Huntington's disease
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Template:DiseaseDisorder infobox | }} Template:DiseaseDisorder infobox | }} Huntington's disease or Huntington's chorea (HD) is an inherited disorder characterized by abnormal body movements called chorea, and a reduction of various mental abilities. It takes its name from the Ohio physician George Huntington who first described it precisely in 1872. The incidence is 5 to 8 per 100,000.
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Symptoms and signs
Symptoms of the disorder include loss of cognitive ability (thinking, speaking), changes in personality, jerking movements of the face and body in general and unsteady walking. These symptoms develop into dementia and an advanced form of rapid jerking called chorea, the Greek word for dance.
The symptoms of Huntington’s disease occur gradually over time - there is no sudden loss of abilities and it is hard to determine when symptoms initially occur. One-half to three-fourths of the patients present abnormal movement or rigidity. The remainder of the patients present mental status changes, such as irritability, moodiness, or antisocial behavior. Most of the patients eventually exhibit chorea, which is jerky, random, uncontrollable, rapid movements. Typically, the abnormal movements begin at the extremities and then later progress.
Disease Associations
Woody Guthrie's wife, Marjorie Guthrie, helped found the Committee to Combat Huntington's Disease, after his death whilst suffering from HD, in 1967. This eventually became the Huntington's Disease Society of America. Since then lay organisations have been formed in many countries around the world.
Diagnosis
To determine if a patient has the initial symptoms a physical and/or psychological examination is required. Usually the uncontrollable movements are the first noticeable symptoms.
Pre-symptomatic testing is possible by means of a blood test which counts the number of repetitions of the gene. If this test is positive then the patient is considered 'at risk', this means that they are at risk from HD but haven't exhibited any symptoms yet. In-vitro and embryonic genetic screening are also possible, enabling sufferers the option of having children that are clear of the disease.
The full pathological diagnosis is established by neurological examination findings and/or demonstration of cell loss, especially in the caudate nucleus, supported by a cranial CT or MRI scan findings.
Pathophysiology
Degeneration of the caudate and the putamen (striatum) can be found. There is also neuronal loss and astrogliosis, as well as loss of medium spiny neurons, a GABAergic result. Intranuclear inclusions that stain for ubiquitin and huntingtin can be seen, as well as huntingtin in cortical neurites. Genetically, huntingtin is found on chromosome 4, as are CAG repeats. It is suspected that the cross-linking of huntingtin results in aggregates which are toxic, and can lead to dysfunction of the proteosome system. This mitochondrial dysfunction can lead to excitotoxicity and oxidative stress.
Linkage between CAG repeats (huntingtin) and mitochondrial failure, however, is far from clear. There is some evidence that aggregates may trap critical enzymes that are involved in energy metabolism.
Genetics
The causative gene for Huntington's disease, HD, one of the first genes identified to cause an inherited disease, is located on chromosome 4. Huntington's disease is inherited in an autosomal dominant fashion. That is, a recipient of the gene only needs one allele, from one parent, to inherit the disease. More often, genetic diseases are autosomal recessive, meaning that they need two alleles, one from each parent, to inherit the disease. The dominant nature of Huntington's disease increases the chance of the disease occurring in offspring. A parent who has the disorder has a 50% chance of passing on the gene to each child.
The product of this gene is a 348 kDa cytoplasmic protein called huntingtin. The continuous aggregation of huntingtin molecules in neuronal cells gives rise to cell death, especially in the frontal lobes and the basal ganglia (mainly in the caudate nucleus) by some unknown mechanism. Some think that the form of apoptosis is the splitting of the Lysosome so that the hydrolytic enzymes within are released. This will cause the cell membrane to be split and the cell to die. Huntingtin has a characteristic sequence of fewer than 40 glutamine amino acid residues (encoded by CAG trinucleotide repeats) in the normal form; the mutated huntingtin causing the disease has more than 40 residues. The severity of the disease is proportional to the number of extra residues.
When the gene has more than 35 repeats, the 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.[1] This is known as anticipation. Because age of onset and severity is correlated to repeat number, these also show aniticipation.
While theories as to how the mutation brings about disease remain diverse and speculative, researchers have identified many specific subcellular abnormalities associated with the mutant protein, 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 nanotube1 in vitro, and the mutated forms are long enough in principle to pierce cell membranes.
Treatment and Prevention
Current
There is no treatment to fully stop the progression of the disease. There are already treatments available to help reduce some disease symptoms, though some treatments aggravate other symptoms like bradykinesia and dystonia (very slow movement and stiffness). Beyond treatments that are available to control abnormal movements, other agents may help with emotional symptoms like antidepressants, sedatives, and tranquilizers.
Nutrition is an important part of treatment, most HD sufferers need an unusually high number of calories (3000-6000 calories a day) to maintain body weight,so a nutritionist's advice is needed.
Speech therapists can help by improving speech and swallowing methods, this advice should be sought early as the ability to learn new things is reduced as the disease progresses.
When swallowing becomes hazardous the option of using a stomach PEG for intake of nutrients is often chosen, this reduces the chances of pnuemonia due to aspiration of food.
Prospective
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.[2]
Calorie Restriction
It has been shown that a calorie restrictive (CR) diet delays the onset of symptoms in HD mice[3].
Omega-III EPA
Candidate treatments to slow the progression of the disease are under study, yet have been slow to reach HD sufferers. EPA, an Omega-III fatty acid, has been shown to slow and possibly reverse the progression of the disease. It is currently in FDA clinical trial, as Miraxiom© (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.
Others
According to initial research, other agents and measures might also slow the progress of Huntingon's. They include dopamine receptor blockers, creatine, CoQ10, the antibiotic Minocycline, Trehalose, 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. Research is underway on all these and other approaches that have shown some promise in various experimental models. This research is reviewed on various websites for Huntington's patients 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.
In 2004 it was found that a simple sugar called trehalose can alleviate symptoms in genetically modified mice.
Pig cell implants in Huntington's Disease trial: Living Cell Technologies in New Zealand has attempted trials with positive results in primates World health Article, but is yet to conduct a human trial.
There is a vast amount of research and clinical trials of various treatment. For example the US registar of trials has 79 ongoing trials and about 300 past trials (see HD clinical trials ).
Prognosis
Onset of Huntington's disease seems to be correlated to the number of CAG repeats a person has in the their HD gene. Generally, the higher the number of repeats the sooner onset is.[4] 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 patients in their mid 30s to their mid 40s.
About 10 percent of Huntington's disease cases occur in people under the age of 20 years and is called juvenile Huntington’s disease. It has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are very different from those of adult-onset HD and is generally more rapidly progressive. Individuals with juvenile HD often become stiff or rigid in their movements (instead of having chorea). Any case of HD with an onset before the age of 20 is considered to be the juvenile form.
Mortality is due to complications resulting from Huntington's Disease rather than the disease itself and is usually 10 to 25 years after the onset of neurological and psychological impairment.
Ethical aspects
Huntington's disease presents individuals and families with several dilemmas:
- Testing for the presence of the disease
- Whether to have children
- Informing children with an HD positive parent that they are at risk
- Coping with the discovery of the disease in a family member.
- Testing of grandchildren of a sufferer has serious ethical implications if their parent declines testing, a positive result in a grandchild's test automatically diagnoses the parent.
- Coping with the social and personal impacts of significant impairment of memory.
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).
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.
Parents and grandparents recently discovered to possess the disease are left with the question of when and how to tell their children and grandchildren. It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.
History
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.
One of the early medical descriptions of Huntington's disease 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.
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 where linked and set about describing it. His definiton of the disease in 1872 is still largely accurate.
Research Landmarks
- 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 The general location of the gene is found using DNA marking methods for the first time - an important first step toward the Human Genome Project.
- 1993 The Huntington's Disease Collaborative Research Group isolates the actual gene.
- 1996 A transgenic mouse was created that could be made to exhibit HD greatly advancing how much experimentation can be achieved.
The full record of research is extensive.[5][6]
References
1. Perutz, M.F., J.T. Finch, J. Berriman, and A. Lesk. (2002) Amyloid fibers are water-filled nanotubes. Proceedings of the National Academy of Sciences, 99: 5591-5595.
External links
- Huntington's Disease Support Club
- Australian Huntington's Disease Association (NSW) Inc.
- Huntington's Disease Lighthouse
- Huntington's Disease Society of America
- European HD Network
- Huntington's Disease Association UK
- Hereditary Disease Foundation
- HDF Everest 2005 Expedition
- Living Cell Technologies
- Huntington's Disease Research - Recent research abstracts on Huntington's Disease.
- Huntington Disease; HD (143100), Online Mendelian Inheritance in Man, Johns Hopkins University
- Stanford University HOPES
- Huntington Project
- Huntington Study Groupde:Chorea Huntington
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