La maladie de Huntington est une affection dégénérative du cerveau d’origine I -Présentation de la chorée de Huntington et description de ses troubles. La clozapine, antipsychotique atypique, semble efficace sur les symptômes psychotiques liés à la chorée de Huntington. Nous rapportons le cas d’une patiente. PDF | On, R. de Diego Balaguer and others published ASPECTS CLINIQUES ET NEUROPSYCHOLOGIQUES DE LA MALADIE DE HUNTINGTON.
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Huntington’s disease HDalso known as Huntington’s choreais an inherited disorder that results in death of brain cells.
There is no cure for HD. The first likely description of the disease was in by Charles Oscar Huntongton. The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea.
Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowingand speaking. Seizures are also a common symptom of this form of HD. Cognitive abilities are progressively impaired.
Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic memory of one’s lifeprocedural memory of the body of how to perform an activity and working memory. Reported neuropsychiatric manifestations are anxietydepressiona reduced display of emotions blunted affectegocentrismaggressionand compulsive behaviorthe latter of which can cause or worsen addictionsincluding alcoholismgamblingand hypersexuality.
Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophycardiac failureimpaired glucose toleranceweight lossosteoporosisand testicular atrophy. The gene is also called HD and IT15which stands for ‘interesting transcript 15’.
Part of this gene is a repeated section called a trinucleotide repeatwhich varies in length between individuals and may change length between generations.
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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 the huntingtoj of pathological changes which in turn cause the disease symptoms.
The Huntington’s disease mutation is genetically dominant and almost fully penetrant: It is not inherited according to sex, but the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent. HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.
Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly.
Huntington’s disease – Wikipedia
The remaining variation is attributed to environment and other genes that modify the mechanism of HD. In some cases the onset may be so late that symptoms are never noticed. 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. This probability is sex-independent. Trinucleotide CAG repeats over 28 are huntinggon during replicationand this instability increases with the number of repeats present.
Individuals with both genes affected are rare.
For some time HD was thought to be the only disease for which possession of 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.
The huntingtin protein interacts with over other proteins, and appears to have multiple biological functions. Early damage is most evident in the striatumbut as the disease progresses, other areas of the brain are also more conspicuously affected. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood and higher cognitive function.
HTT is expressed in all cells. The highest concentrations are found in the brain and testeswith moderate amounts in the liverheartand lungs. It interacts with proteins which are involved in transcription, cell signalingand intracellular transporting.
Caspasean 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 anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factora protein which protects neurons and regulates their creation during neurogenesis.
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 huntinhton, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the basal ganglia called the neostriatumwhich 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  and the motor circuit. To dr 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 yuntington or hntington 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 CBPa transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of huntingtton 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 chored 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 huntiington, relatives and relationships. A physical examinationsometimes combined with a psychological examinationcan determine whether the onset of the disease has begun. If these are abrupt and have random timing and distribution, they suggest hcoree diagnosis of HD.
Cognitive or behavioral symptoms are rarely chores 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 scalewhich provides an overall rating system based on motor, behavioral, cognitive, and chlree 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 PETcan 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, ee then be used to ensure embryos affected with HD genes are not implanted, and therefore cgoree offspring will not inherit the disease.
Some forms of preimplantation genetic diagnosis—non-disclosure or ve 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, huntingtoh 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 huntingtln 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 pregnancyand on the difficulties of a child with chodee 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 choreee 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 huntingtin 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 hhntington advances.
This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the hkntington 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. Additionally, an increasing number of people with Huntington’s disease 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 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, 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. Also covered is information concerning family planning choices, care management, and other considerations.