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Huntington's disease

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Huntington's disease
   Classifications and external resources

   George Huntington, wrote a paper describing the disease in 1872.
   ICD- 10 G 10.
   ICD- 9  333.4
    OMIM   143100

   CAPTION: Dementia in Huntington's disease
   Classifications and external resources

   ICD- 10 F 02.2
   ICD- 9  294.1

   Huntington's disease (HD), also known as Huntington disease and
   previously as Huntington's chorea and chorea maior, is a rare inherited
   neurological disorder affecting up to 8 people per 100,000. It takes
   its name from the Ohio physician George Huntington who described it
   precisely in 1872 in his first medical paper. HD has been heavily
   researched in the last few decades and it is one of the first inherited
   genetic disorders for which an accurate test can be performed.

   HD is caused by a trinucleotide repeat expansion in the Huntingtin
   (Htt) gene, and is one of several polyglutamine (or PolyQ) diseases.
   This produces an extended form of the mutant Huntingtin protein (mHtt),
   which causes cell death in selective areas of the brain.

   HD's most obvious symptoms are abnormal body movements called chorea
   and lack of coordination, but it also affects a number of mental
   abilities and some aspects of personality. These physical symptoms
   commonly become noticable in a person`s forties, but can occur at any
   age. If the age of onset is below 20 years then it is known as Juvenile
   HD. Being a genetic disorder, there is currently no cure, but the
   symptoms are managed with medication and appropriate care.

Signs and symptoms

   There is no sudden loss of abilities or exhibition of symptoms, but
   there is a progressive decline, and some symptoms may disappear as the
   disease progresses. Physical signs are usually the first noticed, but
   it is unknown how long before this that cognition and psychiatric
   condition are affected. Physical symptoms are almost always shown,
   cognitive symptoms are exhibited differently from person to person, and
   psychiatric problems may not be evident at all. The list of possible
   symptoms are:

Physical

   Most people with HD eventually exhibit chorea, which is jerky, random,
   uncontrollable, rapid movements, although some exhibit very slow
   movement and stiffness ( bradykinesia, dystonia). These abnormal
   movements gradually increase as the disease progresses, initially
   exhibited as general lack of coordination and an unsteady gait. This
   causes problems with loss of facial expression (called "masks in
   movement") or exaggerated facial gestures, ability to sit or stand
   stably, speech, chewing and swallowing (which can lead to weight loss
   if diet or eating methods aren't adjusted accordingly), and loss of
   continence. In the latter stages of the disease, speaking, eating and
   mobility unassisted are extremely difficult, if not impossible, and
   full-time care is required.

Cognitive

   Selective cognitive abilities are progressively impaired, whereas
   others remain intact. Abilities affected are executive function
   (planning, cognitive flexibility, abstract thinking, rule acquisition,
   initiating appropriate, and inhibiting inappropriate, actions),
   psychomotor function (slowing of thought processes to control muscles),
   speech (but not actual language skills), perceptual and spatial skills
   of self and surrounding environment, selection of correct methods of
   remembering information ( but not actual memory itself), and ability to
   learning new skills depending on the affected parts of the brain.

Psychiatric

   These vary more than cognitive and physical symptoms, and may include
   anxiety, depression, a reduced display of emotions called blunting,
   egocentrism, aggressive behaviour, compulsivity which can cause
   addictions such as alcoholism and gambling, or hypersexuality.

Causes

   HD is inherited in an autosomal dominant fashion.
   Enlarge
   HD is inherited in an autosomal dominant fashion.

   The gene involved in HD, called the HD gene, is located on the short
   arm of chromosome 4 (4p16.3). The end of the HD gene has a sequence of
   three DNA bases, cytosine- adenine- guanosine (CAG), that is repeated
   multiple times (i.e. ...CAGCAGCAG...), this is called a trinucleotide
   repeat. CAG is the codon for the amino acid glutamine. A sequence of
   fewer than 40 glutamine amino acid residues is the normal form,
   producing a 348  kDa cytoplasmic protein called huntingtin (Htt). More
   repeats, of CAG, than this and a mutated form of Htt that causes the
   disease, mHtt, is produced. The continuous build up of the mHtt
   molecules in neuronal cells causes them to die off in selected regions
   of the brain. The speed of cell degeneration is generally proportional
   to the number of extra CAG repeats, also causing earlier onset of
   symptoms.

   Commonly, genetic disorders are autosomal recessive, meaning that they
   need an affected allele from each parent to inherit the disorder, which
   is a one in four chance. HD is autosomal dominant, needing only one
   affected allele from either parent, to inherit the disease, which means
   there is a one in two chance of inheriting the disorder from an
   affected parent.

   When the gene has more than 35 copies of the repeated trinucleotide
   sequence, the DNA replication process becomes unstable and the number
   of repeats can change in successive generations. If the gene is
   inherited from the mother the count is usually similar, but tends to
   increase if inherited from the father. Because of the progressive
   increase in length of the repeats, the disease tends to increase in
   severity and have an earlier onset in successive generations. This is
   known as anticipation.

Mechanism

   The continuous build up of mHtt molecules in neuronal cells causes cell
   death, especially in the frontal lobes and the basal ganglia (mainly in
   the caudate nucleus). Degeneration of the striatum (a part of the brain
   consisting of the caudate nucleus and the putamen) can be found. There
   is also neuronal loss and astrogliosis, as well as loss of medium spiny
   neurons, a GABAergic (the chief inhibitory neurotransmitter in the
   vertebrate central nervous system) result. This results in the
   selective degeneration of the indirect (inhibitory) pathway of the
   basal ganglia, via the lateral pallidum and the subthalamic nucleus
   coupled pacemaker system. Intranuclear inclusions that stain for
   ubiquitin and Htt can be seen, as well as Htt in cortical neurites.

   It is suspected that the cross-linking of Htt results in aggregates
   which are toxic, causing a mitochondrial dysfunction in the proteasome
   system, leading to neurons being damaged by excitotoxicity and
   oxidative stress.

   The exact link between CAG repeats that produce mHtt and mitochondrial
   failure is unknown. There is evidence that aggregates may trap critical
   enzymes that are involved in energy metabolism. Some think that the
   cause of cell death is the splitting of the lysosome so that the
   hydrolytic enzymes within it are released. This will cause the cell
   membrane to split and the cell to die.

   While theories as to how the mutation brings about disease remain
   diverse and speculative, researchers have identified many specific
   subcellular abnormalities associated with mHtt, as well as unusual
   properties of the protein in vitro. Just as one example, in 2002, Max
   Perutz, et al discovered that the glutamine residues form a nanotube in
   vitro, and the mutated forms are long enough in principle to pierce
   cell membranes.

   In the June 16, 2006 issue of Cell, scientists at the University of
   British Columbia (UBC) and Merck Labs presented findings that the
   neurodegeneration caused by mHtt is related to the caspase-6 enzyme
   cleaving the Htt protein. Transgenic mice that have caspase-6 resistant
   Htt did not show effects of HD. The researchers found "substantial
   support for the hypothesis that cleavage at the caspase-6 site in mHtt
   represents a crucial rate-limiting event in the pathogenesis of HD....
   Our study highlights the importance of preventing cleavage of htt at
   this site and also reinforces the importance of modulating
   excitotoxicity as a potential therapeutic approach for HD." In essence,
   scientists have managed to prevent the appearance of HD in genetically
   modified mice. Dr. Marian DiFiglia, a world-renowned HD researcher and
   neurobiologist at Harvard University, called this find "very important"
   and "extremely intriguing". and embryonic genetic screenings are also
   possible, giving gene-positive or at-risk individuals the option of
   making sure their children will be clear of the disease. Expense and
   the ethical considerations of abortion are potential drawbacks to these
   procedures. The full pathological diagnosis is established by a
   neurological examination's findings and/or demonstration of cell loss,
   especially in the caudate nucleus, supported by a cranial CT or MRI
   scan findings.

Management

   There is no treatment to fully stop the progression of the disease, but
   symptoms can be reduced or alleviated through the use of correct
   medication and care methods.

Medication

   There are treatments available to help control the chorea, although
   these may have the side effect of aggravating bradykinesia or dystonia.

   Other standard treatments to alleviate emotional symptoms include the
   use of antidepressants and sedatives, with antipsychotics (in low
   doses) for psychotic symptoms. Care needs to be taken with
   antipsychotic usage as people suffering psychotic symptoms of organic
   origin are often more sensitive to the side effects of these drugs.

Nutrition

   Nutrition is an important part of treatment; most HD sufferers need two
   to three times the calories than the average person to maintain body
   weight, so a nutritionist's advice is needed (average daily intake is
   approximately 2000 calories for women and 2500 for children and men).

   Speech therapy can help by improving speech and swallowing methods.
   This advice should be sought early on, as the ability to learn is
   reduced as the disease progresses.

   To aid swallowing, thickener can be added to drinks. The option of
   using a stomach PEG is available when eating becomes too hazardous or
   uncomfortable, this will reduce the chances of pnuemonia due to
   aspiration of food and increase the amount of nutrients and calories
   that can be ingested.

   EPA, an Omega-III fatty acid, slows and possibly reverses the
   progression of the disease. It is currently in FDA clinical trial, as
   Miraxion© (LAX-101), for prescription use. Clinical trials utilize
   2 grams per day of EPA. In the United States, it is available over the
   counter in lower concentrations in Omega-III and fish oil supplements.

   A calorie restrictive diet delays the onset of symptoms in HD mice.

Potential Treatments

   Trials and research are conducted on Drosophila fruit flies and mice
   that have been genetically modified to exhibit HD, before moving on to
   human trials.

   Research is reviewed on various websites for HD sufferers and their
   families, including the Huntington's Disease Lighthouse, Hereditary
   Disease Foundation, and Stanford HOPES websites. Primary research can
   be found by searching the National Library of Medicine's PubMed.
   Clinical trials of various treatments are ongoing, or yet to be
   initiated. For example, the US registrar of trials has nine that are
   currently recruiting volunteers.

Gene silencing

   The most hopeful prospective treatment currently studied is based on
   gene silencing. Since HD is caused by expression of a single gene,
   silencing of the gene could theoretically halt the progression of the
   disease. One study with a mouse model of HD treated with siRNA therapy
   achieved 60% knockdown in expression of the defective gene. Progression
   of the disease halted. Full recovery of motor function is observed in
   late stage Tet/HD94 mice after addition of doxycycline.

Others

   Other agents and measures that have shown promise in initial
   experiments include dopamine receptor blockers, creatine, CoQ10, the
   antibiotic Minocycline, exercise, antioxidant-containing foods and
   nutrients, antidepressants (notably, but not exclusively, selective
   serotonin reuptake inhibitors SSRIs, such as sertraline, fluoxetine,
   and paroxetine) and select Dopamine antagonists, such as Tetrabenazine.

   Pig cell implants in HD trial: Living Cell Technologies in New Zealand
   has attempted trials with positive results in primates, but is yet to
   conduct a human trial.

   The Folding@home project is the second largest distributed processing
   project on the internet. It models protein folding and HD is listed
   amongst the potential benefactors of its results.

Prognosis

   Onset of HD seems to be correlated to the number of CAG repeats a
   person has in their HD gene. Generally, the higher the number of
   repeats the sooner onset is. The number of repeats may change slightly
   with each successive generation, so that the age of onset may vary as
   well. Symptoms of Huntington’s disease usually become noticeable in the
   mid 30s to mid 40s.

   Juvenile HD has an age of onset anywhere between infancy and 20 years
   of age. The symptoms of juvenile HD are different from those of
   adult-onset HD in that they generally progress faster and are more
   likely to exhibit rigidity and bradykinesia (very slow movement)
   instead of chorea.

   Mortality is due to infection (mostly pneumonia), fall-related
   injuries, other complications resulting from HD, or suicide (The
   suicide rate for HD sufferers is much greater than the national
   average.), rather than the disease itself. Life expectancy is generally
   between 10 and 25 years after the onset of obvious symptoms.

Epidemiology

   The prevalence is 5 to 8 per 100,000, varying geographically.

   About 10 percent of HD cases occur in people under the age of 20 years.
   This is referred to as Juvenile HD, "akinetic-rigid", or "Westphal
   variant" HD.

Ethical aspects

   Whether or not to have the test for HD. Genetic counseling may provide
   perspective for those at risk of the disease. Some choose not to
   undergo HD testing due to numerous concerns (for example,
   insurability). Testing of grandchildren of a sufferer has serious
   ethical implications if their parent declines testing, as a positive
   result in a grandchild's test automatically diagnoses the parent.
   Parents and grandparents have to decide when and how to tell their
   children and grandchildren. The issue of disclosure also comes up when
   siblings are diagnosed with the disease, and especially in the case of
   identical twins. It is not unusual for entire segments of a family to
   become alienated as a result of such information or the withholding of
   it.

   For those at risk, or known to have the disease, consideration is
   necessary prior to having children due to the genetically dominant
   nature of the disease. In vitro and embryonic genetic screening now
   make it possible (with 99% certainty) to have an HD-free child;
   however, the cost of this process can easily reach tens of thousands of
   dollars. Financial institutions are also faced with the question of
   whether to use genetic testing results when assessing an individual,
   e.g. for life insurance. Some countries organizations have already
   agreed not to use this information.

History

Research and Discovery

     * c300 There is evidence that doctors as far back as the Middle Ages
       knew of this disease. It was known, amongst other conditions with
       abnormal movements, as St Vitus dance. St Vitus is the Christian
       patron saint of epileptics who was martyred in 303.
     * Middle ages. People with the condition were often persecuted as
       being witches or as being possessed by spirits, and were shunned,
       exiled or worse. Some speculate that the "witches" in the Salem
       Witch Trials in 1692 had HD.
     * 1860 One of the early medical descriptions of HD was made in 1860
       by a Norwegian district physician, Johan Christian Lund. He noted
       that in Setesdalen, a remote and rather secluded area, there was a
       high prevalence of dementia associated with a pattern of jerking
       movement disorders that tended to run in families. This is the
       reason for the disease being commonly referred to as
       Setesdalsrykkja (Setesdalen=the location, rykkja=jerking movements)
       in Norwegian.
     * 1872 George Huntington was one of three generations of medical
       practitioners in Long Island. With their combined experience of
       several generations of a family with the same symptoms, he realised
       their conditions were linked and set about describing it. A year
       after leaving medical school , in 1872, he presented his accurate
       definition of the disease to a medical society in Middleport, Ohio.
     * c1923 Smith Ely Jelliffe (1866-1945) and Frederick Tilney
       (1875-1938) began analyzing the history of HD sufferers in New
       England.
     * 1932 P. R. Vessie expanded Jelliffe and Tilney's work, tracing
       about a thousand people with HD back to two brothers and their
       families who left Bures in Essex for Suffolk bound for Boston in
       1630.

     * 1979 The U.S-Venezuela Huntington's Disease Collaborative Research
       Project began an extensive study which gave the basis for the gene
       to be discovered. This was conducted in the small and isolated
       Venezuelan fishing village of Barranquitas. Families there have a
       high presence of the disease, which has proved invaluable in the
       research of the disease.
     * 1983 Professor Wexler, James Gusella, David Housman, P. Michael
       Conneally and their colleagues find the general location of the
       gene, using DNA marking methods for the first time - an important
       first step toward the Human Genome Project.
     * 1992 Anita Harding,et al. find that trinucleotide repeats affect
       disease severity
     * 1993 The Huntington's Disease Collaborative Research Group isolates
       the precise gene at 4p16.3.
     * 1996 A transgenic mouse was created that could be made to exhibit
       HD greatly advancing how much experimentation can be achieved.
     * 1997 Researchers discovered that mHtt bunches up ( mis folds) to
       form nuclear inclusions.
     * 2001 Christopher Ross and his team at Johns Hopkins University
       described how mHtt causes the death of cells.

   The full record of research is extensive.

Relevant organizations

     * 1967 Woody Guthrie's wife, Marjorie Guthrie, helped found the
       Committee to Combat Huntington's Disease, after his death whilst
       suffering from HD. This eventually became the Huntington's Disease
       Society of America. Since then, lay organizations have been formed
       in many countries around the world.
     * 1968 After experiencing HD in his wife's family, Dr. Milton Wexler
       was inspired to start the Hereditary Disease Foundation (HDF).
       Professor Nancy S. Wexler, Dr. Wexler's daughter, was in the
       research team in Venezeula and is now president of the HDF.
     * 1974 the first international meeting took place when the founders
       of the Canadian HD Society (Ralph Walker) and of the British HD
       Society (Mauveen Jones) attended the annual meeting of the American
       HD Society
     * 1977 second meeting organized by the Dutch Huntington Society the
       "Vereniging van Huntington", representatives of six countries were
       present.
     * 1979 International Huntington Association (IHA) formed during
       international meeting in Oxford (England) organized by HDA of
       England.
     * 1981-2001 Biennial meetings held by IHA which became the World
       Congress on HD.
     * 2003 the first World Congress on Huntington's Disease was held in
       Toronto. This is a biennial meeting for associations and
       researchers to share ideas and research, which is held on
       odd-number years. The Euro-HD Network was started as part of the
       Huntington Project, funded by the High-Q Foundation.

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