What Is Huntington Chorea?

Huntington's disease (HD) is a rare autosomal dominant genetic disease. Patients generally develop middle-aged symptoms with motor, cognitive, and mental symptoms. The clinical symptoms of Huntington's disease are complex and changeable, and the patient's condition is progressively worsening, usually dying 15 to 20 years after onset. The onset of the disease is hidden, and the progress is slow. Dance-like movements with progressive cognition, mental dysfunction and finally dementia are the main characteristics of the disease. The etiology is the incorrect expression of the polynucleotide repeat sequence on the Huntington gene, which affects different molecular pathways and eventually leads to neurological dysfunction and degradation.

Basic Information

nickname

Huntington's disease, Huntington's disease, chronic progressive dance disease

Visiting department

Neurology

Common locations

brain

Common causes

Misrepresentation of Repeated Polynucleotide Sequences on Huntington Gene

Common symptoms

Dance-like movements with progressive cognition, mental dysfunction and finally dementia are the main characteristics of the disease

Contagious

no

Causes of Huntington's disease

Huntington's disease is a fully penetrating autosomal dominant hereditary disease. After confirming the gene locus, it took many years of research to find its pathogenic gene Htt (Huntingtin). This gene encodes the Htt protein (Huntingtinprotein), and in its first exon, it contains a repeated CAG triplet codon. In HD, the number of repetitions of this triple codon will increase abnormally. Individuals with more than 36 CAG repeat triplets will develop the disease. However, if the number of repetitions is 36 to 39, the total penetrance is low. The number of triad repeats is unstable, and it can change when inherited to the next generation. The mutant Htt protein expressed in the brain causes neural function to degenerate through different molecular mechanisms. Mutated proteins not only promote the abnormal function of the protein but also lead to the loss of normal functions. The normal Htt protein itself has a variety of cellular functions, and Htt protein mutations cause these dysfunctions. Protein mutations often first appear as abnormal expression of related genes. Previous studies have shown that the genes related to nerve conduction in HD striatum have abnormal expression. In addition, CAG's abnormal repetition can affect intermolecular interactions on a large scale, leading to disordered intracellular protein transport. Htt protein mutations not only disrupt the gene regulation of mitochondrial function-related proteins, but also react with proteins on the surface of mitochondrial membranes, damage the function of the respiratory chain, prevent mitochondria from fixing to microtubules, affect dynamic fusion and division of mitochondria, and increase calcium transmission. Mutated proteins can also inhibit autophagy, promote apoptosis, change neurotrophic energy supply and biological and signal synthesis in the cell cytoplasm.

The prevalence of HD varies greatly among different populations. The prevalence of HD is 4 to 8 in 100,000 people. Recent studies have shown that the prevalence of HD in China / Japan is 0.40, while the prevalence in Europe / North America and Oceania is 5.7. In the Chinese literature, there have been only a few case reports before, but as the disease is recognized, case reports will gradually increase.

Clinical manifestations of Huntington's disease

The main clinical symptoms of Huntington's disease (HD) are usually divided into three categories, including motor symptoms, cognitive dysfunction and mental disorders. In addition, HD also affects other systems, and other system symptoms can be primary or secondary complications. The onset of HD is usually around 40 years old. However, there are also very young or very old cases. These patients usually have atypical clinical symptoms, such as children with severe developmental delay and Westphal variant, and the symptoms of elderly patients may be very mild.

The typical symptom of HD is chorea. Chorea itself is similar to dyskinesia caused by levodopa. It is characterized by short-term uncontrollable disguised faces, nodding, and finger beating. With the worsening of the condition, the involuntary movement gradually increases, and typical dance-like involuntary movements, difficulty in swallowing, and dysphonia appear.

Cognitive symptoms of HD sometimes appear many years before chorea. Studies have found that 40% of HD gene carriers have mild cognitive dysfunction, and the closer the disease is, the more obvious their cognitive impairment is. These early changes severely affect patient function. The type of cognitive dysfunction in HD patients is different from other neurodegenerative diseases such as Parkinson's or Alzheimer's disease. In the early stages of HD disease, cognitive impairment is mainly limited to a single brain domain without affecting the entire brain. In the early stage of the disease, not only the episodic memory is affected, but the executive dysfunction is also obvious. Patients may also have emotional cognition, especially aversive cognitive deficits. This may seriously hamper their ability to socialize. Executive dysfunction is also a major problem in HD. Patients with HD often fail to recognize the severity of the symptoms. With the development of the disease, the symptoms of dementia often worsen, but even in severe cases, some cognitive functions may still be preserved.

The psychiatric symptoms of HD are often complex and variable, and are associated with impairment of brain function during the course of the disease. Long before the onset of motor symptoms, HD patients may develop anxiety and develop symptoms of depression due to their family history and disease risk. Later, patients may also experience slight changes in personality, as well as aggressive and de-inhibiting behaviors.

Affected by the disease, HD patients will have sleep disturbances, such as prolonged sleep latency, decreased sleep efficiency, increased number of nocturnal awakenings and reduced deep and slow wave sleep. Changes in sleep conditions are closely related to the severity of other clinical symptoms and brain morphological changes.

Huntington's disease examination

The disease mainly affects the basal ganglia and cerebral cortex, with the caudate nucleus and putamen atrophy being the most prominent. Neuronal loss and glial cell proliferation occur. The cerebral cortex (especially the frontal lobe) atrophy, especially the loss of pyramidal nerve cells and small neurons in layers III, V and VI, without glial cell proliferation. Nerve cell loss can also affect the ventrolateral nucleus of the thalamus, the hypothalamus, the substantia nigra reticulum, the olive body, the thin and nuclei, the white matter, and the mesencephalon nucleus.

There were no special manifestations in early imaging examinations. As the disease progresses, symptomatic caudate nucleus atrophy is typical, and the caudate nucleus area of the forefoot of the lateral ventricle bulges outward, showing a "butterfly sign." The further development of the disease can occur with varying degrees of cortical and subcortical atrophy.

Huntington's disease diagnosis

Diagnosis based on positive family history, typical dance-like movements, mental disorders and progressive dementia, and positive genetic test results.

Huntington's disease treatment

Several existing HD therapies can be classified as symptomatic or causative. The purpose of symptomatic treatment is to directly alleviate the patient's condition based on the objective diagnosis of the doctor and the subjective feedback from the patient. Symptomatic treatment can be further classified. According to the treatment of different main symptoms of sports, mental and cognitive aspects, it can be divided into HD specific and HD non-specific symptomatic treatment.

For the treatment, direct gene therapy and other indirect molecular therapies. The former treats the mutant gene and its transcript as the sole cause, and directly treats it; the latter aims to correct the complex molecules and neural-related pathways that cause the disease. Although it is not possible to achieve treatment at present, a lot of research is being carried out on the different molecular pathways mentioned above in order to slow down the disease. In addition, we must take care of HD patients to support their families. Because it is very important to treat symptoms according to the needs of patients, it is best to implement them through multidisciplinary cooperation. Before the onset and the first stage of the disease, this multidisciplinary team can include neurologists, psychiatrists and genetic counselors.As the patient's condition changes, physical therapists, language and occupational therapists, caregivers and others Join professional medical staff. And hospice care and terminal treatment are getting more and more attention. The main purpose of treatment is still to improve the quality of life of patients. According to the patient's needs, if symptoms such as stigma, physical damage, gait instability, difficulty working, and disturbed sleep are indicated, it is necessary to start taking medication for chorea. Psychotropic drugs are the first choice when patients have psychiatric or aggressive behavior. Tebufenazine is one of the drugs approved by the US Food and Drug Administration (FDA) to treat HD dance movements. The main mechanism of tetrabenazine is to inhibit monoamine vesicle transport. When the drug is used in a large amount, it can significantly reduce dance symptoms, but if the drug is stopped, the dance symptoms will be aggravated. Use of these drugs requires attention to side effects, including bradykinesia and tremors. Also pay attention to depression. Psychotropic drugs also include olanzapine, risperidone, or tapilil. Note that the dose needs to be adjusted according to the patient's response when taking the drug. For some specific patients, sometimes it may be necessary to try several different psychotropic drugs in order to find the most suitable. Baclofen and benzodiazepine are effective in the treatment of dyskinesia at the end of the disease. And chemical nerve blockers such as botulinum toxin can treat local spasms, such as bruxism or focal hyperspasm hyperreflexia. At the same time, physical therapy is also important. Recent studies have shown that focused training posture and gait can be of great help to HD patients.

As there are few studies on the treatment of HD cognitive impairment with drugs, no drug has yet been shown to be effective.

For compulsive and irritable symptoms, stepwise treatment can be recommended. In patients with mild cognitive impairment, serotonin reuptake inhibitors can be used first and can be combined with behavioral therapy. If depression, anxiety, and obsessive-compulsive behavior occur at the same time, serotonin reuptake inhibitors can also be used as first-line drugs. After the medication is adjusted to the optimal dose, the medication should be combined. Behavioral therapy is also available.

Difficulty swallowing generally occurs in the later stages of the disease. There are currently guidelines for swallowing food (beginning before cognitive impairment affects learning ability), including guidelines for proper food preparation and food provision in a monitored environment. It is important to increase the energy intake of the patient in an appropriate way. There is currently no specific effective treatment for Huntington's disease. Some medications can alleviate symptoms but cannot stop the progress of the disease. Etiological treatment is performed at the gene level or the cell level, but they are all at the research stage.

Deep brain stimulation has been applied to patients with relatively rapid progression of motor symptoms due to its unique advantages. The target of electrical stimulation is mainly located on the inner side of bilateral pale globules, and some studies have found that electrical stimulation can not only improve motor symptoms in HD patients, but also improve mood, physical strength, and daily life. Therefore, for patients with high levels of cortical function, the improvement of motor function can significantly improve the quality of life and prolong the time of independent living.

As an emerging therapeutic method, gene therapy, especially RNAi, neurotrophic factor gene introduction and other methods, has shown certain effects in Huntington's disease animal model experiments. However, the transformation from animal experiments to human experiments is still a long way.

HD patients and their loved ones will also face many social and medical problems, which need to be properly addressed by trained professionals.

Huntington's disease prevention

There are already many symptomatic treatments available for HD, and comprehensive care plans also benefit patients and their families. Clinical research and care programs are in place, and a large network of clinics, researchers, and medical organizations has been established worldwide. With the cooperation of researchers, medical workers, patients, and the social environment, I believe that HD patients can get early diagnosis and optimal treatment.