Huntington's disease

Huntington's disease, known historically as Huntington's chorea and chorea maior, is a rare inherited neurological disorder affecting up to approximately 1 person per 10,000 people of Western European descent and 1 per 1,000,000 of Asian and African descent. It takes its name from the New York 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 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 gene coding for Huntingtin (Htt) and is one of several polyglutamine diseases. This expansion produces an altered form of the Htt protein, mutant Huntingtin (mHtt), which results in neuronal cell death in select areas of the brain. Huntington's disease is a terminal illness.

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 personality. These physical symptoms occur in a large range of ages, with a mean occurrence in a person's late forties/early fifties. If the age of onset is below 20 years then it is known as Juvenile HD. As there is currently no proven cure, symptoms are managed with various medications and care methods.

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Symptomatology and pathology

Although there is no sudden loss of affected abilities, there is a progressive decline of them. Physical signs are usually the first noticed, with cognitive and psychiatric deficits manifesting subsequently. Physical symptoms are almost always visible; cognitive symptoms exhibit differently from person to person, and psychiatric problems may not be evident.

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.

Physical

Most people with HD eventually exhibit jerky, random, 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 sit or stand stably, speech, chewing and swallowing (which can lead to weight loss if diet and eating methods are not adjusted accordingly^[1][2]), and loss of determination. In the later stages of the disease, speaking is impaired with slurred words and uncontrollable movements of the mouth, eating and mobility are extremely difficult if not impossible, and full-time care is required.

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), and ability to learn new skills, depending on the affected parts of the brain.

Psychopathological

Psychopathological symptoms vary more than cognitive and physical symptoms, and may include anxiety, depression, a reduced display of emotions (blunting) and decreased ability to recognize negative expressions like anger, disgust, fear or sadness in others^[3], egocentrism, aggressive behavior, compulsivity which can cause addictions such as alcoholism and gambling, or hypersexuality.

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 and other trinucleotide repeat disorders is more complex.

When the gene has more than 36 copies of the repeated trinucleotide sequence, the DNA replication process becomes unstable and the number of repeats can change in successive generations. This can mean that in a parent without HD but with a count close to 36, the count may increase above the threshold that causes HD.

If the gene is inherited from the mother, the count is usually similar. Paternal inheritance tends to increase the number of repeats.^[4] 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.

De novo mutations (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.

Causes

See also: HD (gene)

The gene involved in Huntington's disease, called the HD gene or Interesting Transcript 15 (IT15), 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 36 glutamines, produces a cytoplasmic protein called huntingtin (Htt), whereas a sequence of 40 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, othertimes not.

Having mHtt instead of Htt causes certain neurons in select areas of the brain to have an increased mortality, progressively affecting neurological functioning. Observations show that generally, the greater the number of CAG repeats, the earlier the onset of symptoms.^[5]

Mechanism

See also: Huntingtin

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 in two; identifying the normal processes of Htt, the abnormal processes of mHtt, and the effects of parts 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.^[6][7]

MHtt reduces the production of brain-derived neurotrophic factor (BDNF) which protects neurons in the striatum.^[8] This loss of BDNF may contribute to striatal cell death, which does not follow apoptotic pathways as the neurons appear to die of starvation.^[9]

Degradation

Both Htt and mHtt are cleaved (the first step in degradation) by Caspase-3, which removes the (amino end) N-terminal.^[10] 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.^[11] These repeats left in the cell, called aggregates or N-fragments, are able to affect polyQ dependent transcription.^[12] Specifically, mHtt binds with TAF_II130, a coactivator to CREB dependent transcription.^[13] The aggregates also interact with SP₁, thereby preventing it from binding to DNA,the normal functioning of these proteins.^[14]

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.^[15]

In genetically altered "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease.^[16] Aggregates of mHtt are present in the brains of both HD patients^[17] and HD mice,^[18] 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 ^[19][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]

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, better access to water especially, lived much longer than mice who were not well cared for.

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^{[citation needed]}, so a nutritionist's advice is needed (the normal population's 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 pneumonia 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.^{[citation needed]} 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.

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.^[26]

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.^[27][28] 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.^[29] 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.^[30]

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% reduction in expression of the mHtt and progression of the disease was stalled.^[31] In another study, mouse models in late stages of the disease recovered motor function after expression of mHtt was shut down.^[32]

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. ^[33]

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 ^[34]. 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 ^[35]. 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 ^[36],^[37]), 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^[38].

Following the onset of the “classical” symptoms of the disorder, patients generally live for a further 15 to 20 years ^[39]. Death, however, is not caused by Huntington’s disease per se, but rather by associated complications. The most common causes of death of HD patients includes pneumonia (one third of all patients), heart failure (although heart disease, cerebrovascular disease and atherosclerosis show no increase), choking and nutritional deficiencies^[40]. Suicide is an associated risk, with suicide rates of up to 7.3 per cent of all patient deaths; four times that of the general population ^[41]. This rather taboo subject is likely to be under-reported, with up to 27 per cent of possibly affected individuals attempting suicide at least once ^[42]. Likewise, suicide in the general population is likely to be underestimated; however, some reports have accounted for this and still find a significant increase in suicide rate amongst HD patients ^[43]

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 a descendant of a person 'at-risk', has serious ethical implications, as a positive result in a child'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.

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. Another consideration regarding genetic testing is the fact that this kind of screening is a form of eugenics. Indeed, historically, Huntington's disease patients were one of the targets groups for the eugenic improvement of the human gene pool. The American scientist Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be aimed at those afflicted with HD (amongst other diseases) [1]

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.

Cultural references

HD has been depicted in a variety of media:

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 Tulson's 2002 American 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 Anerican 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. ^[44].

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; she 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

History

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 Christian 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.^[45]
• 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, which has proved invaluable in the research 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^[46]
• 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.^[47]
• The full record of research is extensive.^[48][49][50]

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.^[51] 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^[52]. 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^[53] was started as part of the Huntington Project,^[54] funded by the High-Q Foundation.^[55]

See also

• Parkinson's disease
• Proteopathy

References

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. 

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
• 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
• European HD Network
• Australian Huntington's Disease Association (NSW) Inc.
• Huntington's Disease Association UK

Other

• Mind Matters: RTÉ Radio 1 programme on Huntington's Disease, featuring a family affected from Ireland. Podcast feed: www.rte.ie/radio1/podcast/podcast_mindmatters.xml
• 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.