97-874: Robley may refer to: People [ edit ] Given name [ edit ] Robley Dunglison (1798–1869), English physician Robley D. Evans (admiral) (1846–1912), United States Navy rear admiral Robley D. Evans (physicist) (1907–1995), American physicist Robley Rex (1901–2009), World War II-era veteran Robley S. Rigdon , retired Georgia Army National Guard brigadier general Robley C. Williams (1908–1995), American biologist and virologist Robley Wilson (1930–2018), American poet, writer, and editor Middle name [ edit ] Charles Robley Evans (1866–1954), American politician Geoffrey Robley Sayer (1887–1962), British civil servant and historian Surname [ edit ] Horatio Gordon Robley (1840–1930), British soldier, artist, and collector of
194-457: A psychological examination , can determine whether the onset of the disease has begun. Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far
291-516: A reduced display of emotions , egocentrism , aggression , and compulsive behavior and hallucination and delusion . Other common psychiatric disorders could include obsessive–compulsive disorder , mania , insomnia and bipolar disorder . Difficulties in recognizing other people's negative expressions have also been observed. The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33 and 76%. For many with
388-467: A trinucleotide repeat expansion – a short repeat , which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHtt). The differing functions of these proteins are
485-516: A trinucleotide repeat expansion ) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells through a number of possible mechanisms. The mutant protein is dominant , so having one parent who is a carrier of the trait is sufficient to trigger the disease in their children. Diagnosis is by genetic testing , which can be carried out at any time, regardless of whether or not symptoms are present. This fact raises several ethical debates:
582-427: A blood sample taken from the mother (via venipuncture ) between six and 12 weeks of pregnancy. It has no procedure-related risk of miscarriage. About 99% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like (HDL) syndromes . The cause of most HDL diseases
679-912: A diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the HTT alleles. Cutoffs are given as follows: Testing before the onset of symptoms is a life-changing event and a very personal decision. The main reason given for choosing to test for HD is to aid in career and family decisions. Predictive testing for Huntington's disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993. At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested. Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment. A key issue
776-472: A family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase. In centuries past, various kinds of chorea were at times called by names such as Saint Vitus' dance , with little or no understanding of their cause or type in each case. The first definite mention of HD
873-665: A faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of slowness of movement , rigidity, and tremors is more typical in juvenile HD, as are seizures . Cognitive abilities are progressively impaired and tend to generally decline into dementia . Especially affected are executive functions , which include planning, cognitive flexibility, abstract thinking , rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. Different cognitive impairments include difficulty focusing on tasks, lack of flexibility,
970-557: A heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA. This is marketed as Austedo. Psychiatric symptoms can be treated with medications similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotics are recommended for psychosis and behavioral problems. Specialist neuropsychiatric input
1067-498: A lack of impulse, a lack of awareness of one's own behaviors and abilities and difficulty learning or processing new information. As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity), and working memory . Reported neuropsychiatric signs are anxiety , depression ,
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#17327907105621164-424: A local founder effect , a historical migration of carriers into an area of geographic isolation . Some of these carriers have been traced back hundreds of years using genealogical studies. Genetic haplotypes can also give clues for the geographic variations of prevalence. Iceland , on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended from
1261-651: A monthly publication, the American Medical Library and Intelligencer . He co-edited the journal along with Granville Sharp Pattison until 1842 when the journal was discontinued. In 1838, Dunglison became a naturalized U.S. citizen. In 1840, Dunglison was appointed by Jefferson Medical College as a representative to the National Medical Convention for the revision of the United States Pharmacopeia . He
1358-491: A secluded mountain valley in Norway , the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families. The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of
1455-412: A second mutated gene did not affect symptoms and progression, but it has since been found that it can affect the phenotype and the rate of progression. Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions. The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly brain cells . Early damage
1552-438: A transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways. CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain. Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP. In addition, when CBP
1649-420: A tremor. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing , and speaking . Sleep disturbances and weight loss are also associated symptoms. Eating difficulties commonly cause weight loss and may lead to malnutrition. Weight loss is common in people with Huntington's disease, and it progresses with the disease. Juvenile HD generally progresses at
1746-482: A typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing,
1843-528: Is McLeod syndrome . Treatments are available to reduce the severity of some HD symptoms. For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete. As the disease progresses, the ability to care for oneself declines, and carefully managed multidisciplinary caregiving becomes increasingly necessary. Although relatively few studies of exercises and therapies have shown to be helpful to rehabilitate cognitive symptoms of HD, some evidence shows
1940-415: Is expressed in all cells, with the highest concentrations found in the brain and testes , and moderate amounts in the liver , heart , and lungs . Its functions are unclear, but it does interact with proteins involved in transcription , cell signaling , and intracellular transporting . In animals genetically modified to exhibit HD, several functions of Htt have been identified. In these animals, Htt
2037-568: Is pneumonia , which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs, and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia . The second-greatest risk is heart disease , which causes almost a quarter of fatalities of those with HD. Suicide is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms
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#17327907105622134-434: Is 5–10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seven per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of
2231-419: Is Huntington's disease caused by a new mutation , where neither parent has over 36 CAG repeats. In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. For some time, HD was thought to be the only disease for which possession of
2328-487: Is also possible, using fetal genetic material acquired through chorionic villus sampling . An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation. This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing
2425-535: Is considered the "Father of American Physiology" after the publication of his landmark textbook Human Physiology in 1832. He was the personal physician to Thomas Jefferson , James Madison and James Monroe . He consulted in the treatment of Andrew Jackson and was in attendance at Jefferson's death. He served as chair of materia medica, therapeutics, hygiene and medical jurisprudence at the University of Maryland School of Medicine from 1833 to 1836 and chair of
2522-489: Is different from Wikidata All article disambiguation pages All disambiguation pages Robley Dunglison Robley Dunglison (4 January 1798 – 1 April 1869) was an English-American physician, medical educator and author who served as the first full-time professor of medicine in the United States at the newly founded University of Virginia from 1824 to 1833. He authored multiple medical textbooks and
2619-466: Is due to environmental factors and other genes that influence the mechanism of the disease. Life expectancy in HD is generally around 10 to 30 years following the onset of visible symptoms. Juvenile Huntington's disease has a life expectancy rate of 10 years after onset of visible symptoms. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk
2716-602: Is important for embryonic development, as its absence is related to embryonic death. Caspase , an enzyme which plays a role in catalyzing apoptosis , is thought to be activated by the mutated gene through damaging the ubiquitin-protease system. It also acts as an antiapoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor , a protein that protects neurons and regulates their creation during neurogenesis . Htt also facilitates synaptic vesicular transport and synaptic transmission , and controls neuronal gene transcription. If
2813-489: Is information concerning family planning choices, care management, and other considerations. The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms. Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic. The remaining variation
2910-418: Is most evident in the subcortical basal ganglia , initially in the striatum , but as the disease progresses, other areas of the brain are also affected, including regions of the cerebral cortex . Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function. DNA methylation also appears to be changed in HD. Htt
3007-477: Is mostly inherited . The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea . As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and
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3104-477: Is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels. Initially, damage to the brain is regionally specific with the dorsal striatum in the subcortical basal ganglia being primarily affected, followed later by cortical involvement in all areas. Other areas of
3201-439: Is one of several trinucleotide repeat disorders that are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases —cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the three-letter genetic code ( codon ) for
3298-555: Is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general. Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of
3395-399: Is recommended since people may require long-term treatment with multiple medications in combination. There has been a number of alternative therapies experimented in ayurvedic medicine with plant-based products, although none have provided good evidence of efficacy. A recent study showed that the stromal processing peptidase (SPP), a synthetic enzyme found in plant chloroplasts , prevented
3492-444: Is recommended. People with Huntington's disease may see a physical therapist for noninvasive and nonmedication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and airway clearance techniques with
3589-486: Is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result. Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result. Individuals found to have not inherited the disorder may experience survivor guilt about family members who are affected. Other factors taken into account when considering testing include
3686-464: Is unclear, as they signify a desire to avoid the later stages of the disease. Suicide is the greatest risk of this disease before the diagnosis is made and in the middle stages of development throughout the disease. Other associated risks include choking; due to the inability to swallow, physical injury from falls, and malnutrition. The late onset of Huntington's disease means it does not usually affect reproduction. The worldwide prevalence of HD
3783-701: Is unknown, but those with known causes are due to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the TATA box-binding protein ( SCA17, sometimes called HDL4 ). Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy . Also, some autosomal recessive disorders resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration . One X-linked disorder of this type
3880-546: Is with tetrabenazine . HD affects about 4 to 15 in 100,000 people of European descent. It is rare among the Finnish and Japanese, while the occurrence rate in Africa is unknown. The disease affects males and females equally. Complications such as pneumonia , heart disease , and physical injury from falls reduce life expectancy; although fatal aspiration pneumonia is commonly cited as the ultimate cause of death for those with
3977-489: The Hereditary Disease Foundation . Research and support organizations began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research. Research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications and their delivery to treat symptoms or slow
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4074-591: The Royal College of Surgeons and the Society of Apothecaries and began the practice of medicine. He obtained his M. D. from the University of Erlangen , Germany, in 1823. He received his degree remotely by submitting a thesis (De Neuralgia) and a fee since the M.D. degree was not offered in London at the time. Dunglison initially focused on obstetrics and accepted an appointment as physician-accoucheur at
4171-416: The amino acid glutamine , so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the polyQ region . Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the cytoplasmic protein huntingtin. However, a sequence of 36 or more glutamines results in
4268-451: The basal ganglia affected include the substantia nigra ; cortical involvement includes cortical layers 3, 5, and 6 ; also evident is involvement of the hippocampus , Purkinje cells in the cerebellum , lateral tuberal nuclei of the hypothalamus and parts of the thalamus . These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells. Striatal medium spiny neurons are
4365-780: The Eastern Dispensary in London. He was a member of the London Medical Society and the Hunterian Society . In 1824, Thomas Jefferson and the Board of Visitors of the University of Virginia commissioned Francis Walker Gilmer to find professors in England for the new University. Gilmer offered the anatomy and medicine professorship to Dunglison. The agreement with the University of Virginia
4462-452: The HD pathology through multiple cellular changes. In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion. These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds. These aggregates share
4559-516: The Institutes of Medicine and Medical Jurisprudence at Jefferson Medical College from 1836 to 1868. He assisted William Beaumont in some of his experiments on gastric digestion and published the first description of Huntington's disease in his textbook The Practice of Medicine in 1842. Dunglison was born in Keswick, Cumbria , England to William and Elizabeth (Robley) Dunglison. His father
4656-457: The advanced stages of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically. Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek
4753-416: The age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results. No cure for HD is known, and full-time care is required in the later stages. Treatments can relieve some symptoms and in some, improve quality of life . The best evidence for treatment of the movement problems
4850-493: The age of 20 years, and are known as juvenile HD , which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea. HD is typically inherited from an affected parent , who carries a mutation in the huntingtin gene ( HTT ). However, up to 10% of cases are due to a new mutation. The huntingtin gene provides the genetic information for huntingtin protein (Htt). Expansion of CAG repeats of cytosine - adenine - guanine (known as
4947-429: The age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterized by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers. Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele ) from an affected parent. Since
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#17327907105625044-420: The age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD. About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed. With very large repeat counts (more than 60), HD onset can occur below
5141-796: The aggregation of proteins associated with Huntington's disease. However, repeat studies and clinical validation are needed to confirm its true therapeutic potential. The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. The Patient Education Program for Huntington's Disease has been created to help educate family members, caretakers, and those diagnosed with Huntington's disease. Also covered
5238-454: The brain. These abnormalities include muscle atrophy , cardiac failure , impaired glucose tolerance , weight loss , osteoporosis , and testicular atrophy . Everyone has two copies of the huntingtin gene ( HTT ), which codes for the huntingtin protein (Htt). HTT is also called the HD gene, and the IT15 gene, (interesting transcript 15). Part of this gene is a repeated section called
5335-402: The cause of pathological changes, which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant ; mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene; hence its severity can be influenced by the sex of the affected parent. HD
5432-495: The cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells. Several pathways by which mHtt may cause cell death have been identified. These include effects on chaperone proteins , which help fold proteins and remove misfolded ones; interactions with caspases , which play a role in the process of removing cells ; the toxic effects of glutamine on nerve cells ; impairment of energy production within cells; and effects on
5529-444: The cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to
5626-442: The condition. Suicide is the cause of death in about 9% of cases. Death typically occurs 15–20 years from when the disease was first detected. The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters. The condition was described in further detail in 1872 by American physician George Huntington . The genetic basis was discovered in 1993 by an international collaborative effort led by
5723-515: The development of respiratory problems. Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network. Goals of early rehabilitation interventions are prevention of loss of function. Participation in rehabilitation programs during the early to middle stage of the disease may be beneficial as it translates into long-term maintenance of motor and functional performance. Rehabilitation during
5820-513: The disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization . Early behavioral changes in HD result in an increased risk of suicide. Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments. Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside
5917-455: The disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments. Medical imaging , such as a CT scan or MRI scan , can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. Cerebral atrophy can be seen in
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#17327907105626014-466: The disorder progresses. These are signs that the system in the brain that is responsible for movement has been affected. Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. When muscle control is affected such as rigidity or muscle contracture this is known as dystonia . Dystonia is a neurological hyperkinetic movement disorder that results in twisting or repetitive movements, that may resemble
6111-475: The early Germanic tribes of Scandinavia which also gave rise to the Swedes ; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century. Finland , as well, has a low incidence of only 2.2 per 100,000 people. Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and
6208-404: The embryo's DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed. Obtaining a prenatal diagnosis for an embryo or fetus in the womb
6305-399: The expansion of the HTT gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy , and on the difficulties of a child with the identified gene. In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in
6402-423: The expression of Htt is increased, brain cell survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics are more as seen in the presence of mHtt. Accordingly, the disease is thought not to be caused by inadequate production of Htt, but by a toxic gain-of-function of mHtt in the body. The toxic action of mHtt may manifest and produce
6499-416: The expression of genes. Mutant huntingtin protein has been found to play a key role in mitochondrial dysfunction . The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species . Glutamine is known to be excitotoxic when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine
6596-432: The late stage aims to compensate for motor and functional losses. For long-term independent management, the therapist may develop home exercise programs for appropriate people. Additionally, an increasing number of people with HD are turning to palliative care , which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments. Tetrabenazine
6693-656: The macabre Other [ edit ] Robley, Virginia , an unincorporated community Rob R. Robley, one of Robbie Rotten's disguises in LazyTown Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title Robley . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=Robley&oldid=1066097194 " Category : Disambiguation pages Hidden categories: Short description
6790-414: The magrums as well. Dunglinson married Harriette Leadam on 4 October 1824. Together they had seven children including: He died on 1 April 1869 and was interred at Laurel Hill Cemetery . A dormitory at the University of Virginia was named in his honor. Huntington%27s disease Huntington's disease ( HD ), also known as Huntington's chorea , is an incurable neurodegenerative disease that
6887-468: The most vulnerable, particularly ones with projections towards the external globus pallidus , with interneurons and spiny cells projecting to the internal globus pallidus being less affected. HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia . The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of
6984-481: The motion or motions to be unintentionally initiated or in a motion to be halted before or beyond its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a dyskinesia . Because of the basal ganglia's inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia). CREB-binding protein (CBP),
7081-438: The mouth may also be of use to prevent choking. If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This feeding tube, permanently attached through the abdomen into the stomach , reduces the risk of aspirating food and provides better nutritional management. Assessment and management by speech-language pathologists with experience in Huntington's disease
7178-413: The number of repeats present. This usually leads to new expansions as generations pass ( dynamic mutations ) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in
7275-441: The number of repeats that produces fully penetrant HD. The earlier age of onset and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic anticipation . Instability is greater in spermatogenesis than oogenesis ; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. Rarely
7372-701: The onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals. The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea . Many people are not aware of their involuntary movements, or impeded by them. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements . These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear appearance of symptoms such as rigidity, writhing motions, or abnormal posturing appear as
7469-528: The penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele, so are affected with the disorder (see figure). This probability is sex-independent. Sex-dependent or sex-linked genes are traits that are found on the X or Y chromosomes. Trinucleotide CAG repeats numbering over 28 are unstable during replication , and this instability increases with
7566-423: The person is unable to talk. Mental abilities generally decline into dementia , depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation . About eight percent of cases start before
7663-408: The personal physician to Thomas Jefferson, James Madison and James Monroe and was called into consultation for the treatment of Andrew Jackson . He was a frequent visitor to Jefferson at Monticello and was in attendance during his illness and death in 1826. While at the University of Virginia, Dunglison published his landmark textbook Human Physiology (1832), which established his reputation as
7760-551: The possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it. In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations. Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of
7857-729: The prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000. Additionally, some localized areas have a much higher prevalence than their regional average. One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela , where HD affects up to 700 per 100,000 persons. Other areas of high localization have been found in Tasmania and specific regions of Scotland , Wales and Sweden . Increased prevalence in some cases occurs due to
7954-415: The production of a protein with different characteristics. This altered form, called mutant huntingtin (mHtt), increases the decay rate of certain types of neurons . Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of
8051-454: The progression of the disease, and studying procedures such as stem-cell therapy with the goal of replacing damaged or lost neurons. Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age and present as a triad of motor, cognitive, and psychiatric symptoms. When developed in an early stage, it is known as juvenile Huntington's disease. In 50% of cases,
8148-448: The psychiatric symptoms appear first. Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase. In the early stages, subtle personality changes, problems in cognition and physical skills, irritability , and mood swings occur, all of which may go unnoticed, and these usually precede the motor symptoms. Almost everyone with HD eventually exhibits similar physical symptoms, but
8245-452: The same fundamental cross-beta amyloid architecture seen in other protein deposition diseases . Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuronal function. Inclusion bodies have been found in both the cell nucleus and cytoplasm . Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for
8342-1002: The testing process. Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's. Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxia . Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer's disease and breast cancer . The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results. Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis . This technique, where one or two cells are extracted from
8439-520: The trinucleotide repeat (CAG) in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so. A physical examination , sometimes combined with
8536-443: The usefulness of physical therapy , occupational therapy , and speech therapy . Weight loss and problems in eating due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances. Thickening agents can be added to liquids, as thicker fluids are easier and safer to swallow. Reminding the affected person to eat slowly and to take smaller pieces of food into
8633-437: The “Father of American Physiology.” He took an active role in the scientific experiments on gastric digestion conducted by William Beaumont . Dunglison performed some of the experiments on gastric juice, outlined additional chemical experiments to be conducted and designed further experiments for Beaumont to conduct. He would have also published the work but deferred to Beaumont to publish the work himself. In 1832, Dunglison
8730-586: Was a member of the Franklin Institute . He worked as an attending physician at Philadelphia General Hospital . He received an honorary LL.D. degree from Jefferson College in Canonsburg, Pennsylvania in 1852. One of Dunglison's recently graduated students at Jefferson Medical College, Charles Oscar Waters, provided his professor with a description of the "magrums" (a folk name for what is now called Huntington's disease ), which Waters observed
8827-624: Was a textile manufacturer but died at the age of 35. His great-uncle was a Governor of British Tobago and it was planned for Robley to become a West Indies planter but the uncle died and the plans to move to the West Indies were abandoned. He began the study of medicine locally in 1814 and moved to London to complete his studies. He attended lectures at the University of Edinburgh and the Ecole de Medecine in Paris. In 1819, he received diplomas from
8924-654: Was also personal physician to Peter Stephen Du Ponceau toward the end of his life. Dunglison successfully campaigned for the creation of an asylum for Philadelphia's mentally ill residents. In 1844, he became an officer at the Pennsylvania Institution for the Instruction of the Blind (later known as Overbrook School for the Blind ). He co-developed a form of raised type to allow the blind to read. He served as president of The Musical Fund Society and
9021-875: Was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US. Although other drugs had been used " off label ", tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s. An alternative to tetrabenazine is amantadine but there is limited evidence for its safety and efficacy. Other drugs that help to reduce chorea include antipsychotics and benzodiazepines . Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid . Tentative evidence has found ethyl eicosapentaenoic acid to improve motor symptoms at one year. In 2017, deutetrabenazine ,
9118-895: Was elected to the American Philosophical Society and served in multiple leadership roles. In 1833, he accepted a position as chair of materia medica, therapeutics, hygiene and medical jurisprudence at the University of Maryland and moved to Baltimore. In 1836, the Chair of the Institutes of Medicine and Medical Jurisprudence was created for him at the Jefferson Medical College in Philadelphia , and Dunglison served in that role until 1868. He also served as dean of faculty from 1854 to 1868. He retired in 1868 due to poor health but continued to serve as professor emeritus . In 1837, he established
9215-854: Was in a letter by Charles Oscar Waters (1816–1892), published in the first edition of Robley Dunglison 's Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. In 1846 Charles Rollin Gorman (1817–1879) observed how higher prevalence seemed to occur in localized regions. Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia, Johan Christian Lund [ no ] (1830–1906) also produced an early description in 1860. He specifically noted that in Setesdalen ,
9312-474: Was prevalent in Westchester County, New York . Although he had never seen a case, Dunglison included a description of the disease in his 1842 textbook The Practice of Medicine . Waters's account of the disease was one of the first to note that the disease is hereditary, "within the third generation at farthest." Another of Dunglison's students at Jefferson, Charles R. Gorman, wrote his thesis on
9409-399: Was that beyond medical consultation with Jefferson and select others, he would not practice medicine. This made him the first full-time professor of medicine in the United States. He received an M.D. degree in 1825 from Yale College . Dunglinson was known to own slaves while at the University of Virginia and purchased some of the slaves previously owned by Thomas Jefferson. Dunglison was
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