Genetic Testing

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After raising a family she worked at Securian Financial for 23 years, retiring in This will let them know that you are interested in graduate study. E, Glencoe, MN Retrieved 8 September We shop at Cub Foods and deliver directly to the kitchen. She is deeply loved and will be profoundly missed. During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance.

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HTT also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription. There are multiple cellular changes through which the toxic function of mHTT may manifest and produce the HD pathology.

Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuron function. Inclusion bodies have been found in both the cell nucleus and cytoplasm. Several pathways by which mHTT may cause cell death have been identified. An additional theory that explains another way cell function may be disrupted by HD proposes that damage to mitochondria in striatal cells is of central importance numerous accounts of mitochondrial metabolism deficiency have been found.

Mutant Huntingtin protein has been found to play a key role in mitochondrial dysfunction. The interactions of the altered huntingtin protein with numerous proteins in neurons leads to an increased vulnerability of glutamine, which, in large amounts, has been found to be an excitotoxin. Excitotoxins may cause damage to numerous cellular structures. Although glutamine is not found in excessively high amounts, it has been postulated that because of the increased vulnerability, even normal amounts glutamine can cause excitotoxins to be expressed.

HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the basal ganglia called the neostriatum , which is composed of the caudate nucleus and putamen. The basal ganglia—the part of the brain most prominently affected in early HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system [18] and the motor circuit.

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 motion or motions to be unintentionally initiated, or 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. Because of the basal ganglia's inability to inhibit movements, individuals affected by it will inevitably experience a reduced ability to produce speech and swallow foods and liquids dysphagia. CREB-binding protein CBP , 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.

Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus. Medical diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease.

Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat 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. A physical examination , sometimes combined with a psychological examination , can determine whether the onset of the disease has begun. 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 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. Cerebral atrophy can be seen in 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, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis.

Testing before the onset of symptoms is a life-changing event and a very personal decision. It occurred at higher rates within personal relationships than health insurance or employment relations.

Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxias.

Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis PGD. This technique, where one or two cells are extracted from 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, and therefore 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, the embryos' 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 non-disclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.

It is also possible to obtain a prenatal diagnosis for an embryo or fetus in the womb, 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. 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, non-invasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother via venipuncture between six and twelve weeks of pregnancy.

Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. There are also autosomal recessive disorders that resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration. One X-linked disorder of this type is McLeod syndrome.

There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms. Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the risk of aspirating food and provides better nutritional management. People with Huntington's disease may see a physical therapist for non-invasive and non-medication-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 the development of respiratory problems.

Participation in rehabilitation programs during early to middle stage of the disease may be beneficial as it translates into long term maintenance of motor and functional performance.

Rehabilitation during the late stage aims to compensate for motor and functional losses. Tetrabenazine was approved in for treatment of chorea in Huntington's disease in the EU, and in in the US. Psychiatric symptoms can be treated with medications similar to those used in the general population. The families of individuals 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. Also covered is information concerning family planning choices, care management, and other considerations.

A longer repeat results in an earlier age of onset and a faster progression of symptoms. The largest risk 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.

It is unclear to what extent suicidal thoughts are influenced by behavioral symptoms, as they signify sufferers' desires to avoid the later stages of the disease. The late onset of Huntington's disease means it does not usually affect reproduction. The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per , people, and is lower in the rest of the world; e.

A epidemiological study of the prevalence of Huntington's disease in the UK between and found that the average prevalence for the UK was Until the discovery of a genetic test , statistics could only include clinical diagnosis based on physical symptoms and 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.

Although Huntington's has been recognized as a disorder since at least the Middle Ages , the cause has been unknown until fairly recently. Huntington's was given different names throughout this history as understanding of the disease changed.

Originally called simply 'chorea' for the jerky dancelike movements associated with the disease, HD has also been called "hereditary chorea" and "chronic progressive chorea". Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease.

The first thorough description of the disease was by George Huntington in 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 the disease as his first paper.

Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance. When either or both the parents have shown manifestations of the disease But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.

Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described.

During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.

The search for the cause of this condition was enhanced considerably in , when the Hereditary Disease Foundation HDF was created by Milton Wexler , a psychoanalyst based in Los Angeles , California , whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease. The foundation was involved in the recruitment of over scientists in the Huntington's Disease Collaborative Research Project who over a year period worked to locate the responsible gene.

Thanks to the HDF, the ongoing US-Venezuela Huntington's Disease Collaborative Research Project was started in , and reported a major breakthrough in with the discovery of the approximate location of a causal gene. It involved over 18, people—mostly from a single extended family.

Among other innovations, the project developed DNA -marking methods which were an important step in making the Human Genome Project possible. In the same time frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding 's research group on the effects of the gene's length. Modelling the disease in various types of animals, such as the transgenic mouse developed in , enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans, results from experiments are received sooner, speeding research.

The discovery that mHTT fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.

The condition was formerly called 'Huntington's chorea' but this term has been replaced by 'Huntington's disease' because not all patients develop chorea and due to the importance of cognitive and behavioral problems. Huntington's disease, particularly the application of the genetic test for the disease, has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters.

There was controversy when Charles Davenport proposed in that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells. The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.

There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of an effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.

There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease. This would require parts of the process to be kept secret from the parent. In , after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation HDF , with the aim of curing genetic illnesses by coordinating and supporting research. Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD.

A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network. The largest funder of Huntington's disease research globally, in terms of financial expenditure, [] is the CHDI Foundation , a US non-profit biomedical foundation that aims to "rapidly discover and develop drugs that delay or slow Huntington's disease".

Research into the mechanism of HD has focused on identifying the functioning of HTT, how mHTT differs or interferes with it, and the brain pathology that the disease produces.

Research is conducted using in vitro methods, animal models and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Research is being conducted on many different approaches to prevent Huntington's disease or slow its progression. Disease-modifying strategies can be broadly grouped into three categories: In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than disease-modifying therapies, and include phosphodiesterase inhibitors.

Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHTT is reduced, symptoms improve.

One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele. Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors , modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.

Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials.

Several clinical trials of new experimental treatments are underway and planned in Huntington's disease. Compounds that have failed to prevent or slow progression of Huntington's disease in human trials include remacemide , coenzyme Q10 , riluzole , creatine , minocycline , ethyl-EPA , phenylbutyrate and dimebon. From Wikipedia, the free encyclopedia. List of Huntington's disease media depictions. Archived from the original on 27 July Retrieved 19 July A Journey through History".

Tremor and other hyperkinetic movements New York, N. Archived from the original on 4 July Archived from the original on 19 November Retrieved 18 November Huntington's Disease Society of America. Archived from the original on 9 April Retrieved 17 March J Neuropsychiatry Clin Neurosci. Archived from the original on 10 February Retrieved 12 March Huntington's Outreach Project for Education, at Stanford.

Archived from the original on 8 August Retrieved 4 August Huntington's Disease — Third Edition. Neurology, Psychiatry and Brain Research 8: Archived PDF from the original on 23 March Retrieved 1 April HD Society of Canada. Archived PDF from the original on 25 June Retrieved 10 August Bradley's neurology in clinical practice 6th ed. Archived from the original on 9 July Color Atlas of Genetics 2nd ed. Journal of Medical Genetics. Archived from the original on 14 July Journal of Huntington's disease.

Retrieved 27 April Molecular basis of neurodegeneration". Expert Rev Mol Med. Nature Reviews Disease Primers: