Huntington's disease ( HD ), also known as Huntington's chorea , is a congenital disorder that causes brain cells to die. The earliest symptoms are subtle problems with mood or mental ability. Lack of irregular coordination and gait often occurs. As the disease develops, uncoordinated body movements, the jerky becomes more obvious. Physical abilities gradually deteriorate until coordinated movements become difficult and the person can not speak. Mental abilities generally decrease to dementia. The specific symptoms are somewhat different between people. Symptoms usually begin between the ages of 30 and 50 years, but can start at any age. This disease can develop earlier in life in each subsequent generation. Approximately eight percent of cases begin before the age of 20 years and usually present with symptoms that are more similar to Parkinson's disease. People with HD often underestimate the extent of their problems.
HD is usually inherited from one's parents, although up to 10% of cases are caused by new mutations. The disease is caused by an autosomal dominant mutation in one of two copies of a gene called Huntingtin . This means a child from an affected person usually has a 50% chance of inheriting the disease. The Huntingtin genes provide genetic information for a protein also called "huntingtin". The repeated expansion of triplets of CAG (cytosine-adenine-guanine) in a gene encoding Huntingtin protein produces an abnormal protein, which gradually damages cells in the brain, through mechanisms that are not fully understood. Diagnosis is done by genetic testing, which can be done at any time, regardless of whether the symptoms are present or not. This fact raises some ethical debate: the age at which an individual is considered mature enough to choose the test; whether the parent has the right to test his or her child; and manage the confidentiality and disclosure of test results.
There is no cure for HD. Full-time treatment is needed in the final stages of the disease. Treatment can relieve some symptoms and in some improve the quality of life. The best evidence for the treatment of motion problems is with tetrabenazine. HD affects about 4 to 15 out of 100,000 people of European descent. Very rare among Japanese, while the incidence rate in Africa is unknown. This disease affects men and women alike. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy. Suicide is the cause of death in about 9% of cases. Death usually occurs fifteen to twenty years since the disease was first detected.
The first description of the disease was in 1841 by Charles Oscar Waters. The condition was further explained in 1872 by doctor George Huntington, after what his name was. The genetic base was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation. Research and support organizations began to form in the late 1960s to raise public awareness, to provide support for individuals and their families, and to promote research. Current research directions include determining the exact mechanisms of disease, improving animal models to assist with research, testing drugs to treat symptoms or slowing disease progression, and studying procedures such as stem cell therapy with the aim of repairing damage caused by disease.
Video Huntington's disease
Signs and symptoms
The symptoms of Huntington's disease most often become visible between the ages of 35 and 44 years, but they can start at any age from infancy to old age. In the early stages, there are subtle changes in personality, cognition, and physical skills. Physical symptoms are usually the first to be noticed, since cognitive and behavioral symptoms are generally not severe enough to be recognized on their own in the early stages. Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, development and level of cognitive and behavioral symptoms vary significantly between individuals.
The most typical initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Chorea may have been initially exhibited as a general anxiety, inconsistent or incomplete little movement, lack of coordination, or slow saccadic eye movements. These mild motor abnormalities usually precede clearer signs of motor dysfunction for at least three years. The obvious appearance of symptoms such as stiffness, stretching movements or abnormal posture arises when the disorder continues. These are signs that the systems in the brain responsible for movement have been affected. Psychomotor function becomes increasingly disturbed, so any action requiring muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulty chewing, swallowing, and talking. Eating difficulties usually lead to weight loss and can lead to malnutrition. Sleep disorders are also an associated symptom. HD juvenile differs from these symptoms in that it generally progresses faster and chorea is exhibited briefly, if at all, with stiffness being the dominant symptom. Seizures are also a common symptom of this form of HD.
Cognitive ability increasingly disturbed. Particularly affected are executive functions, which include planning, cognitive flexibility, abstract thinking, rule acquisition, proper initiation of actions, and inhibition of inappropriate action. As disease develops, memory deficits tend to arise. The reported abnormalities range from short-term memory deficits to long-term memory difficulties, including episodic deficits (memory of a person's life), procedural (body memory of how to perform an activity) and working memory. Cognitive problems tend to worsen over time, eventually leading to dementia. This deficit pattern is called subcortical dementia syndrome to distinguish it from typical effects of cortical dementia for example. Alzheimer's disease.
The reported neuropsychiatric manifestations are anxiety, depression, decreased appearance of emotion (forced influence), egocentrism, aggression, and compulsive behavior, the latter that can cause or aggravate addiction, including alcoholism, gambling, and hypersexuality. The difficulty in recognizing the negative expressions of others has also been observed. The prevalence of these symptoms varies greatly between studies, with an approximate level of lifelong prevalence of psychiatric disorders of between 33% and 76%. For many sufferers and their families, these symptoms are one of the saddest aspects of the disease, often affecting daily functioning and are the reasons for institutionalization. Thoughts for suicide and suicide attempts are more common than in the general population. Often individuals have reduced the awareness of chorea, cognitive and emotional disorders.
Mutant Huntingtin is expressed throughout the body and is associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These disorders include muscle atrophy, heart failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.
Maps Huntington's disease
Genetics
All humans have two copies of the Huntingtin gene ( HTT ), which encodes Huntingtin (HTT) proteins. This gene is also called HD and IT15 , which means 'interesting transcript 15'. Part of this gene is a recurring part called trinukleotide replication, which varies in length between individuals and may change lengths between generations. If repetitions are present in healthy genes, dynamic mutations can increase the number of repetitions and produce defective genes. When the length of the repeated portion reaches a certain threshold, it produces a modified form of protein, called a mutant Huntingtin protein (mHTT). The different functions of this protein are the causes of pathological changes that in turn lead to symptoms of the disease. Mutations of Huntington's disease are genetically dominant and almost entirely penetrant: mutations of one of the human alleles HTT cause disease. It is not inherited by sex, but the length of the gene section repeats itself and hence its severity can be affected by the gender of the affected parent.
Genetic mutations
HD is one of several repetitive disorders of trinucleotides caused by the length of repeated portions of genes that exceed the normal range. The HTT gene is located on the short arm of chromosome 4 on 4p16.3. HTT contains a sequence of three DNA bases - cytosine-adenine-guanine (CAG) - repeated several times (ie... CAGCAGCAG...), known as trinucleotide repeatability. CAG is a 3-letter genetic code (codon) for amino acid glutamine, so that a series of them results in the production of glutamine chains known as polyglutamine (or polyQ tract) channels, and repeated gene sections, PolyQ region .
Generally, people have less than 36 repeated glutamine in the polyQ region that results in the production of the Huntingtin cytoplasmic protein. However, the order of 36 or more glutamine produces the production of proteins that have different characteristics. This altered form, called the huntingtin mutant (mHTT), increases the decay rate of certain neuron types. Brain regions have different amounts and dependencies on these types of neurons, and are affected appropriately. Generally, the number of CAG repetitions is related to how much the process is affected, and accounts for about 60% of the variation in age of onset of symptoms. The remaining variation is associated with the environment and other genes that modify the HD mechanism. 36-39 repetition results in a reduced form of depletion of the disease, with a much slower onset and slower development of symptoms. In some cases, the onset may be so late that the symptoms are never noticed. With enormous amount of repetition, HD has full penetration and can occur under the age of 20 years, when it is then referred to as HD teenager, akinetic-rigid, or the Westphal HD variant. It accounts for about 7% of HD operators.
Inheritance
Huntington's disease has an autosomal dominant heritage, meaning that affected individuals usually inherit one copy of the gene by repeating the extended trinucleotide (mutant allele) of the affected parent. Because the penetration of mutations is very high, those who have copies of the mutated gene will have the disease. In this type of inheritance pattern, each offspring of the affected individual has a 50% risk of inheriting a mutant allele and is therefore affected with the disorder (see figure). This probability does not depend on gender.
Trinucleotide CAG repeats more than 28 unstable during replication, and this instability increases with the number of repetitions available. This usually leads to a new expansion as the generation passes (dynamic mutation) rather than reproducing a copy of the correct trinukleotide repetition. This causes the number of repetitions to change in successive generations, so that unaffected parents with "medium" repetition (28-35), or "reduced penetration" (36-40), can pass on a copy of the gene by increasing the number of repetitions resulting in full HD penetration. The increase in the number of repetitions (and hence the age of early onset and severity of disease) in the next generation is known as genetic anticipation. More instability in spermatogenesis than oogenesis; maternally inherited alleles usually have the same length of repeat, whereas paternally derived ones have a higher likelihood of increasing length. Very rarely for Huntington's disease is caused by a new mutation, in which no parent has more than 36 CAG repetitions.
In rare situations where both parents have an extended HD gene, the risk increases to 75%, and when one parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both affected genes are rare. For some time, HD is considered the only disease in which the possession of the second mutated gene does not affect symptoms and development, but it has since been found that it can affect the phenotype and rate of development.
Mechanism
The huntingtin protein interacts with more than 100 other proteins, and appears to have some biological function. The behavior of this mutated protein is not fully understood, but it is toxic to certain types of cells, especially in the brain. Early damage is most apparent in the striatum, but as the disease develops, other areas of the brain are also more affected. Initial symptoms are due to striatum function and cortical connection - ie control over movement, mood and higher cognitive function. DNA methylation also seems to be changed in HD.
Huntingtin Function
HTT is expressed in all mammalian cells. The highest concentrations are found in the brain and testes, with moderate amounts in the liver, heart, and lungs. HTT function in humans is not clear. It interacts with proteins involved in transcription, cell signaling, and intracellular transport. In animals that are genetically modified to show HD, some HTT functions have been found. In these animals, HTT is important for embryonic development, since its absence is associated with embryonic death. Caspase, an enzyme that plays a role in catalyzing apoptosis, is thought to be activated by genes that mutate by destroying the ubiquitin-protease system. It also acts as an anti-apoptotic agent preventing programmed cell death and controlling the production of brain-derived neurotrophic factors, proteins that protect neurons and regulate their creations during neurogenesis. HTT also facilitates vesicular transport and synaptic transmission and controls the transcription of neuronal genes. If HTT expression increases and more HTT is generated, brain cell survival increases and the mHTT effect decreases, whereas when HTT expression is reduced, the resulting characteristics are more characteristic of mHTT presence. In humans normal gene disorders do not cause disease. It is estimated that the disease is not caused by inadequate HTT production, but by increased toxic function of mHTT in the body.
Mobile changed
There are several cellular changes through which toxic function mHTT can manifest and produce HD pathology. In its mutant form (ie expanded polyglutamine), proteins are more susceptible to cleavage that creates short fragments containing polyglutamine expansion. These protein fragments have a tendency to experience misfolding and aggregation, resulting in fibrillar aggregates in which non-native polyglutamine? -strands of some proteins bound together by hydrogen bonds. This aggregate shares the same fundamental crossovers? Amyloid architecture is seen in other protein deposition diseases. Over time, aggregates accumulate to form inclusion bodies within cells, ultimately disrupting the function of neurons. Neuronal inclusion runs indirect interference. Inclusion bodies have been found in both cell nuclei and cytoplasm. The inclusion bodies in brain cells are one of the earliest pathological changes, and some experiments have found that they can be toxic to cells, but other experiments have shown that they can form as part of the body's defense mechanisms and help protect cells.
Several pathways in which mHTT can cause cell death have been identified. These include: effects on chaperone proteins, which help fold proteins and eliminate misplaced pairs; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells; disruption of energy production in cells; and effects on gene expression.
An additional theory that explains the way other cell functions may be disrupted by HD suggests that mitochondrial damage to striatal cells is very important (many reports of lack of mitochondrial metabolism have been found). Mutant Huntingtin protein has been found to play a key role in mitochondrial dysfunction. Mitochondrial electron transport damage may produce higher levels of oxidative stress and release of reactive oxygen species.
The interaction of a protein-altered protein huntingtin in neurons causes increased susceptibility to glutamine, which, in large quantities, has been found as excitotoxin. Excitotoxins can cause damage to many cellular structures. Although glutamine is not found in very high quantities, it has been postulated that due to increased susceptibility, even the normal amount of glutamine can cause excitotoxins to be expressed.
Macroscopic changes
HD affects the entire brain, but certain areas are more vulnerable than others. The most prominent initial effect is the portion of the basal ganglia called the neostriatum, which is composed of the nucleus and the caucus tooth. Other affected areas include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, the hippocampus, the purkinje cells in the cerebellum, the lateral tubular nucleus of the hypothalamus and part of the thalamus. These areas are affected according to their structure and the types of neurons they contain, reducing the size because they lose the cell. Striatal spiny neurons are the most vulnerable, especially those with projections against the external globus pallidus, with interneurons and spiny cells projecting into the internal pallidum becoming less affected. HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia.
Basal ganglia - the most prominent part of the brain affected in early HD - plays a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the executive system of cognitive and motor circuits. Basal ganglia usually inhibit a large number of circuits that produce special 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 may cause the release or recovery of the obstacles to be irregular and uncontrolled, resulting in a strange start to movement or movement accidentally initiated, or movement to be stopped before, or beyond, the intended settlement. Accumulated damage to this area causes erratic movement of characteristics associated with HD. Spontaneous and erratic physical movements associated with HD are classified as hyperkinetic dysarthria types. Due to the inability of the basal ganglia to inhibit movement, the affected individual will inevitably decrease the ability to produce speech and swallow food and fluids (dysphagia).
Disregulasi transcription
CREB-binding protein (CBP), transcriptional coregulator, is essential for cell function because as a coactivator on a large number of promoters, it activates gene transcription for survival paths. Furthermore, the amino acids that make up CBP include 18 glutamine strips. Thus, glutamine in CBP interacts directly with an increase in the amount of glutamine in the HTT and CBP chains being pulled away from their distinctive location next to the nucleus. Specifically, CBP contains an acetyltransferase domain that HTT binds through a domain containing polyglutamine. The autopsied brain of those with Huntington's disease has also been found to have a significantly reduced amount of CBP. Additionally, when CBP is expressed, polyglutamine-induced death is reduced, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.
Diagnosis
Medical diagnosis of HD onset can be performed after the appearance of specific physical symptoms for the disease. A genetic test can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm whether an individual or embryo carries copies of the extended trinucleotide repetition in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance during the testing procedure, and the implications of the diagnosis are confirmed. These implications include impacts on individual psychology, careers, family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD chose to do so.
Clinical
Physical examination, sometimes combined with psychological examination, can determine whether the onset of the disease has begun. Unintentional excessive movement of any part of the body is often the reason for seeking medical consultation. If this is abrupt and has random timing and distribution, they suggest a HD diagnosis. Cognitive or behavioral symptoms are rarely the first symptoms to be diagnosed; they are usually only recognizable in the back or as they progress further. How far the disease has developed can be measured by using Huntington's integrated scores assessment scores, which provide an overall rating system based on motor, behavioral, cognitive, and functional assessments. Medical imaging, such as computerized tomography (CT) and magnetic resonance imaging (MRI), may show caudate core atrophy early in the disease, as seen in the illustration on the right, but this change is not, by itself, HD diagnostic. Cerebral atrophy can be seen at an advanced stage of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), may show changes in brain activity before the onset of physical symptoms, but they are experimental devices, and are not used clinically.
Predictive genetic test
Because HD follows an autosomal dominant inheritance pattern, there is a strong motivation for individuals at risk of inheriting to look for a diagnosis. The genetic test for HD consists of blood tests that count the number of CAG repetitions in each HTT allele. Cutoff is given as follows:
- 40 or more CAG repeats: full penetration allele (FPA). "Positive test" or "positive result" usually refers to the case. A positive outcome is not considered a diagnosis, as it can be obtained several decades before symptoms begin. However, a negative test means that the individual does not carry an expanded gene copy and will not develop HD. This test will tell someone who initially has a 50 percent chance of inheriting the disease if the risk rises to 100 percent or is eliminated. A person who performs a positive test for this disease will develop HD some time in their life, provided he or she is old enough for the illness to appear.
- 36 to 39 repetitions: incomplete or reduced allele penetration (RPA). This can cause symptoms, usually later in adult life. There is a maximum risk of 60% that a person with RPA will be symptomatic at age 65, and 70% risk becomes symptomatic by 75 years of age.
- 27 to 35 repeats: middle allele (IA), or a large normal allele . It is not associated with symptomatic disease in the tested individual, but may extend to further inheritance to give hereditary symptoms.
- 26 or fewer repetitions: Not related to HD.
Testing before the onset of symptoms is a life-changing event and a very personal decision. The main reason given for choosing testing for HD is to assist in career and family decisions. Before 1993 there were no tests available for individuals to learn if they carried the Huntington gene. At the time, the survey showed that 50-70% of at-risk individuals would be interested in accepting tests, but because predictive testing has been offered, far fewer choose to be tested. Over 95% of individuals at risk of inherited HD are not continuing with testing, largely because there is no treatment. The main problem is the anxiety that a person experiences about not knowing whether they will eventually develop HD, as opposed to the impact of a positive outcome. Regardless of the outcome, stress levels have been found to be lower two years after being tested, but the risk of suicide increases after positive test results. Individuals found not inheriting the disorder may experience a survivor's guilt in respect of affected family members. Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive outcome, which usually means that parents have affected genes and that individual brothers will risk inheriting it. In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurs at a higher level in personal relationships than in health insurance or employment relationships. Genetic counseling in HD can provide information, advice, and support for early decision making, and then, if selected, throughout the testing process. Due to the implications of this test, patients who wish to undergo a test must complete three counseling sessions that provide information about Huntington.
Counseling and guidance on the use of genetic testing for HD has become a model for other genetic disorders, such as dominant autosomal cerebellar ataxia. Presymptomatic tests for HD have also influenced testing for other diseases with genetic variants such as polycystic kidney disease, family Alzheimer's disease and breast cancer. The European Quality Network of Molecular Genetics has published an annual external quality assessment scheme for molecular genetic testing for this disease and has developed best practice guidelines for genetic testing for HD to aid in testing and reporting of results.
Preimplantation genetic diagnosis
Embryos produced using in vitro fertilization may be genetically tested for HD using genetic preimplantation (PGD) diagnosis. This technique, in which one or two cells are extracted from the embryo is usually 4-8 cells and then tested for genetic disorders, can then be used to ensure embryos affected by HD genes are not implanted, and therefore any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis - non-disclosure or exclusion testing - allow people at risk of having offspring without HD without disclosing their own parent genotypes, not providing information about whether they themselves are destined to develop HD. In exclusion testing, embryonic DNA is compared with parental and grandparent DNA to avoid inheriting chromosomal regions containing HD genes from affected grandparents. In non-disclosure testing, only disease-free embryos are replaced in the uterus while parental genotypes and hence the risk of parents for HD are never disclosed.
Prenatal testing
It is also possible to obtain a prenatal diagnosis for the embryo or fetus in the uterus, using fetal genetic material obtained through chorionic villus sampling. Amniocentesis may be performed if the pregnancy continues, within 14-18 weeks. This procedure looks at the amniotic fluid that surrounds the baby for an HD mutation indicator. It can also be paired with exception testing to avoid parental genotype disclosure. Prenatal testing can be done when parents are diagnosed with HD, when they perform genetic testing that shows an extension of the HTT gene, or when they have a 50% chance of inheriting the disease. Parents can be counseled about their choices, including the termination of pregnancy, and the difficulty of the child with the identified gene.
In addition, in risky pregnancies due to the affected male partner, a non-invasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in blood samples taken from the mother (via venipuncture) between six and twelve weeks of pregnancy. There is no risk of miscarriage related to the procedure (except through needle contamination).
Differential diagnosis
About 99% of HD diagnoses based on typical symptoms and family history of the disease are confirmed by genetic testing to repeat the repetition of trinucleotides that cause HD. Most of the rest is called HD-like syndrome (HDL). The causes of most HDL diseases are unknown, but they are known to be due to mutations in the prion protein gene (HDL1), junctophilin 3 gene (HDL2), recessive-derived recessive-derived (HDL3) genes - found only in two families and poorly understood), and genes that encode 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. There is also an autosomal recessive disorder that resembles a sporadic HD case. These include chorea acanthocytosis and neurodegeneration associated with kinase kinase. One X-related disorder of this type is McLeod syndrome.
Management
There is no cure for HD, but there are treatments available to reduce the severity of some of the symptoms. For many of these treatments, evidence to confirm their effectiveness in treating HD symptoms is particularly incomplete. As the disease develops the ability to care for itself declines, and careful multidisciplinary care is becoming increasingly necessary. Although there are relatively few studies on exercise and therapy that help rehabilitate HD cognitive symptoms, there is some evidence for the usefulness of physical therapy, occupational therapy, and speech therapy. The association between caffeine intake and early-onset age in Huntington's disease has been found but, since these findings are based on retrospective questionnaire data rather than randomized trials or controlled case studies, this work is a poor basis for guiding lifestyle decisions..
Therapy
Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common, making nutrition management more important as disease progresses. The thickening agent can be added to the liquid because thicker liquids are easier and safer to swallow. Reminding affected people to eat slowly and taking smaller pieces of food into the mouth can also be useful to prevent choking. If eating becomes too dangerous or uncomfortable, the option of using percutaneous endoscopic gastrostomy is available. This is a filler tube, which is attached permanently through the stomach into the stomach, which reduces the risk of aspiration of food and provides better nutrition management. Assessment and management by a speech-language pathologist with experience in Huntington's disease is recommended.
People with Huntington's disease can see physical therapists for non-invasive and non-treatment ways to manage physical symptoms. Physical therapists can apply risk assessment and prevention of falls, as well as strengthening, stretching, and cardiovascular exercise. A walker can be properly prescribed. Physical therapists also prescribe breathing exercises and airway cleaning techniques with the development of breathing problems. Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network. The goal of early rehabilitation interventions is the prevention of function loss. Participation in rehabilitation programs during the early to intermediate stage of the disease may be useful because it translates into motor maintenance and long-term functional performance. Rehabilitation during the final phase aims to compensate for motor and functional losses. For long-term independent management, therapists can develop home exercise programs for the right people.
In addition, more and more people with Huntington's disease turn to palliative care, aiming to improve quality of life through symptom treatment and stress of serious illness, in addition to other treatments.
Drugs
Tetrabenazine was approved in 2008 for the treatment of chorea in Huntington's disease in the US. Other drugs that help reduce chorea include neuroleptics and benzodiazepines. Compounds such as amantadine or remacemide are still under investigation but have shown positive early results. Hypokinesia and stiffness, especially in adolescent cases, may be treated with antiparkinsonic drugs, and myoclonic hyperkinesia may be treated with valproic acid.
Psychiatric symptoms can be treated with drugs similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotic drugs are recommended for psychoses and behavioral problems. Special neuropsychiatric input is recommended because people may require long-term treatment with some medications in combination.
Education
Individual families who have inherited or at risk of inheriting HD have a generation of HD experience, but may not be aware of new breakthroughs in understanding the disease, and the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to eliminate the unfounded beliefs they may have, and to help them consider their future options and plans. Also included are information on family planning options, care management, and other considerations.
Prognosis
The length of trinucleotide repeat for 60% variation in age symptoms appears and the rate of progress. Longer repetitive results in early age of faster onset and symptom development. Individuals with more than sixty repetitions often develop the disease before the age of 20, while those with fewer than 40 repetitions may never develop any apparent symptoms. The remaining variation is due to environmental factors and other genes that affect the mechanism of the disease.
The life expectancy in HD is generally about 20 years after the onset of visible symptoms. Most life-threatening complications result from muscle coordination and, to a lesser extent, behavioral changes caused by decreased cognitive function. The biggest risk is pneumonia, which causes death in one third of those with HD. Because of the ability to synchronize worsening movements, difficulty clearing the lungs and an increased risk of aspiration for food or drink, both increase the risk of developing pneumonia. The second biggest risk is heart disease, which causes almost a quarter of their deaths with HD. Suicide is the third leading cause of death, with 7.3% of those with HD taking their own lives and up to 27% trying to do so. It is not clear how far suicidal thoughts are affected by behavioral symptoms, because they indicate the desire of the sufferers to avoid the later stages of the disease. Other related risks include choking, physical injury from falling, and malnutrition.
Epidemiology
The onset of late Huntington's disease does not affect reproduction. The prevalence of HD worldwide is 5-10 cases per 100,000 people, but it varies geographically as a result of ethnic, local migration and past immigration patterns. Prevalence is similar for men and women. The highest rate of occurrence in Western European descendants, on average about 7 per 100,000 people, and lower worldwide; for example, one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in Britain between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000. In addition, some local areas have a much higher prevalence than their regional average. One of the highest incidents occurred in isolated populations in the Maracaibo Lake region of Venezuela, where HD affects up to 700 per 100,000 people. Other areas of high localization have been found in Tasmania and certain areas of Scotland, Wales and Sweden. Increased prevalence in some cases occurs due to the effects of local founders, the carrier's historical migration to geographical isolation areas. Some of these operators have been traced back hundreds of years using genealogical studies. Genetic haplotypes may also provide clues to the prevalence of geographic variation. Iceland, on the other hand, has a rather low prevalence of 1 per 100,000, despite the fact that Icelandic people are descended from early Scandinavian tribes that also bear Swedish people; all cases with the exception of one will return almost two centuries after coming from the descendants of a couple who lived in the early 19th century. Finland, too, has a low incidence of just 2.2 per 100,000 people.
Until the discovery of genetic testing, statistics can only include clinical diagnosis based on physical symptoms and family history of HD, excluding those who died from other causes before diagnosis. These cases can now be included in statistics; and, as tests become more widely available, estimates of prevalence and incidence of disorders tend to increase.
History
Although Huntington has been recognized as a disorder since at least the Middle Ages, the cause has not been known until recently. Huntington was given a different name throughout this history because his understanding of his illness changed. Originally referred to simply 'chorea' for the jerky movement associated with disease, HD has also been called "hereditary chorea" and "chronic progressive choreography". The first definite mention of HD is in a letter by Charles Oscar Waters, published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters describes "a form of chorea, vulgarly called magrum", including an accurate description of the chorea, its development, and the heredity of a strong disease. In 1846 Charles Gorman observed how a higher prevalence seemed to occur in the local area. Apart from Gorman and Waters, both Dunglison students at Jefferson Medical College in Philadelphia, Johan Christian Lund also produced a preliminary description in 1860. He specifically noted that in Setesdalen, a remote mountain valley in Norway, there is a high prevalence of dementia related to movement disturbance patterns jerking that happened in the family.
The first comprehensive picture of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of families who exhibited similar symptoms, he realized that their condition should be linked; he presented the definition of his illness in detail and accurately as his first paper. Huntington describes the exact pattern of inherited autosomal dominant diseases many years before the rediscovery by scientists of Mendel's legacy.
"From heredity When one or both parents have shown the manifestation of the disease..., one or more of the offspring almost always suffer from illness... But if by chance these children live without it, the thread is broken and grandchildren and grandchildren of the original shaker can be sure that they are free from disease. ".
Sir William Osler was interested in disorder and chorea in general, and was impressed by Huntington's paper, stating that "In medical history, there have been instances where the disease has been more accurate, more graphic or more briefly described." Osler's continued interest in HD, combined with his influence in medicine, helps spread awareness and knowledge about these disorders rapidly throughout the medical community. Great interest was shown by scientists in Europe, including Louis ThÃÆ'Ã… © ophile Joseph Landouzy, DÃÆ'Ã… © sirÃÆ'Â © -Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of this century, much research on HD was Europe in origin. By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.
During the rediscovery of Mendel's inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. British biologist William Bateson uses the affected family tree to determine that HD has an autosomal dominant inheritance pattern. Strong inheritance patterns encouraged some researchers, including Smith Ely Jelliffe, to try to track and connect family members from previous studies. Jelliffe collects information from New York and publishes some articles on HD genealogy in New England. Jelliffe's research aroused the interest of his college friend Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States family with HD and build their pedigree. Davenport uses this information to document the variable age of onset and various symptoms of HD; he claims that most HD cases in the US can be traced back to a handful of people. The research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left England in 1630 to Boston were the ancestors of HD in the United States. Claims that the earliest ancestors have been formed and eugenics bias by Muncey, Davenport, and Vessie contributed to misunderstandings and prejudices about HD. Muncey and Davenport also popularized the idea that in the past some HD sufferers might have been considered possessed by spirits or magic victims, and sometimes shunned or alienated by society. This idea has not been proven. Researchers have found conflicting evidence; for example, the family community studied by George Huntington openly accommodates those with HD symptoms.
The search for the cause of this condition greatly increased in 1968, when the Hereditary Disease Foundation (HDF) was created by Milton Wexler, a Los Angeles-based psychoanalyst, whose wife Leonore Sabin was diagnosed earlier that year with Huntington's disease.. The three brothers of Wexler's wife also suffered from this disease. The foundation is involved in the recruitment of more than 100 scientists in the Huntington Disease Collaboration Research Project who over a 10 year period worked to find the gene responsible.
Thanks to HDF, the ongoing Huntington US-Venezuela Collaborative Research Project started in 1979, and reported a major breakthrough in 1983 with the discovery of the approximate location of the causal genes. This is the result of an extensive study focusing on populations of two remote villages in Venezuela, Barranquitas and Lagunetas, where there is a very high prevalence of disease. It involves more than 18,000 people - mostly from one big family.
Among other innovations, the project developed DNA tagging methods that are an important step in making the Human Genome Project possible. In 1993, the research group isolated the exact cause gene on 4p16.3, making this the first locus of autosomal disease to be found using genetic analysis of the relationship.
Within the same time frame, key discoveries about the mechanism of the disturbance are being made, including findings by Anita Harding's research group on the effects of gene length.
Modeling diseases in different types of animals, such as transgenic mice developed in 1996, allow for larger scale trials. Because these animals have faster metabolism and a much shorter life span than humans, the results of the experiments are received more quickly, accelerating the study. The discovery in 1997 that the misfold mHTT fragments led to the discovery of nuclear inclusions it generated. These advances have led to more extensive research into the proteins involved with the disease, potential drug treatments, treatment methods, and genes themselves.
This condition was previously called 'Huntington's chorea' but this term has been replaced by 'Huntington's disease' because not all patients develop chorea and because of the importance of cognitive and behavioral problems.
Society and culture
Ethics
Huntington's disease, especially the application of genetic testing for this disease, has raised several ethical issues. Issues for genetic testing include defining how mature a person should be before being deemed eligible for testing, ensuring the confidentiality of results, and whether the company should be allowed to use test results for decisions about employment, life insurance or other financial matters. There was controversy when Charles Davenport proposed in 1910 that mandatory sterilization and immigration control were used for people with certain diseases, including HD, as part of the eugenics movement. In vitro fertilization has some problems regarding the use of embryos. Some HD studies have ethical problems because of the use of animal testing and embryonic stem cells.
Development of accurate diagnostic tests for Huntington's disease has led to social, legal, and ethical concerns about access and use of one's outcomes. Many guidelines and testing procedures have rigorous procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results as well as to whom those results are available. Financial and business institutions are faced with the question of whether to use genetic test results when assessing a person, such as for life or employment insurance. UK insurance companies have agreed that until 2017 they will not use genetic information when writing an insurance policy under GBÃ, Â £ 500,000 , but Huntington is explicitly excluded from this agreement. As with other untreatable genetic conditions with later onset, it is ethically questionable to perform pre-symptomatic tests in children or adolescents, as there will be no medical benefit to the individual. There is consensus to test only individuals who are considered cognitively mature, although there is a counter-argument that parents have the right to make decisions on behalf of their child. With the lack of effective treatment, testing a person under legal age who is not considered competent is considered unethical in most cases.
There are ethical concerns related to pranatal genetic testing or preimplantation genetic diagnosis to ensure that children are not born with certain diseases. For example, prenatal testing raises the issue of selective abortion, an option that some people find unacceptable. Because it is a dominant disease, there are difficulties in situations where parents do not want to know their own diagnosis. This will require part of the process to be kept secret from parents.
Supporting organizations
In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start Hereditary Disease Foundation (HDF), with the aim of curing genetic diseases by coordinating and supporting research. The foundation and daughter of Wexler, Nancy Wexler, is an important part of a team of researchers in Venezuela who discovered the HD gene.
At about the same time when HDF was formed, Marjorie Guthrie helped establish the Huntington Disease Prevention Committee (now the Huntington Institute of America Disease), after her husband Woody Guthrie died of HD complications.
Since then, support and research organizations have been established in many countries around the world and have helped raise public awareness about HD. These numbers are collaborating in umbrella organizations, such as the International Huntington Association and the European HD network. Many support organizations hold annual HD awareness events, some of which have been supported by their respective governments. For example, June 6 was designated a "Huntington National Disease Awareness Day" by the US Senate.
The largest funding of Huntington's global disease research, in terms of financial expenditure, is the CHDI Foundation, a non-profit US biomedical foundation aimed at "rapidly locating and developing drugs that delay or slow Huntington's disease." CHDI was formerly known as High Q Foundation. In 2006, spent $ 50 million on Huntington disease research. CHDI works closely with many academic and commercial laboratories globally and is involved in the monitoring and management of research projects as well as funding. Many organizations exist to support and inform those affected by HD.
Direction of research
Research on HD mechanisms focuses on identifying HTT function, how mHTT is different or disturbing, and brain pathology generated by disease. The study was conducted using the method of in vitro , animal models and human volunteers. Animal models are essential to understanding the underlying mechanisms that cause disease and to support the early stages of drug development. Animals with chemical induced brain injury exhibit HD-like symptoms and are initially used, but they do not mimic the progressive features of the disease. Identification of the causal genes has enabled the development of many models of transgenic animals including nematode worms, Drosophila fruit fly, rats, mice, sheep, pigs and monkeys that express mutant huntingtin and develop progressive and progressive neurodegeneration and HD-like symptoms.
Research is being conducted on many different approaches to prevent Huntington's disease or slow its progression. Modifying disease strategies can be broadly grouped into three categories: reducing the level of mutant hunting protein (including gene grafting and gene muting); approaches aimed at improving neuronal survival by reducing damage caused by proteins for specific cellular pathways and mechanisms (including protein homeostasis and histone deacetylase inhibition); and strategies to replace missing neurons. In addition, new therapies to improve brain function are under development; it seeks to produce symptomatic therapy rather than disease-modifying, and includes phosphodiesterase inhibitors.
Reduce huntingtin production
Gene muting aims to reduce the production of mutant proteins, because HD is caused by a single dominant gene that encodes a toxic protein. Gene silencing experiments in mouse models show that when mHTT expression is reduced, symptoms improve. The specific RNAi non-allele security and ASO gene muting have now been demonstrated in large and human-like mice and brain primates. Specific allele smoothing tries to silence the HTT mutant while leaving untreated wild HTT type. One way to achieve this is to identify polymorphisms that exist only on one allele and produce gene silencing drugs that target polymorphisms only on mutant alleles. The first 'silencing gene' trial involving human HD patients began in 2015, tested the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by the UCL Institute of Neurology. Mutant huntingtin is detected and quantified for the first time in the cerebrospinal fluid from the Huntington mutation disease carrier in 2015 using novel single-molecule counting immunoassays, providing a direct way to assess whether treatment that decreases hunting power achieves the desired effect. Similarly, gene grafting techniques are being seen to try to correct the genome with the wrong genes that cause HD, using tools such as CRISPR/Cas9.
Improve cell survival
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin is the correction of transcriptional regulation using histone deacetylase inhibitors, hunttin aggregation modulation, increasing metabolism and mitochondrial function and restoring synaptic function.
Neuronal replacement
Stem cell therapy is the replacement of damaged neurons with stem cell transplantation to the affected part of the brain. Experiments have produced mixed results using this technique in animal models and early human clinical trials. Whatever the potential for therapy in the future, stem cells have become a valuable tool for studying Huntington's disease in the laboratory.
Clinical test
Several new experimental treatment clinical trials are underway and planned in Huntington's disease.
Compounds that have failed to prevent or slow the progression of Huntington's disease in human trials include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon.
See also
- Huntington Disease Association
References
External links
- Huntington's disease in Curlie (based on DMOZ)
- Jobs related to On Chorea on Wikisource
- HOPE Stanford University HD information projects
- HDBuzz - HD research news written by scientists in plain language
- HD Drugs - news on current treatments and planned trials
Source of the article : Wikipedia
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