Huntington's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Huntington's Disease, including details on genetics, causes, symptoms, treatment.

Huntington's disease (HD), known historically as Huntington's chorea and chorea major, is a rare genetic neurological disorder inherited by approximately 3 to 7 per 100,000 people of Western European descent, varying geographically, down to 1 per 1,000,000 of Asian and African descent.^[1] The name is derived from the physician George Huntington who described it precisely in 1872. The disorder has been heavily researched in the last few decades and it was one of the first inherited genetic disorders for which an accurate test could be performed.

Huntington's disease is caused by a trinucleotide repeat expansion in the Huntingtin gene, which codes for Huntingtin protein, denoted "Htt". (Note: these names are spelled with an 'i' in place of the 'o'). Huntington's disease is one of several polyglutamine diseases. This expansion produces an altered form of the Htt protein, called mutant Huntingtin (mHtt), resulting in neuronal cell death in select areas of the brain. Huntington's disease itself is not a terminal illness, but life expectancy is reduced due to complications caused by its symptoms.

Huntington's disease's most obvious symptoms are abnormal body movements called chorea and a lack of coordination, but it also affects a number of mental abilities and some aspects of behavior. Physical symptoms occur in a large range of ages around a mean occurrence of late forties/early fifties, but if they occur before the age of 20 then the condition is known as Juvenile HD. As there is currently no proven cure, symptoms are managed with various medications and supportive services.

Symptoms

On-set of symptoms does not occur suddenly, but they increase in severity progressively, often becoming noticeable, in stages. Physical signs are quite often the first noticed, with cognitive and psychiatric deficits sometimes manifesting subsequently. However, in many cases psychiatric changes which preempt the physical are overlooked. Physical symptoms are almost always visible; cognitive symptoms which can lead to psychopathological problems exhibit differently from person to person.

Physical

Most people with Huntington's Disease eventually exhibit jerky, random, and uncontrollable movements called chorea, although some exhibit very slow movement and stiffness (bradykinesia, dystonia). These abnormal movements are initially exhibited as general lack of coordination and an unsteady gait and gradually increase as the disease progresses; this eventually causes problems with loss of facial expression (called "masks in movement") or exaggerated facial gestures, inability to walk, sit or stand stably, speech, chewing and swallowing (Dysphagia) which commonly causes weight loss.^[2][3] In the later stages of the disease, speaking is impaired with slurred words and uncontrollable movements of the mouth, continence, eating and mobility are extremely difficult if not impossible.

Cognitive

Selective cognitive abilities are progressively impaired, including: executive function (planning; cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions, and inhibiting inappropriate actions), psychomotor function (slowing of thought processes to control muscles), speech (slurring of words) and some uncontrollable movement of the lips, perceptual and spatial skills of self and surrounding environment, selection of correct methods of remembering information (but not actual memory itself), short-term memory, and ability to learn new skills, depending on the pathology of the individual.

Psychopathological

Psychopathological symptoms vary more than cognitive and physical symptoms, and may include anxiety, depression, a reduced display of emotions (blunted affect) and decreased ability to recognize negative expressions like anger, disgust, fear or sadness in others^[4], egocentrism, aggressive behavior, and compulsivity. The latter can cause or worsen addictions such as alcoholism and gambling, or hypersexuality.

Genetics

Main article: Trinucleotide repeat disorders

The gene involved in Huntington's disease, called Huntingtin (HTT) or Interesting Transcript 15 (IT15) gene and historically as the HD gene, is located on the short arm of chromosome 4 (4p16.3). In the first part (5'end) of the HD gene, there is a sequence of three DNA bases, cytosine-adenine-guanine (CAG), that is repeated multiple times (i.e. ...CAGCAGCAG...); this is called a trinucleotide repeat. CAG is the genetic code for the amino acid glutamine, thus a series of CAG forms a chain of glutamine known as polyglutamine or (polyQ).

A polyQ length of less than 33 glutamines, produces a cytoplasmic protein called huntingtin protein (Htt), whereas a sequence of 36 or more produces an erroneous form of Htt, mHtt (standing for mutant Htt). Counts between these two have not been fully understood, and sometimes result in HD.^{[citation needed]}

Having mHtt instead of Htt causes certain neurons in select areas of the brain to have an increased mortality, progressively interfering with their functioning. Generally, but not always, the greater the number of CAG repeats, the earlier the onset of symptoms.^[5]

Inheritance

Huntington's disease is autosomal dominant, needing only one affected allele from either parent to inherit the disease. Although this generally means there is a one in two chance of inheriting the disorder from an affected parent, the inheritance of HD is more complex due to potential dynamic mutations, which can cause the number of repeats to change in successive generations. This can mean that a parent with a count close to the threshold, may pass on a gene with a count either side of the threshold.

Repeat counts maternally inherited are usually similar, whereas paternally inherited ones tend to increase.^[6] The progressive increase in repeats, increases the severity and reduces the age of onset in successive generations, known as anticipation.

New mutations, in which neither parent has HD, are rare.

Homozygous individuals (where both parents have HD) generally do not show an earlier onset of disease, but may have an increased rate of decline.

Mechanism

See also: Huntingtin protein

Like all proteins, Htt and mHtt are translated, perform or affect biological functioning, and are finally cleared up in a process called degradation. The exact mechanism in which mHtt causes or affects the biological processes of DNA replication and programmed cell death (apoptosis) remains unclear, so research is divided into identifying the functioning of Htt, how mHtt differs or interferes with it, and the proteopathic effects of remnants of the protein (known as aggregates) left after degradation.

Function

Htt is involved in vesicle trafficking as it interacts with HIT1, a clathrin binding protein, to mediate endocytosis, the absorption of materials into a cell.^[7][8]

mHtt reduces the production of brain-derived neurotrophic factor (BDNF) which protects neurons in the striatum.^[9] This loss of BDNF may contribute to striatal cell death, which does not follow apoptotic pathways as the neurons appear to die of starvation.^[10]

Degradation

Both Htt and mHtt are cleaved (the first step in degradation) by Caspase-3, which removes the (amino end) N-terminal.^[11] Caspase-2 then further breaks down the amino terminal fragment ( the CAG repeat part) of Htt, but cannot act upon all of the repeats of mHtt.^[12] These repeats left in the cell, called aggregates or N-fragments, are able to affect polyQ dependent transcription.^[13] Specifically, mHtt binds with TAF_II130, a coactivator to CREB dependent transcription.^[14] The aggregates also interact with SP₁, thereby preventing it from binding to DNA,the normal functioning of these proteins.^[15]

In transgenic mice neurodegeneration caused by mHtt is related to the caspase-6 enzyme cleaving the Htt protein, as they did not show effects of HD in experiments.^[16]

In genetically altered "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease.^[17] Aggregates of mHtt are present in the brains of both HD patients^[18] and HD mice,^[19] and are most prevalent in cortical pyramidal neurones, less so in striatal medium-sized spiny neurones and almost absent in most other brain regions including hippocampus and cerebellum ^[18][20][21] These aggregates consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the cytoplasm and nucleus of neurons.^[22] The presence of these aggregates however does not correlate with cell death.^[23] Thus mHtt acts in the nucleus but does not cause apoptosis through aggregation.^[24]

Pathophysiology

Degeneration of neuronal cells, especially in the frontal lobes and caudate nucleus (the striatum) of the basal ganglia occurs. There is also astrogliosis and loss of medium spiny neurons. 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.

In more detail, the neurological changes involved with Huntingtons are as follows. Inside the brain, the initiation of motion is sent down the spinal cord from the primary motor areas, which in turn have received signals from the other regions that deal with motor function. At the same time that the stimulus is being sent down the spinal cord, the subthalamic nuclei of the striatum excite the internal globus pallidus. In a normally functioning individual, the signal would fully inhibit the internal globus pallidus, which would in turn inhibit the thalamus and modulate motion. The problem in Huntington's disease is that the subthalamic nuclei no longer generate enough excitation to the internal globus pallidus. The globus pallidus thus sends an abnormally weak inhibitory signal to the thalamus. The thalamus in turn then sends a strong excitatory signal to the putamen. The end result is a lack of modulation via two pathways, direct and indirect. All signals inside the striatum are too weak to inhibit the appropriate target regions. The only exception is the external globus pallidus, which over- inhibits when signalled, and alters the flow of excitation from the subthalamic nuclei, contributing to the lowered function and loss of movement control. This creates the characteristic jerky uncontrolled movement.

Diagnosis

To determine whether initial symptoms are evident, a physical and/or psychological examination is required. The uncontrollable movements are often the symptoms which cause initial alarm and lead to diagnosis; however, the disease may begin with cognitive or emotional symptoms, which are not always recognized. Pre-symptomatic testing is possible by means of a blood test which counts the number of repetitions in the gene.

A negative blood test means that the individual does not carry the expanded copy of the gene, will never develop symptoms, and cannot pass it on to children. A positive blood test means that the individual does carry the expanded copy of the gene, will develop the disease, and has a 50% chance of passing it on to children. A pre-symptomatic positive blood test is not considered a diagnosis, because it may be decades before onset.

Because of the ramifications on the life of an at-risk individual, with no cure for the disease and no proven way of slowing it, several counseling sessions are usually required before the blood test. Unless a child shows significant symptoms or is sexually active or considered to be Gillick competent, children under eighteen will not be tested. The members of the Huntington's Disease Society of America strongly encourage these restrictions in their testing protocol. A pre-symptomatic test is a life-changing event and a very personal decision.

For those living in America, there is a list of testing centers available on the HDSA homepage^[25] and embryonic genetic screening is also possible, giving mutation-positive or at-risk individuals the option of making sure their children will not inherit the disease. Expense and the ethical considerations of abortion are potential drawbacks to these procedures. A full pathological diagnosis can only be 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.

It is possible to test an embryo either in the womb (prenatal diagnosis) or to ensure a child will not have HD by utilising in vitro fertilisation and testing before implantation.

Management

There is no treatment to fully arrest the progression of the disease, but symptoms can be reduced or alleviated through the use of medication and care methods. Huntington mice models exposed to better husbandry techniques, especially better access to food and water, lived much longer than mice that were not well cared for.^{[citation needed]},

Medication

Other standard treatments to alleviate emotional symptoms include the use of antidepressants and sedatives, with antipsychotics (in low doses) for psychotic symptoms.

Nutrition

Nutrition is an important part of treatment; most HD sufferers need two to three times the calories of the average person to maintain body weight^[26], so a nutritionist's consultation is often helpful.

Speech therapy helps by improving speech and swallowing methods, this therapy is more effective if started early on, as the ability to learn is reduced as the disease progresses.

Thickening agent can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. The option of using a stomach PEG is available when eating becomes too hazardous or uncomfortable, this greatly reduces the chances of aspiration of food, and the subsequent increased risk of pneumonia, and increases the amount of nutrients and calories that can be ingested.

EPA, an Omega-3 fatty acid, slows and possibly reverses the progression of the disease.^{[citation needed]},^[27] It is currently in FDA clinical trial, as Miraxion (LAX-101), for prescription use. Clinical trials utilise 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-3 and fish oil supplements.

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 clinical trials. There are trials of various compounds that are in development, currently in progress or have been completed, some to the point of testing on larger numbers of people, known as phase III of the trials. The US registrar of trials has several trials that are currently recruiting volunteers.^[28]

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.

Intrabody Therapy

Engineered intracellular antibody fragments (intrabodies) have shown efficacy in vivo as therapeutic agents against pathogenic mutant huntingtin protein in fly models of HD. An intracellularly expressed single-chain Fv against the amino-terminal end of mutant huntingtin (mHtt) has been shown to reduce mHtt aggregate formation and increase turnover of the mHtt fragments in tissue culture models of HD.^[29][30] In a drosophila HD model, the expression of this anti-HD intrabody rescued fly survival through the larval and pupal stages to adult emergence. Additionally, the intrabody delayed neurodegeneration in the fly model, and significantly increased the mean adult lifespan.^[31] The engineered antibody approach shows promise as a tool for drug discovery and as a potential novel therapeutic for other neurodegenerative disorders resulting from protein misfolding or abnormal protein interactions, including Parkinson’s, Alzheimer’s and prion diseases.^[32]

Gene silencing

The pathology of HD has been conclusively linked to a single gene, researchers have investigated using gene knockdown of mHtt as a potential treatment. Using a mouse model of HD, siRNA therapy achieved a 60 percent reduction in expression of the mHtt and progression of the disease was stalled.^[33] In another study, mouse models in late stages of the disease recovered motor function after expression of mHtt was shut down.^[34]

Stem Cell Implants

This treatment is based on the replacement of damaged neurons by injecting stem cells (a type of cell that can form itself into a specialized cell) into the damaged area. If enough damaged neurons are replaced, symptoms should be alleviated. This treatment would not prevent further neuronal damage. Experiments have yielded some positive results in animal models. ^[35]

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.

Prognosis

Development of Huntington’s disease is highly CAG repeat length-dependent. In the normal population, the CAG repeat is of between 7 and 35 repeats. Individuals carrying more than approximately 40 repeats will, however, go on to develop the disease at some point within their lifetime ^[36]. The age of onset (and to a degree the severity of the disease) and hence the age at death, are inversely correlated with the length of the expanded CAG repeat, such that those with longer repeats develop the disease earlier. Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease ^[37]. There is a large variation in age of onset for any given CAG repeat length within the intermediate range (40-50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age (North American and Canadian population). This variation means that, although logarithmic algorithms have been proposed for predicting the age of onset (for example see ^[38],^[39]), in reality predicting the precise age at which clinical signs will manifest is not practical.

Juvenile HD has been defined as having an onset younger than 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 instead of chorea and often include seizures^[40].

Following the onset of obvious physical diagnosis of the disorder, life expectancy is generally a further 15 to 20 years ^[41]. Death, however, is not caused by Huntington’s disease per se, but rather by associated complications, these include pneumonia (which causes one third of fatalities), heart failure (although heart disease, cerebrovascular disease and atherosclerosis show no increase), choking and nutritional deficiencies^[42]. Suicide is an associated risk, with suicide rates of up to 7.3 percent; four times that of the general population ^[43][44]. Suicide, in general, is likely to be underestimated; reports, which have accounted for this, estimate up to 27 percent of possibly affected individuals attempt suicide. ^[45]

Social impact

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 a descendant of a person, who is 'at-risk', has serious ethical implications as a positive result automatically diagnoses one of the parents.

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.

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 percent certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars.

Huntington's disease was one of the targets of the eugenics movement, for example the American scientist Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be aimed at those afflicted with HD (among other diseases)^[46]

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' organisations have already agreed not to use this information.

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.

History

In the first part of the twentieth century and earlier, many people with HD were misdiagnosed as suffering from alcoholism or manic depression. Previously mortality due to starvation or dehydration was a major risk.

Research and discovery

• c. 300: Along with other conditions with abnormal movements, it may have been referred to as St Vitus' dance. St Vitus is the patron saint of epileptics who was martyred in 303.
• Middle Ages: People with the condition were probably 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.^[47]
• 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 the third generation of a family medical practice 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.
• c. 1923: 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 villages of Barranquitas and Lagunetas. Families there have a high presence of the disease.
• 1983: James Gusella, David Housman, P. Michael Conneally, Nancy Wexler, 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^[48]
• 1993: The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16.3.
• 1996: A transgenic mouse ([the R6 line]) was created that could be made to exhibit HD, greatly advancing how much experimentation can be achieved.
• 1997: DiFiglia M, Sapp E, Chase KO, et al., discover that mHtt aggregates (misfolds) to form nuclear inclusions.^[18]
• The full record of research is extensive.^[49][50][51]

Organizations

• 1967: Woody Guthrie's wife, Marjorie, helped found the Committee to Combat Huntington's Disease, after his death from HD complications. This eventually became the Huntington's Disease Society of America.^[52] 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 Venezuela 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^[53]. 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^[54] was started as part of the Huntington Project,^[55] funded by the High-Q Foundation.^[56]

Cultural references

Books

• Jacqueline Susann's 1966 American novel Valley of the Dolls (night club singer Tony Polar).
• Kurt Vonnegut's 1985 American novel Galapagos.
• Pål Johan Karlsen's 2002 Norwegian novel Daimler (main character Daniel Grimsgaard is afflicted).
• Diane Tullson's 2001 Canadian novel Saving Jasey (Trist, Jasey and their Grandfather).
• Nancy Werlin's 2004 American novel Double Helix (Ava Samuels, Kayla Matheson and others).
• Steven T. Seagle's autobiographical 2004 American graphic novel It's a Bird features the author coming to grips with the presence of HD in his family.
• Ian McEwan's 2005 British novel Saturday. The character of Baxter is negatively portrayed in his affliction. ^[57]
• Joe Klein's Woody Guthrie: A Life The book discloses the effects of the disorder in both Woody Guthrie and his mother.

Films

• Arlo Guthrie's 1969 film Alice's Restaurant

Television

• Dr. Samantha O'Hara from the Australian medical drama All Saints.
• Hannah's father from the American drama Everwood, as revealed in the episode "Need to Know" (3x10).
• Characters in the episodes "Pad'ar" (3x08) and "the Sins of the Father" (4x03) of Gene Roddenberry's Earth: Final Conflict.
• Angie Padgett from the episode "In Which Charlotte Goes Down the Rabbit Hole" (1x06) of Private Practice.
• The character known as "Thirteen", in the episode "You Don't Want to Know" (4x08) of House, may have inherited the disease from her mother, who died of Huntington's, but refuses to be tested.
• An episode of the BBC drama Waterloo Road
• The ER season 9 episode "Insurrection" featured a completely disabled man with Huntington's. During the chaos caused when Dr. John Carter leads a walk-out to protest unsafe working conditions, the man's mother disconnects his ventilator so that he can die in peace. Dr. Susan Lewis figures out what the mother did but protects her.

References

1. ^ NCBI OMIM. Huntington's Disease. Retrieved on 2008-05-22.
2. ^ Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN (2005). "Energy balance in early-stage Huntington disease". Am. J. Clin. Nutr. 81 (6): 1335–41. PMID 15941884. 
3. ^ Caregiver's Handbook for Advanced-Stage Huntington Disease. Booklet by the Huntington Society of Canada, retrieved 2007-04-11.
4. ^ Johnson SA, Stout JC, Solomon AC, et al (2007). "Beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington's disease". Brain 130 (Pt 7): 1732–44. doi:10.1093/brain/awm107. PMID 17584778. 
5. ^ Kieburtz K, MacDonald M, Shih C, et al (1994). "Trinucleotide repeat length and progression of illness in Huntington's disease". J. Med. Genet. 31 (11): 872–4. PMID 7853373. 
6. ^ RM Ridley, CD Frith, TJ Crow and PM Conneally (1988). "Anticipation in Huntington's disease is inherited through the male line but may originate in the female". Journal of Medical Genetics 25: 589-595. PMID 2972838. 
7. ^ Velier J, Kim M, Schwarz C, et al (1998). "Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways". Exp. Neurol. 152 (1): 34–40. doi:10.1006/exnr.1998.6832. PMID 9682010. 
8. ^ Waelter S, Scherzinger E, Hasenbank R, et al (2001). "The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis". Hum. Mol. Genet. 10 (17): 1807–17. PMID 11532990. 
9. ^ Canals JM, Pineda JR, Torres-Peraza JF, et al (2004). "Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease". J. Neurosci. 24 (35): 7727–39. doi:10.1523/JNEUROSCI.1197-04.2004. PMID 15342740. 
10. ^ Sawa A, Nagata E, Sutcliffe S, et al (2005). "Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts". Neurobiol. Dis. 20 (2): 267–74. doi:10.1016/j.nbd.2005.02.013. PMID 15890517. 
11. ^ Kim YJ, Yi Y, Sapp E, et al (2001). "Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis". Proc. Natl. Acad. Sci. U.S.A. 98 (22): 12784–9. doi:10.1073/pnas.221451398. PMID 11675509. 
12. ^ Hermel E, Gafni J, Propp SS, et al (2004). "Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease". Cell Death Differ. 11 (4): 424–38. doi:10.1038/sj.cdd.4401358. PMID 14713958. 
13. ^ Freiman RN, Tjian R (2002). "Neurodegeneration. A glutamine-rich trail leads to transcription factors". Science 296 (5576): 2149–50. doi:10.1126/science.1073845. PMID 12077389. 
14. ^ Bae BI, Xu H, Igarashi S, et al (2005). "p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease". Neuron 47 (1): 29–41. doi:10.1016/j.neuron.2005.06.005. PMID 15996546. 
15. ^ Dunah AW, Jeong H, Griffin A, et al (2002). "Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease". Science 296 (5576): 2238–43. doi:10.1126/science.1072613. PMID 11988536. 
16. ^ Graham RK, Deng Y, Slow EJ, et al (2006). "Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin". Cell 125 (6): 1179–91. doi:10.1016/j.cell.2006.04.026. PMID 16777606. 
17. ^ Murphy KP, Carter RJ, Lione LA, et al (2000). "Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation". J. Neurosci. 20 (13): 5115–23. PMID 10864968. 
18. ^ ^{a b c} DiFiglia M, Sapp E, Chase KO, et al (1997). "Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain". Science 277 (5334): 1990–3. doi:10.1126/science.277.5334.1990. PMID 9302293. 
19. ^ Davies SW, Turmaine M, Cozens BA, et al (1997). "Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation". Cell 90 (3): 537–48. PMID 9267033. 
20. ^ Gutekunst CA, Li SH, Yi H, et al (1999). "Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology". J. Neurosci. 19 (7): 2522–34. PMID 10087066. 
21. ^ Sieradzan KA, Mechan AO, Jones L, Wanker EE, Nukina N, Mann DM (1999). "Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein". Exp. Neurol. 156 (1): 92–9. doi:10.1006/exnr.1998.7005. PMID 10192780. 
22. ^ Cooper JK, Schilling G, Peters MF, et al (1998). "Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture". Hum. Mol. Genet. 7 (5): 783–90. PMID 9536081. 
23. ^ Fusco FR, Chen Q, Lamoreaux WJ, et al (1999). "Cellular localization of huntingtin in striatal and cortical neurons in rats: lack of correlation with neuronal vulnerability in Huntington's disease". J. Neurosci. 19 (4): 1189–202. PMID 9952397. 
24. ^ Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998). "Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions". Cell 95 (1): 55–66. PMID 9778247. 
25. ^ www.hdsa.org
26. ^ Gaba, Anna. Family Guide Series - Nutrition and Huntington's Disease (English). Huntington's Disease Society of America Publications. Retrieved on 2008-04-02.
27. ^ Huntington's Disease Reversed
28. ^ clinicaltrials.gov
29. ^ Lecerf JM, Shirley TL, Zhu Q, et al (2001). "Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4764–9. doi:10.1073/pnas.071058398. PMID 11296304. 
30. ^ Miller TW, Zhou C, Gines S, et al (2005). "A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease". Neurobiol. Dis. 19 (1-2): 47–56. doi:10.1016/j.nbd.2004.11.003. PMID 15837560. 
31. ^ Wolfgang WJ, Miller TW, Webster JM, et al (2005). "Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies". Proc. Natl. Acad. Sci. U.S.A. 102 (32): 11563–8. doi:10.1073/pnas.0505321102. PMID 16061794. 
32. ^ Miller TW, Messer A (2005). "Intrabody applications in neurological disorders: progress and future prospects". Mol. Ther. 12 (3): 394–401. doi:10.1016/j.ymthe.2005.04.003. PMID 15964243. 
33. ^ Harper SQ, Staber PD, He X, et al (2005). "RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model". Proc. Natl. Acad. Sci. U.S.A. 102 (16): 5820–5. doi:10.1073/pnas.0501507102. PMID 15811941. 
34. ^ Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, María A. Morán, Pilar Gómez-Ramos, Jordi Alberch, and José J. Lucas (October 19, 2005). "Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease". The Journal of Neuroscience 25 (42): 9773-9781. doi:10.1523/JNEUROSCI.3183-05.2005. PMID 16237181. 
35. ^ World health Article
36. ^ Andrew SE, Goldberg YP, Kremer B, et al (1993). "The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease". Nat. Genet. 4 (4): 398–403. doi:10.1038/ng0893-398. PMID 8401589. 
37. ^ Harper PS (1999). "Huntington's disease: a clinical, genetic and molecular model for polyglutamine repeat disorders". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 354 (1386): 957–61. doi:10.1098/rstb.1999.0446. PMID 10434293. 
38. ^ Rubinsztein DC, Leggo J, Chiano M, et al (1997). "Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease". Proc. Natl. Acad. Sci. U.S.A. 94 (8): 3872–6. PMID 9108071. 
39. ^ Adams P, Falek A, Arnold J (1988). "Huntington disease in Georgia: age at onset". Am. J. Hum. Genet. 43 (5): 695–704. PMID 2973230. 
40. ^ Kremer B. Clinical neurology of Huntington's disease. In: Huntington's Disease (Third ed.), edited by Bates GP, Harper PS and Jones L. Oxford: Oxford University Press, 2002, p. 28-61.
41. ^ Roos RA, Hermans J, Vegter-van der Vlis M, van Ommen GJ, Bruyn GW (1993). "Duration of illness in Huntington's disease is not related to age at onset". J. Neurol. Neurosurg. Psychiatr. 56 (1): 98–100. PMID 8429330. 
42. ^ Lanska DJ, Lanska MJ, Lavine L, Schoenberg BS (1988). "Conditions associated with Huntington's disease at death. A case-control study". Arch. Neurol. 45 (8): 878–80. PMID 2969233. 
43. ^ Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM (1993). "Suicide risk in Huntington's disease". J. Med. Genet. 30 (4): 293–5. PMID 8487273. 
44. ^ Schoenfeld M, Myers RH, Cupples LA, Berkman B, Sax DS, Clark E (1984). "Increased rate of suicide among patients with Huntington's disease". J. Neurol. Neurosurg. Psychiatr. 47 (12): 1283–7. PMID 6239910. 
45. ^ Kremer B. Clinical neurology of Huntington's disease. In: Huntington's Disease (Third ed.), edited by Bates GP, Harper PS and Jones L. Oxford: Oxford University Press, 2002, p. 28-61.
46. ^ [1]
47. ^ The brief history of HD on stanford.edu
48. ^ La Spada AR, Roling DB, Harding AE, et al (1992). "Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy". Nat. Genet. 2 (4): 301–4. doi:10.1038/ng1292-301. PMID 1303283. 
49. ^ Achievements of Hereditary Disease Foundation
50. ^ HDA research news—medical research into treatment & prevention on hda.org.uk
51. ^ Bates G, Harper PS, Jones L (2002) Huntington's disease, 3rd Edition. Oxford: Oxford University Press.
52. ^ Huntington's Disease Society of America
53. ^ World Congress on Huntington's Disease
54. ^ Euro-HD Network
55. ^ Huntington Project
56. ^ High-Q Foundation
57. ^ Nancy S Wexler and Michael D Rawlins (2005). "Prejudice in a portrayal of Huntington's disease". The Lancet 366 (9491): 1069-1070. 

Sources

• Conomy, John P., M.D., J.D. Dr. George Sumner Huntington and the Disease Bearing His Name.
• Huntington, G. (1872-04-13). "On Chorea". Medical and Surgical Reporter of Philadelphia 26 (15): 317-321. 
• Online Mendelian Inheritance in Man, Article 143100 - Huntington Disease, Johns Hopkins University
• Online Mendelian Inheritance in Man, Article 606438 - Huntingtons Disease-Like 2, Johns Hopkins University
• Stevenson, Charles S. (April 1934). "A Biography of George Huntington, M.D." (Microsoft Word). Bulletin of the Institute of the History of Medicine II (2). Johns Hopkins University. Retrieved on 2007-12-05. 
• Vessie, P. R. (1932). "On the transmission of Huntington's chorea for 300 years—the Bures family group". Journal of Nervous and Mental Disease, Baltimore 76: 553–573. 

Bibliography

• Bates, Gillian, Peter Harper, and Lesley Jones (2002). Huntington's Disease - Third Edition. Oxford: Oxford University Press. ISBN 0-19-851060-8. 

External links

Professional and research

• Huntington Project - worldwide umbrella organization for the clinical research efforts for HD.
• Huntington Study Group
• Huntington's Disease Research - Research abstracts on HD.
• Huntington's Outreach Project for Education, at Stanford (HOPES) - A layperson's guide to HD
• Worldwide Education and Awareness for Movement Disorders - HD section
• University College London Huntington's Disease Research
• TRACK-HD, an international observational study of HD

Support and advocacy

• The International Huntington Association - Coordinates support organizations in 39 countries, and individual contacts in others.
• Hereditary Disease Foundation - Spearheaded Venezuela Collaborative Huntington's Disease Project.
• Huntington's Disease Lighthouse - Reports on the latest research and studies.
• Huntington's Disease Advocacy Center - Provides community support through shared stories and forums.
• Huntington's Disease Support Club
• European HD Network European research network
• Australian Huntington's Disease Association (NSW) Inc.
• Huntington's Disease Society of America
• Huntington Society of Canada - Resource materials, latest in Canadian and International HD research and description of comprehensive services portfolio to help families struggling with HD
• Scottish Huntingtons Association - Provides expert care and information for people affected by Huntingtons Disease. Just as importantly, support is offered by families for families via a network of local family support groups.
• Huntington's Disease Association UK United Kingdom support group

Other

• Mind Matters: RTÉ Radio 1 programme on Huntington's Disease, featuring a family affected from Ireland.
• Huntington's Disease Drug Works - Website covering results and progress of clinical trials and alternative treatments for HD.
• WeAreHD.org - Online Community for those living with Huntington's Disease.

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