imaging studies can be useful to rule out other diagnoses that may mimic HD, because those may involve other specific brain changes.

An important step in diagnosing HD is to take a careful family history. Strong family histories with multiple generations affected, with roughly equal males and females affected, are common in HD.

Many hereditary conditions mimic HD. People who are diagnosed with HD much later in life may seem similar to people with Parkinson's disease, because abnormal movements may be the primary symptom. Neuroacanthocytosis is a hereditary condition with chorea, but it should be considered if muscle loss, absent lower limb tendon reflexes, neuropathy, and specific results on a blood test are present. Benign hereditary chorea is an autosomal dominant condition in which the chorea is not progressive, and does not involve any cognitive decline. Dentatorubropallidoluysian atrophy (DRPLA) is another hereditary condition that mimics HD; it typically affects adults and involves dementia, ataxia, and seizures, along with chorea. As a group, the hereditary spinocerebellar ataxias (SCAs) may mimic some of the movement abnormalities seen in HD. However, the psychological and cognitive components may not be present in the SCAs.

Often, diagnosis is most clearly made with genetic testing, which is done to confirm a suspected clinical diagnosis. Genetic testing identifies the exact number of CAG repeats in each copy of a person's HD gene.

There are several CAG repeat ranges that may be found through testing. Each genetic laboratory may use slightly different ranges, so test results should be interpreted carefully. Generally, a range of 10–27 CAG repeats is considered to be normal. If someone has results in these ranges, this person does not have HD, and will not develop signs of it.

A range of 27–35 CAG repeats will not cause symptoms of HD in the person. In this range, the repeat size may rarely increase when passed on to children. In other words, the person with this test result will not develop symptoms of HD, but he or she may have a child who develops symptoms. This would particularly be the case if the person were a man, because of the anticipation phenomenon.

A range of 36–39 CAG repeats is considered a range where the person may or may not develop HD symptoms at some point in his or her life. Additionally, the repeat may or may not expand to his or her children.

People with an HD gene that has greater than 39 CAG repeats will develop symptoms of HD at some point in their lives. They would have a 50% chance of passing this gene on to future children.

People with juvenile HD usually have much larger CAG repeat sizes than those who have the typical form of HD. Despite this, it is still impossible to predict exactly when someone may develop symptoms, or to predict the exact symptoms they will experience.

Genetic testing for those who have symptoms is fairly straightforward, and often ordered with the aid of a neurologist. Predictive testing for HD, as it is called when the person does not have symptoms, is a bit more complicated. This is because there are many complex factors in the testing process.

Ideally, at-risk asymptomatic individuals have several appointments before genetic testing is performed. They should see a neurologist for a thorough examination to identify any subtle signs of HD. They should also see a neuropsychologist for an evaluation. The neuropsychologist can help assess whether a person is a good candidate for genetic testing, potentially reducing the risk for poor outcomes, like suicide, following positive results. Individuals should also see a medical geneticist and genetic counselor to receive thorough information about the risks, benefits, and limitations of genetic testing.

Much has been studied about the myriad of issues with genetic testing in HD. Risks from any outcome can be considerable, and these may include a sudden change in family dynamics, self-image, or serious emotional and psychological harms.

Health, life, or disability insurance discrimination from HD testing may be a possibility, especially related to positive results. Employment may also be an issue. In October 2003, a young teacher in Germany was refused a permanent job because members of her family have HD; she was found to be at risk for the condition during a required governmental medical examination. Currently, there is not enough documentation in the medical literature to know what the actual risks are related to these issues. Awareness and discussion of these issues are important in pretest counseling.

Limitations and benefits from genetic testing should be given equal weight as well. Results may not be easily understood, simply identifying one and one's children to be potentially at risk. These types of vague results can cause great angst to an at-risk individual. However, benefits from testing may include relief from years of worry, empowerment from medical knowledge, and the ability to make life plans or tailor medical care based upon more accurate information.

Generally, at-risk asymptomatic children under age 18 are not tested for HD. The decision to learn their genetic status should be theirs, and at a time they feel is appropriate. Along the same lines, prenatal genetic testing for HD is not done, except in cases involving special circumstances or assistive reproductive techniques.

Treatment team

Treatment for people with HD is highly dependent on their symptoms. A multidisciplinary team and approach can be very helpful. A treatment team may include a neurologist, neuropsychologist, medical geneticist, genetic counselor, physical therapist, occupational therapist, speech therapist, registered dietitian, social worker, psychotherapist, psychiatrist, ophthalmologist, and a primary care provider. Some hospitals offer day clinics devoted to people with HD, which makes things much easier in terms of coordinating appointments. Pediatric specialists in these fields may help in the care for children.

Treatment

Currently, there is no known cure for Huntington disease. No specific treatment is known to slow, stop, or reverse the progressive nature of the disease. Current treatment for HD is mainly focused on relieving symptoms and reducing the impact of physical and mental complications related to the disease.

Medications are available to help treat chorea in HD, including therapies for blocking dopamine receptors, or those that deplete dopamine from its natural storage sites in the brain. Medications like these are tetrabenazine, pimozide, and haloperidol. They can have side effects, like drowsiness and a lessened ability to make voluntary movements. Some find the side effects to be more troublesome than the chorea, so medications should be prescribed under careful supervision.

Psychiatric problems in HD are often treated with medications as well. Some selective serotonin reuptake inhibitors (SSRIs) with trade names like Celexa, Paxil, Prozac, and others have been effective. Some tricyclic antidepressants like Nordil, Marplan, and Eldepryl have been effective. Lastly, some monoamine oxidase inhibitors (MAOIs) like Elavil, Tofranil, and Anafranil have been useful in treating depression.

Benzodiazepine and antipsychotic drugs can be used to treat anxiety, irritability, and agitation in HD. It is rare to find a medication without side effects, and drug interactions are also important to consider. As yet, no medications have been found helpful to treat the cognitive problems in HD.

Other therapies have been tested through clinical trials to see whether the disease progression may be slowed in any way. A combination of coenzyme Q10 and remacemide has been tested in mice, showing it to be helpful in reducing weight loss and brain loss. In a study by The Huntington Study Group in 2001, people with early-stage HD were given coenzyme Q10 or remacemide, but neither had significant effects. A 2000 study found that minocycline, an antibiotic, delayed motor decline in mice by 14%.

Riluzole is a drug currently used to treat people with amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). In clinical trials with HD patients in 1999, the drug reduced chorea in about a third of people over six weeks. Behavior was improved by about 61% after 12 months.

Studies are under way to see whether transplanting fetal cells from the corpus striatum will be helpful to treat people with HD. This follows closely on the heels of similar trials with people who have Parkinson's disease. As of early 2004, preliminary results seem promising but much more time is needed to fully study and interpret them.

Recovery and rehabilitation

Supportive therapy for people with HD is very helpful, and often greatly needed as time goes on. It may begin shortly after diagnosis and continue for years, until the disease becomes advanced and supportive care is needed.

Physical therapy, speech therapy, and dietary advice can be extremely important and most effective when in tandem. Special consideration should be given to nursing and supportive care, home health care options, diet, special adaptive equipment, and eligibility for governmental benefits. A practical approach with common sense, emotional support, and careful attention to a family's needs is effective for many people with HD.

Clinical trials

As of early 2004, many clinical trials were under way to study Huntington disease:

Family Health after Predictive Huntington Disease (HD) Testing, sponsored by National Institute of Nursing Research (NINR).
Minocycline in Patients with Huntington's Disease, sponsored by FDA Office of Orphan Products Development.
Prospective Huntington At-Risk Observational Study (PHAROS), sponsored by National Institute of Neurological Disorders and Stroke (NINDS) and National Human Genome Research Institute (NHGRI).
Neurobiological Predictors of Huntington's Disease (PREDICT-HD), sponsored by NINDS.
Brain Tissue Collection for Neuropathological Studies, sponsored by National Institute of Mental Health (NIMH).

Prognosis

Prognosis has historically been somewhat bleak for people with HD. Complications related to movement abnormalities and immobility, such as pneumonia and respiratory complications, are a common cause of death in HD. Though no cure is currently available, treatments or therapies may be available in the future to maintain a better quality of life, and these continue to offer hope.

Resources

BOOKS

Parker, James N., and Philip M. Parker. The Official Patient's Sourcebook on Huntington's Disease: A Revised and Updated Directory for the Internet Age. San Diego: Icon Health Publishers, 2002.

Quarrell, Oliver. Huntington's Disease: The Facts. Oxford: Oxford University Press, 1999.

PERIODICALS

Burgermeister, Jane. "Teacher Was Refused Job because Relatives Have Huntington's Disease." British Medical Journal (October 11, 2003) 327 (7419): 827.

Grimbergen, Yvette A. M., and Raymond A. C. Roos. "Therapeutic Options for Huntington's Disease." Current Opinion in Investigational Drugs (2003) 4(1): 51–54.

Margolis, Russell L., and Christopher A. Ross. "Diagnosis of Huntington Disease." Clinical Chemistry (2003) 49(10): 1726–1732.

Sutton Brown, M., and O. Suchowersky. "Clinical and Research Advances in Huntington's Disease." The Canadian Journal of Neurological Sciences (2003) 30 (Suppl. 1): S45–S52.

WEBSITES

Caring for People with Huntington's Disease. (June 2, 2004). http://www.kumc.edu/hospital/huntingtons/index.html.

GeneTests/GeneReviews. (June 2, 2004). http://www.genetests.org.

National Institute of Neurological Disorders and Stroke. (June 2, 2004). http://www.ninds.nih.gov/index.htm.

Testing for Huntington Disease: Making an Informed Choice. (June 2, 2004). http://depts.washington.edu/neurogen/HuntingtonDis.pdf.

Testing Guidelines in Huntington's Disease. (June 2, 2004). http://www.hdfoundation.org/testread/hdsatest.htm.

ORGANIZATIONS

Huntington's Disease Society of America. 158 West 29th Street, 7th Floor, New York, NY 10001-5300. (212) 242-1968 or (800) 345-HDSA (4372); Fax: (212) 239-3430. hdsainfo@hdsa.org. http://www.hdsa.org.

Huntington Society of Canada. 151 Frederick Street, Suite 400, Kitchener, Ontario N2H 2M2, Canada. (519) 749-7063 or (800) 998-7398; Fax: (519) 749-8965. info@hsc-ca.org. http://www.hsc-ca.org.

International Huntington Association. Callunahof 8, 7217 St Harfsen, The Netherlands. + 31-573-431595. iha@huntington-assoc.com. http://www.huntingtonassoc.com.

Deepti Babu, MS, CGC

Sci-Tech Encyclopedia: Huntington's disease

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A rare hereditary disorder of the basal ganglia causing progressive motor incoordination, abnormal involuntary movements (chorea), and intellectual decline. The disease, which progresses gradually over 15–20 years, is invariably fatal. Inherited as an autosomal dominant mendelian trait, Huntington's disease inevitably develops in those who carry the gene if they live long enough. Men and women are affected equally. The average age at onset is between 35 and 40 years, but the disease can begin as early as 2 years or as late as 80 years.

Therapy is merely supportive: no medications significantly affect the course of the disease or functional capacity of the sufferer. Depression or psychosis, however, can be temporarily alleviated by antidepressant and antipsychotic medications.

The gene for Huntington's disease, termed IT15, has been localized at the end of the short arm of chromosome 4. The IT15 gene is thought to encode a protein, huntingtin, which does not resemble any known protein. Offspring of individuals suffering from the disease have a 50% risk of developing it, and can be tested by recombinant genetic technology. See also Chromosome; Human genetics; Mutation; Nervous system disorders.

Britannica Concise Encyclopedia: Huntington chorea

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Relatively rare, hereditary neurological disease that is characterized by irregular and involuntary movements of the muscles. Huntington chorea is caused by a genetic mutation that causes degeneration of neurons in a part of the brain that controls movement. Symptoms usually appear between ages 35 and 50. They begin with occasional jerking or writhing movements, which are absent during sleep, and progress to random, uncontrollable, and often violent twitchings and jerks. Symptoms of mental deterioration begin later and include memory loss, dementia, bipolar disorder, or schizophrenia. There is no effective therapy or cure, and the disease invariably proves fatal. A child of a person with Huntington chorea has a 50% chance of developing the disease.

For more information on Huntington chorea, visit Britannica.com.

Columbia Encyclopedia: Huntington's disease

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Huntington's disease, hereditary, acute disturbance of the central nervous system usually beginning in middle age and characterized by involuntary muscular movements and progressive intellectual deterioration; formerly called Huntington's chorea. The disease is sometimes confused with chorea or St. Vitus's dance, which is not hereditary. It attacks the cells of the basal ganglia, clusters of nerve tissue deep within the brain that govern coordination.

The onset is insidious and inexorably progressive; no treatment is known. Psychiatric disturbances range from personality changes involving apathy and irritability to bipolar or schizophreniform illness. Motor manifestations include flicking movements of the extremities, a lilting gait, and motor impersistence (inability to sustain a motor act such as tongue protrusion).

In 1993 the gene responsible for the disease was located; within that gene a small segment of code is, for some reason, copied over and over. Genetic counseling is extremely important, since 50% of the offspring of an affected parent inherit the gene, which inevitably leads to the disease.

World of the Mind: Huntington's disease

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Several types of cerebral degeneration occur which lead to loss of mental powers in middle age. All are rare. One type is Huntington's 'chorea', which owes its name to George Huntington (1850–1916), an American physician, who first described the disease. Among its cardinal features Huntington mentioned 'a tendency to insanity and suicide'. In the early stages spontaneous movements give the impression of clumsiness and fidgetiness, but, as the disease progresses, the characteristic jerking and writhing movements become more prominent, particularly affecting the face, tongue, and upper limbs, although, ultimately, all parts of the body musculature may be involved. The disease runs in families, and its pattern of distribution within families shows it to be due to a single autosomal dominant gene. It survives because the average age of onset is in the middle thirties, late enough for most carriers of the gene to have begotten children. The patients described by Huntington were said all to be descendants of a family of three brothers who had emigrated from England.

Two expectations have to be met before a disease is attributed to a dominant gene. One parent must have been affected, and the proportion of children affected must not depart significantly from one-half. Cases of Huntington's disease do occur occasionally in which neither parent seems to have been affected. In some of these, a parent has died young; in others, there is doubt about the identity of the father. The proportion of children affected has usually been found to be about one in three. The probable reason why this falls short of one-half is that a relatively high proportion of the sibship have died young; some of those affected die before birth.

The course is progressive, with increasing disability due to the loss of neurons leading to dementia. The cerebrum atrophies and loses weight. The ventricles enlarge. The caudate nucleus and putamen of the midbrain are especially affected. Severe depression is a common complication which may end in suicide attempts or actual suicide, which is the cause of death of 7 per cent of non-hospitalized patients.

Numerous attempts have been made to identify carriers of the gene before they enter the reproductive period of life but, so far, none has been of proven validity. In any case, predicting a progressive, incapacitating neuropsychiatric illness in somebody who may at the time be relatively healthy raises ethical problems which may outweigh the potential eugenic advantages.

The first polymorphic DNA marker linked to Huntington's disease (HD) gene locus was discovered in 1983 and was cloned in 1993. The HD gene (IT15) is on the short arm of chromosome 4 (4p16.3) and regulates, controls, or encodes production of the protein huntingtin. The exact function of huntingtin is unknown but it has been suggested that it may be involved in cytoskeletal transport. The IT15 gene in healthy individuals contains an expanded trinucleotide repeat (CAG) that ranges from 9 to 35. In contrast, those with the disorder may have about 36 to 180 repeats. The length of the expanded CAG repeats is thought to have some relation to the age at symptom onset where those with a large number of repeats tend to develop symptoms at an earlier age. Extremely large CAG repeats (of 80 or more) are often associated with a disease onset during childhood (juvenile HD or the 'Westphal variant'). It must be recognized that age of onset is variable in individuals and does not always correlate with repeat size.

With the discovery of the IT15 gene, genetic testing for Huntington's disease has become available, which can be pre-symptomatic (i.e. at-risk individuals can have a blood test and find out if they carry the gene), or prenatal (parents having a child can find out if the fetus has inherited the gene). Pre-implantation genetic diagnosis also exists where the genotype of an oocyte can be determined before fertilization and only non-carrier embryos are implanted. Pre-implantation genetic diagnosis became possible due to simultaneously developing in vitro fertilization techniques (IVF). IVF treatment, however, can be both psychologically and physically demanding and does not necessarily result in success. Genetic testing raises all sorts of ethical issues (see Evers-Kiebooms and Decruyenaere 1998 for a review) and has actually proved much less popular than predicted, with the number of people taking the test at about 2–16 per cent compared with the anticipated 60 per cent.

(Published 1987)

— Derek Russell Davis

Bibliography

Evers-Kiebooms, G., and Decruyenaere, M. (1998). 'Predictive testing for Huntington's disease: a challenge for persons at risk and for professionals'. Patient Education and Counselling, 37.
Georgiou-Karistianis, N., Smith, E., Bradshaw, J. L., Chua, P., Lloyd, J., Churchyard, A., and Chiu, E. (2003). 'Future directions in research with presymptomatic individuals carrying the gene for Huntington's disease'. Brain Research Bulletin, 59/5.
Myrianthopoulos, N. C. (1966). 'Huntington's chorea'. Journal of Medical Genetics, 3.
Ross, C. A., and Margolis, R. L. (2001). 'Huntington's disease'. Clinical Neuroscience Research, 1.

Wikipedia: Huntington's disease

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Huntington's disease
Classification and external resources
Medium spiny neurons (yellow) with nuclear inclusions, which occur as part of the disease process, stained orange
ICD-10	G 10., F 02.2
ICD-9	333.4, 294.1
OMIM	143100
DiseasesDB	6060
MedlinePlus	000770
eMedicine	article/1150165 article/792600 article/289706
MeSH	D006816

Huntington's disease, also known as Huntington disease, Huntington's chorea, chorea major, sometimes abbreviated as HD, is the most common genetic cause of the pattern of repetitive abnormal movements called chorea.^[1]^[2] It is a neurodegenerative disorder named after the American physician George Huntington who accurately described it in 1872, and has no current cure.^[3]^[4] HD prevalence, per country, is up to 7 people in 100,000 (in populations of Western European inheritance), but can be much higher in localized regions.^[1] Physical symptoms of the disorder can begin at any age, although the mean is 35 to 44 years of age.^[5] Less commonly, onset is before age 20, and the condition, classified as juvenile HD (also known as akinetic-rigid HD or Westphal variant HD), progresses faster with slightly different symptoms.^[6] In 1993 genetic testing was made possible with the discovery of a single causal gene, the first non-sex-linked dominant disease gene to be found.^[7] Consequently counseling for HD had to be developed and became a model for other genetically dominant disorders.^[8] The test can be performed before the onset of symptoms, at any age—even pre-birth,^[1] which has raised various ethical issues and heated debates.^[9]

The disease runs strongly in families: it is inherited dominantly, so the offspring of an affected person have a 50% risk of suffering it, and an individual will often experience several generations of family members suffer from the disease in their lifetime.^[1] The exact way HD affects an individual varies, even between family members, but there is a characteristic progression.^[10] The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances uncoordinated, jerky body movements become more apparent, as does a decline in mental abilities and behavioral and psychiatric problems.^[1] Physical abilities are gradually impeded mental abilities generally decline into dementia, necessitating full-time care in the later stages of the disease.^[1] Although the disorder itself is not fatal, complications reduce life expectancy to around twenty years after onset of symptoms.^[1]

The mechanism of the disease is not fully understood, but a number of factors have been identified.^[1] A mutation in the Huntingtin gene causes the production of an abnormal form of the protein huntingtin, which in turn produces cellular and anatomical changes in the brain.^[11] There is no cure for HD, although there are treatments to relieve some of its symptoms.^[1]

Since the late 1960s and the formation of the Hereditary Disease Foundation by Dr. Milton Wexler and the Committee to Combat Huntington's Disease by Marjorie Guthrie, both spouses of HD sufferers, lay organizations have increased in number, playing a key factor in stimulating research, increasing public awareness and providing support for families in many countries.^[12] Research directions include determining the exact mechanism of the disease, improvement of animal models to speed research, clinical trials of pharmaceuticals to treat symptoms or slow the progression of the disease, and studying procedures such as stem cell therapy with a view to repairing damage caused by the disease.^[1]

Signs and symptoms

Huntington's disease is a neurodegenerative disorder.^[1] Symptoms can appear at any age,^[1] but most commonly the age of onset is between 35 and 44 years.^[5] The early stage of the disease involves subtle changes in personality, cognition, or physical skills.^[1] The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at this stage.^[1] Almost everyone with Huntington's disease eventually exhibits all physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.^[10]

The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.^[1] Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, incoordination, or slowed saccadic eye movements.^[1] These minor motor abnormalities usually precede obvious signs of motor dysfunction by at least 3 years.^[10] The clear appearance of symptoms such as rigidity, repetitive motions or abnormal posturing appear as the disorder progresses.^[1] These symptoms are regarded as the onset stage of the disease, and gradually become the dominant physical symptoms.^[1] These are signs that the brain's psychomotor function is affected; this is the system that achieves a desired movement by using perceptual and spatial skills to send messages to the muscles.^[13] Psychomotor functions are increasingly impaired, such that any action that requires muscle control is affected, resulting in physical instability, abnormal facial expression, and difficulties chewing, swallowing and speaking.^[1] Eating difficulties commonly cause weight loss and may lead to malnutrition.^[14]^[15] Sleep disturbances are also associated symptoms.^[16] Juvenile HD differs from these symptoms, in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. Additionally, Seizures are a common symptom of this form of HD.^[1]

Reported prevalences of behavioral and psychiatric symptoms in HD^[17]
Depressed mood	33–69%
Anxiety	34–61%
Irritability	38–73%
Apathy	34–76%
Obsessive and compulsive	10–52%
Psychotic	3–11%

Cognitive abilities are impaired progressively.^[13] Especially affected are executive functions which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions.^[13] As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity) and working memory.^[13] Cognitive problems tend to worsen over time, leading ultimately to dementia.^[13] This pattern of deficits has been called a "subcortical dementia" syndrome to separate it from the typical effects of "cortical dementias" such as Alzheimer's disease.^[13]

Possible neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted affect), egocentrism, aggression, and compulsive behavior, which can cause or worsen addictions, including alcoholism and gambling, or hypersexuality.^[17] Difficulties in recognizing other people's negative expressions have also been observed.^[13] Prevalence of these symptoms is also highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.^[17] For many sufferers and their families these symptoms are among the most distressing aspects of the disease, heavily affecting daily functioning and often constituting reason for institutionalisation.^[17] Suicidal thoughts and suicide attempts are more common than in the general population.^[1]

Genetics

All humans have the Huntingtin gene, which provides the genetic code to produce the protein huntingtin, abbreviated to HTT. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein or mHTT. The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant, and the gene is not on a sex-linked chromosome; however, the scale of the changes in length can depend on the gender of the parent it is inherited from.^[1]

Genetic mutation

HD is one of several trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding a normal range.^[1] HTT is located on the short arm of chromosome 4.^[1] HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...), known as a trinucleotide repeat.^[1] CAG is the genetic code for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine or polyQ tract, and the repeated part of the gene, the PolyQ region.^[18]

Classification of the trinucleotide repeat and the disease status of the person depending on the number of CAG repeats^[1]
Repeat count	Classification	Disease status
<27	Normal	Unaffected
27–35	Intermediate	Unaffected
36–39	Reduced Penetrance	+/- Affected
>39	Full Penetrance	Affected

Generally, people have less than 27 repeated glutamines in the polyQ.^[1] A polyQ region containing fewer than 36 glutamines results in production of the cytoplasmic protein Huntingtin.^[1] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.^[1] This altered form, called mHTT (mutant HTT), increases the decay rate of medium spiny neurons, affecting regions of the brain according to their reliance on them for normal functioning.^[1] Generally, the number of CAG repeats is related to how much this process is affected, and correlates with age at onset and the rate of progression of symptoms.^[1] For example, 36–39 repeats result in much later onset and slower progression of symptoms than the mean, such that individuals may die of other causes before they manifest symptoms; this is termed "reduced penetrance".^[1] With very large repeat counts, HD can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.^[6]

Inheritance

HD is inherited in an autosomal dominant fashion. The probability of offspring inheriting an affected gene is 50% independent of gender, and the gene does not skip generations.

Huntington's disease is inherited autosomal dominantly, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent.^[1] In this type of inheritance pattern, each offspring of an affected individual has a 50% chance of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.

Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the number of repeats present.^[1] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.^[1] This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–39), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.^[1] Such increase in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.^[1] Maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length; therefore the anticipation phenomenon occurs only when the person transmitting HD is a male.^[1]^[19] This occurs because instability is greater in spermatogenesis than oogenesis.^[1] It is rare for Huntington's disease to be caused by a new mutation, where neither parent have over 36 CAG repeats.^[20]

Homozygous individuals, with two affected genes, are very rare except in large consanguineous families.^[21] For some time HD was thought to be the only disease for which homozygosity did not affect the expression of the disease,^[22] but it has since been found that it can affect the phenotype and the rate of progression.^[1]^[21] In identical twins their age of onset typically varies by years and clinical phenotypes can also differ.^[21]

Mechanism

The HTT protein interacts with over 100 other proteins, and appears to have multiple biological functions.^[23] The mutated mHTT protein behaves differently in ways that are not completely understood, and is toxic to certain types of cells. The brain is greatly affected, with damage initially in the striatum, and then later, as the disease progresses, in other brain areas as well. As the damage accumulates, symptoms associated with the functions of these brain areas appear, usually starting with symptoms that affect the planning and modulation of movement, which are the main functions of the striatum.^[1]

HTT function

Cellular changes due to mHTT

Neuron with inclusion (stained orange) caused by HD

There are multiple cellular changes through which the toxic function of mHTT may manifest and produce the HD pathology.^[11] During the biological process of posttranslational modification of mHTT, cleavage of the protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion.^[11] These fragments can then misfold and coalesce, in a process called protein aggregation, to form inclusion bodies within cells.^[11] Inclusion bodies have been found in both the nucleus and the cytoplasm of the cell.^[11] Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the bodies defense mechanism and help protect cells.^[11] Several pathways by which mHTT may cause cell death have been identified, including effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases which play a role in the process of removing cells; the toxic effects of glutamate on nerve cells; impairment of energy production within cells; and effects on the expression of genes. A 2009 study shed new light on this question, by showing that the cytotoxic effects of mHTT are strongly enhanced by interactions with a protein called Rhes, which is expressed mainly in the striatum.^[26] Rhes was found to induce sumoylation of mHTT, which causes the protein clumps to disaggregate—studies in cell culture showed that the clumps were much less toxic than the disaggregated form.^[26]

Macroscopic changes due to mHTT

Area of the brain damaged by Huntington's disease - striatum (shown in pink).

HD affects specific areas of the brain. The most prominent early effects are in a part of the basal ganglia called the striatum, which is composed of the caudate nucleus and putamen.^[1] Other areas affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, hippocampus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.^[1] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.^[1] Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus; interneurons and spiny cells projecting to the internal pallidum are less affected.^[1]^[27] HD also causes an abnormal increase in astrocytes.^[28]

The basal ganglia—the part of the brain most prominented affected in HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system,^[13] and the motor circuit.^[1]^[29] Regarding motor function the basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To activate a particular motor behavior, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. In HD, damage to the basal ganglia causes behaviors to be released in an erratic and uncontrollable way, or to be terminated before they have been completed.^[1]^[29] Depending on the precise distribution of damage, the intrusive behaviors may consist of complex patterns such as walking motions, simple movements such as twitching a limb, or many other combinations of motor elements.

Diagnosis

With the appearance of symptoms HD can be diagnosed clinically.^[1] Genetic testing can confirm if an individual carries an expanded copy of the gene, even before onset of symptoms, and can also be used for embryonic testing. Although the initial motivation for having a pre-symptomatic test is strong, the considered implications and relevance of having a confirmed diagnosis mean that less than 5% of individuals choose to do so.^[1]

Clinical

Coronal brain section from a patient with HD showing dilatation of the ventricles (blue arrows) and atrophy of caudate nucleus (red arrows)

A physical, sometimes combined with a psychological examination can determine whether onset of the disease has begun.^[1] Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Rarely, cognitive or psychiatric symptoms may be the first diagnosed, but they are usually only recognized in hindsight or when they further develop. How far the disease has progressed can be measured using the Unified Huntington's disease rating scale (UHDRS), which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments, but is primarily used for clinical trials.^[30]^[31] Functional neuroimaging techniques such as fMRI or PET can show changes in brain activity before symptom onset, but are rarely used. Other methods such as computerized tomography (CT) or magnetic resonance imaging (MRI) only show a visible volume reduction in the striatum in advanced stages.^[1]

Genetic

Embryonic

Preimplantation genetic diagnosis can be used after in vitro fertilisation to choose an embryo that does not carry the affected gene is implanted and will therefore not be at risk of HD. It is possible to obtain a prenatal diagnosis for an embryo in the womb, which gives individuals who are not opposed to abortion the option of ensuring the disease will not be inherited.^[35]

Differential diagnosis

In a person with typical symptoms, and a family history of the disease, diagnosis is not usually complicated.^[1] Of all the genetic disorders that cause chorea, ninety percent are attributable to HD, while most of the remainder are collectively labeled HD-like (HDL).^[2] Genetic testing for HD confirms if the remaining ten percent of causes should be considered.^[1] The causes of most of these HDL diseases are unknown, but those that are have been found to be caused by mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene (HDL3 — only found in one family and poorly understood), and the gene encoding the TATA box-binding protein (HDL4/SCA17).^[2]

Management

Chemical structure of tetrabenazine, an approved compound for the management of chorea in HD

There is no cure for HD; available treatments offer relatively small symptomatic benefit and remain palliative in nature.^[1] As HD gradually renders people incapable of tending to their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.^[1]

Tetrabenazine, an orphan drug, is useful in the reduction of chorea,^[1] and was approved in 2008 for this use in the US.^[36] Other drugs that help to reduce it include neuroleptics and benzodiazepines.^[5] Compounds such as amantadine or remacemide are still under investigation but have shown preliminary positive results.^[1] Hypokinesia and rigidity can be treated with antiparkinsonians and myoclonic hyperkinesia with valproic acid.^[5]

Psychiatric symptoms can be treated with medications similar to those used in the general population.^[1] Selective serotonin reuptake inhibitors and mirtazapine for depression, and atypical antipsychotic drugs for psychosis and behavioural problems have been recommended, however more studies on the efficacy of these and other treatments are needed.^[37] Patients, their families, and individuals at risk of having HD may benefit from counselling.^[1]

Although there are relatively few studies of rehabilitation for HD there is some evidence for the usefulness of physical therapy and speech therapy but more rigorous studies are needed for health authorities to endorse them.^[38] A multidisciplinary approach may be important to limit disability.^[39]

Nutrition management is important. Weight loss and eating difficulties due to dysphagia, as well as difficulty getting food into the mouth due to lack of muscle coordination are common as the disease advances.^[1] Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow.^[1] Reminding the patient to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking.^[1] If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the chance of aspirating food and provides better nutritional management.^[40]

Prognosis

A CT image of aspiration pneumonia, a common cause of death in HD

The age of onset decreases, and the rate of progression of symptoms increases, with the number of CAG repeats.^[41] However there is a variation in age of onset for any given CAG repeat length: only 60% of the variation in age of onset is explained by the number of CAG repeats, with genes and environment also being important.^[1] Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease.^[42]

The life expectancy is around 20 years following diagnosis.^[1] Mortality is not caused by Huntington’s disease directly, but by associated complications. The largest risk is pneumonia, which is the cause of one third of deaths. The risk of pneumonia increases as the ability to synchronise movements to clear the lungs is compromised and sometimes caused as a result of aspiration of food or drink. The other leading cause of death is heart disease, which causes almost a quarter of fatalities. Other associated risks include choking, physical injury from falls and malnutrition.^[1] Suicide is an associated risk, with increased suicide rates of up to 7.3%, and attempted suicides of up to 27%.^[43]^[44] Survival expectancy is similar in all regions independent of their economic development and the accessibility of treatment.^[1]

Epidemiology

HD is autosomal dominant. Because of the late age of symptom onset, it does not usually affect reproduction.^[1] The prevalence varies greatly geographically as a result of ethnicity, local migration and past immigration patterns; however it is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 people of Asian and African descent.^[1] Additionally, some localized areas have a much higher prevalence than their regional average.^[1] An example is in the isolated populations of the Lake Maracaibo region of Venezuela, which have prevalences of up to 700 per 100,000 and were studied to locate the marker for the gene.^[1]^[45] Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden.^[46] Increased prevalence in some cases occurs according to a local founder effect; a historical migration of carriers into an area of geographic isolation.^[46]^[47] Some of these carriers have been traced back hundreds of years using genealogical studies.^[46] Genetic haplotypes can also give clues for the geographic variations of prevalence.^[46]^[48]

Since the discovery of a genetic test that can be used pre-symptomatically, estimates of the prevalence and incidence of the disorder are likely to increase. Without the test, only individuals displaying physical symptoms and a family history were diagnosed, excluding any who died of other causes before symptoms or diagnosis occurred. These cases can now be included in statistics as the test becomes more widely available.^[46]^[49]

History

In 1872 George Huntington described the disorder in his paper "On Chorea".^[3]

Until the 19th century Huntington's disease was grouped with numerous movement disorders, and as with many of these disorders, people with the condition may have been persecuted as witches or thought to be possessed by spirits, and shunned or exiled by society.^[50] For example a woman, named Elizabeth Knap, was judged in the Salem witch trials although she probably suffered from HD.^[51]^[52] Not all communties were so ignorant however, as the family that was cause for George Huntington's description were accepted by their local community, working all their lives until physically unable.^[53]

The first definite description of HD was in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described 'a form of chorea, vulgarly called magrums', this included accurate descriptions of the chorea, it's progression, and also highlighted the strong heredity of the disease^[54] In 1846 Charles Gorman observed how prevalence seemed to occur in localized regions.^[54] Both Gorman and Waters were students of Dungison at Jefferson Medical College.^[53] Independently, Johan Christian Lund also produced an early description in 1860.^[54] He specifically noted that in Setesdalen, a rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.^[55] The first widely recognized description was by George Huntington in 1872. Huntington was a third generation physician on Long Island. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked and presented his detailed and accurate definition of the disease as his first paper.^[3]^[56] Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, even wishing to reassess the family involved a decade later.^[54] Osler's interest in HD combined with his influence in medicine circles helped to spread knowledge of the disorder rapidly.^[54]

As Mendelian inheritance was being rediscovered at the turn of the century, HD was used tentatively as an example of autosomal dominant inheritence.^[54] Charles Davenport in 1911 made major contributions to early understanding of the disease, proving that it was indeed autosomal dominant, and proceeding to document most of the inheritance variabilities like age of onset. He also described the range of psychiatric and physical symptoms, providing much of the framework for following research.^[54] Davenport's interested was created by his college friend Smith Ely Jelliffe, who was intrigued by the strong inheritance pattern of the disease.^[53] Jellife collected information from across New York State and published several articles regarding the genealogy of HD in New England.^[57] This work was expanded upon in 1932 by P. R. Vessie, who traced about a thousand people with HD back to two brothers who left England in 1630, bound for Boston.^[58]

Research into the disorder continued progressively, and was given a major boost in 1983 when the US–Venezuela Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene.^[47] This was the result of an extensive study begun in 1979, focusing on the populations of isolated Venezuelan villages of Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. Among other innovations, the project developed DNA marking methods which were an important step in making the Human Genome Project possible.^[59] In 1993 the research group isolated the precise gene at 4p16.3;^[60] making this the first autosomal disease locus to be found using genetic linkage analysis.^[61] In the same time frame key discoveries concerning the mechanisms of the disorder were being made—for example, the finding by Anita Harding's research group that the length of the gene affected disease severity.^[62]

A transgenic mouse that could be made to exhibit HD, the R6 line, was developed in 1996. This enabled larger scale testing, and as the mouse's metabolism is faster and lifespan shorter, results could be obtained more quickly.^[63]^[64] These advancements, and the 1997 discovery that mHTT fragments misfold, led to the discovery of nuclear inclusions,^[65] which in turn led to increasingly extensive research into the interactions of HTT, mHTT, and mHTT fragments, potential drug treatments, care methods, and the gene itself.^[54]^[66]^[67]

Society and culture

Ethics

Huntington's disease has tested society's ethics in various ways. HD was one of the targets of the eugenics movement, in which Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD.^[68] The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access and use of a person's results.^[69]^[70] Financial institutions and businesses are faced with the question of whether to use results when assessing an individual, such as for life insurance or employment. Some countries' organizations have agreed not to use this information.^[71] As with other genetic conditions with later onset and no treatment, it is ethically questionable to perform pre-symptomatic testing for a child or adolescent.^[9]^[72]^[73] There are opponents against permitting testing until individuals are cognitively mature, and defenders of the parents' right to make the decision; with much greater acceptance of the former position.^[9]^[72]^[73] Testing a person under legal age who is not judged as competent is considered unethical in most cases.^[9]^[72]^[73] The balance of opinion would change with an effective treatment.^[9]^[72]^[73] Abortion after prenatal genetic testing with positive results and preimplantation genetic diagnosis in order to ensure that the disorder is not passed on are not free of ethical concerns.^[74] Finally, research with embryonic stem cells is controversial in any disease.^[75]

Support organizations

The death of Woody Guthrie led his wife to found the Committee to Combat Huntington's Disease.

In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF); with the aim of curing genetic illness by coordinating and supporting research.^[12] The foundation; and especially his daughter, Nancy S. Wexler, were a key part of the research team in Venezuela which discovered the HD gene.^[12] Nancy Wexler is the current president of the Foundation.^[12] At the same time, Woody Guthrie's wife, Marjorie, had helped to found the Committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after his death from HD complications.^[76]^[76] Since then, lay organizations have been formed in many countries around the world and have helped to increase the awareness on HD. A number of these collaborate in larger organizations, like the International Huntington Association and the EuroHD network.^[77] Many support organizations hold an annual HD awareness event - some of which have been endorsed by their respective governments. For example, June 6 is designated "National Huntington's Disease Awareness Day" by the US senate.^[78]

Media depictions

The earliest references to HD in the popular media are made in Arlo Guthrie's 1969 film Alice's Restaurant^[79] and Jacqueline Susann's 1966 novel Valley of the Dolls. As awareness of HD has increased, so has the number of depictions in books, films and TV series, such as ER,^[80] Private Practice,^[81] Everwood,^[82] All Saints,^[83] House,^[84] and Steven T. Seagle's It's a Bird.^[85]

Research directions

Main article: Huntington's disease clinical research

Research into the mechanism has focused on identifying the functioning of HTT, how mHTT differs or interferes with it and the brain pathology that the disease produces.^[11] Most research is conducted in animals. Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.^[1] Mice and monkeys, chemically induced to exhibit HD like symptoms were initially used,^[1]^[86]^[87] but they did not mimic the progressive features of the disease. Since the Huntingtin gene was identified, transgenic animals (mice,^[1]^[88]^[89] Drosophila fruit flies,^[1]^[90] and more recently monkeys^[91]) exhibiting HD-like syndromes can be generated by inserting a CAG repeat expansion into the gene. Nematode worms also provide a valuable model when the gene is expressed.^[1]^[92]

Genetically engineered intracellular antibody fragments called intrabodies have shown therapeutic results preventing larval and pupal mortality in drosophila models. Their mechanism of action was an inhibition of mHTT aggregation.^[1]^[93]^[94] As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT in mice as a potential treatment.^[1]^[95]^[96] Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded some positive results in animal models and preliminary human clinical trials.^[97] All of these advances are at their first stages and there are important practical difficulties for the use of such techniques in humans.^[1]^[97]

Different drugs have also been reported to produce benefits in animals; some of them are being tested on humans in clinical trials at different stages of development.^[1] Examples of substances that have shown promise in initial experiments include creatine, coenzyme Q10 or the antibiotic minocycline.^[1]

References

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External links

Wikisource has original text related to this article:

On Chorea

DMOZ HD links directory at the Open Directory Project.
Huntington's Disease Outreach Project for Education, at Stanford (HOPES) - A layperson's guide to HD
Worldwide Education and Awareness for Movement Disorders - HD section

WHO ICD-10 mental and behavioral disorders (F · 290–319)

Neurological/symptomatic

Dementia (Alzheimer's disease, multi-infarct dementia, Pick's disease, Creutzfeldt–Jakob disease, Huntington's disease, Parkinson's disease, AIDS dementia complex, Frontotemporal dementia, Elopement, Sundowning, Wandering) · Delirium · Post-concussion syndrome · Organic brain syndrome

Psychoactive substance

alcohol (acute alcohol intoxication, drunkenness, alcohol dependence, alcoholic hallucinosis, Alcohol withdrawal, delirium tremens, Korsakoff's syndrome, alcohol abuse) · opioids (opioid overdose, opioid dependency) · sedative/hypnotic (benzodiazepine overdose, benzodiazepine dependence, benzodiazepine withdrawal) · cocaine (cocaine dependence) · general (Intoxication/Drug overdose, Drug abuse, Physical dependence, Rebound effect, Withdrawal)

Schizophrenia, schizotypal
and delusional

Psychosis (Schizoaffective disorder, Schizophreniform disorder, Brief reactive psychosis) · Schizophrenia (Disorganized schizophrenia, Delusional disorder, Folie à deux) · Personality disorder (Schizotypal personality disorder)

Mood (affective)

Mania · Bipolar disorder (Bipolar I, Bipolar II, Cyclothymia) · Depression (Major depressive disorder, Dysthymia, Seasonal affective disorder)

Neurotic, stress-related
and somatoform

Anxiety disorder/ adjustment disorder	phobic anxiety disorders: Agoraphobia · Social anxiety/Social phobia (Anthropophobia) · Specific phobia (Claustrophobia) Panic disorder/Panic attack · Generalized anxiety disorder · OCD · stress (Acute stress reaction, PTSD)

Somatoform disorder	Somatization disorder · Body dysmorphic disorder · Hypochondriasis · Nosophobia · Da Costa's syndrome · Psychalgia · Conversion disorder (Ganser syndrome, Globus pharyngis) · Neurasthenia

Dissociative disorder	Dissociative identity disorder · Psychogenic amnesia

Physiological/physical
behavioral

Adult personality
and behavior

Personality disorder · Impulse control disorder (Kleptomania, Trichotillomania, Pyromania) · Factitious disorder (Munchausen syndrome) · Ego-dystonic sexual orientation · Paraphilia (Voyeurism, Fetishism)

Mental disorders
diagnosed in childhood

Mental retardation

X-Linked mental retardation

Psychological development
(developmental disorder)

Specific	speech and language (expressive language disorder, aphasia, expressive aphasia, receptive aphasia, Landau–Kleffner syndrome, lisp) · Scholastic skills (dyslexia, dysgraphia, Gerstmann syndrome) · Motor function (developmental dyspraxia)

Pervasive	Autism · Rett syndrome · Asperger syndrome

Behavioral and emotional

ADHD · Conduct disorder (ODD) · emotional disorder (Separation anxiety disorder) · social functioning (Selective mutism, RAD, DAD) · Tic disorder (Tourette syndrome) · Speech (Stuttering, Cluttering) · Stereotypic movement disorder

Pathology of the nervous system, primarily CNS (G00–G47, 320–349)

Brain/
encephalopathy

Inflammatory

Encephalitis (Viral encephalitis, Herpesviral encephalitis) · Cavernous sinus thrombosis · Brain abscess (Amoebic)

Degenerative

Demyelinating

autoimmune (Multiple sclerosis, Neuromyelitis optica, Schilder's disease) · hereditary (Adrenoleukodystrophy, Alexander, Canavan, Krabbe, ML, Pelizaeus-Merzbacher, VWM, MFC, CAMFAK syndrome) · Central pontine myelinolysis · Marchiafava-Bignami disease · Alpers'

Episodic/
paroxysmal

CSF

Intracranial hypertension (Hydrocephalus/Normal pressure, Idiopathic intracranial hypertension) · Cerebral edema · Intracranial hypotension

Other

Brain herniation · Reye's · Hepatic encephalopathy · Toxic encephalopathy

Spinal cord/
myelopathy

Inflammatory	Myelitis: Poliomyelitis · Demyelinating disease (Transverse myelitis) · Tropical spastic paraparesis

Other	Syringomyelia · Syringobulbia · Morvan's syndrome · Vascular myelopathy (Foix-Alajouanine syndrome) · Spinal cord compression

Both/either

Inflammatory

Encephalomyelitis (Acute disseminated)

Meningitis/Arachnoiditis: Bacterial (Tuberculous, Haemophilus, Pneumococcal) · Viral (Herpesviral) · Fungal (Cryptococcal) · Aseptic (Drug-induced)

Meningoencephalitis

Systemic atrophies

SA	Friedreich's ataxia · Ataxia telangiectasia

MND	UMN only: PLS · PP · HSP LMN only: PMA · PBP (Fazio-Londe, Infantile progressive bulbar palsy) · SMA (SMN-linked, Kennedy disease, SMAX2, DSMA1) both: ALS

see also congenital, tumors

Non-Mendelian inheritance: anticipation

Trinucleotide repeat disorders

Polyglutamine (PolyQ)	Dentatorubral-pallidoluysian atrophy · Huntington's disease · Kennedy disease · Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease)

Non-Polyglutamine	Fragile X syndrome · Friedreich's ataxia · Myotonic dystrophy type 1 · Spinocerebellar ataxia 8, 12

Four nucleotides

Myotonic dystrophy type 2

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		Medical Encyclopedia. © 2006 through a partnership of Answers Corporation. All rights reserved. Read more
		Dictionary. The American Heritage® Dictionary of the English Language, Fourth Edition Copyright © 2007, 2000 by Houghton Mifflin Company. Updated in 2007. Published by Houghton Mifflin Company. All rights reserved. Read more
		Neurological Disorder. Gale Encyclopedia of Neurological Disorders. Copyright © 2005 by The Gale Group, Inc. All rights reserved. Read more
		Sci-Tech Encyclopedia. McGraw-Hill Encyclopedia of Science and Technology. Copyright © 2005 by The McGraw-Hill Companies, Inc. All rights reserved. Read more
		Britannica Concise Encyclopedia. Britannica Concise Encyclopedia. © 2006 Encyclopædia Britannica, Inc. All rights reserved. Read more
		Columbia Encyclopedia. The Columbia Electronic Encyclopedia, Sixth Edition Copyright © 2003, Columbia University Press. Licensed from Columbia University Press. All rights reserved. www.cc.columbia.edu/cu/cup/ Read more
		World of the Mind. The Oxford Companion to the Mind. Second Edition. Copyright © Oxford University Press, 2004. All rights reserved. Read more
		Wikipedia. This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Huntington's disease". Read more

Huntington's chorea

Contents

Signs and symptoms

Genetics

Genetic mutation

Inheritance

Mechanism

HTT function

Cellular changes due to mHTT

Macroscopic changes due to mHTT

Diagnosis

Clinical

Genetic

Embryonic

Differential diagnosis

Management

Prognosis

Epidemiology

History

Society and culture

Ethics

Support organizations

Media depictions

Research directions

References

External links