Huntington's chorea: diagnosis, symptoms and treatment

The prevalence of the genetic disease Huntington's chorea is about 10 cases per 100 thousand people in the world. Pronounced signs of diagnosis include disturbances in the functioning of the musculoskeletal system, convulsions, sudden unconscious jerks of the limbs and deterioration of consciousness. Treatment for Huntington's chorea (a disease involving a disorder of the protein structure of genes) has not yet been created; it is only possible to reduce the patient's symptoms with medication, as well as help reduce movement disorders.

Huntington's chorea, what kind of disease is it?

According to its typology, Huntington's chorea is a neurodegenerative disease during which a person experiences elongation of repeats of the gene that is responsible for the huntingtin protein. Until now, scientists have not been able to unambiguously establish the function performed by the protein. However, in medicine there are certain standards that indicate the length of triplets (genes) in a healthy person.

Huntington's chorea, what kind of disease is it from the point of view of complex human genetics? In healthy people, the number of repetitions of the huntingtin protein varies depending on age and other characteristics in the body, ranging from 11 to 34 triplets. When diagnosing Huntington's chorea, the number of repetitions starts at 37 and can reach 100 triplets. This gene defect does not begin to appear from birth, but only after a person reaches the age of 30-40 years.

Huntington's chorea disease

Scientists have proven that in more than 90% of patients worldwide, Huntington's chorea is diagnosed at the age of 40-50 years. It is during this period of life that the patient begins to actively manifest all the symptoms and signs of a gene disease that cannot be stopped. Currently, this disease is considered incurable, since it manifests itself against the background of a violation of the genetic structure of the brain. Treatment of chorea is based on the principle of making life easier for the patient and reducing the manifestation of symptoms associated with dysfunction of the musculoskeletal system.

Throughout the world, the disease varies in the length of time a person survives after diagnosis. The average life expectancy of a patient with Huntington's chorea is 15 years. Such a long period is observed only in people receiving constant conservative treatment. Those patients who do not receive proper treatment and are not observed by specialists live no more than 7-9 years.

Optogenetics

Optogenetics is a method that combines the approaches of genetics and optics for fine control of the electrical activity of electrically excitable cells (neurons and muscle fibers) [9]. To do this, genes of special light-sensitive proteins—microbial opsins, which are ion channels or pumps—are introduced into the cells under study (Fig. 7). The first work showing the possibility of controlling the electrical activity of neurons using opsin was published in 2005. Over the next few years, a number of experimental works appeared that made it possible to refine this technique and prove its applicability under various experimental conditions.

In recent years, many different opsins have been discovered, of which halorhodopsins and channelrhodopsins have found the most application in optogenetics. When the opsin gene is delivered using genetic engineering methods into a neuron, light-sensitive channels appear on the plasma membrane, and the cell itself becomes light-sensitive. When exposed to blue light, the channelrhodopsin pore opens (maximum absorption - 470 nm), which causes the movement of positively charged ions into the cell, ensuring depolarization of the neuron membrane and the generation of action potentials. When exposed to yellow light, halorhodopsin is activated (maximum absorption - 580 nm), the neuron membrane is hyperpolarized, causing inhibition of the neuron. The high temporal resolution of optogenetics allows for very fine regulation of synaptic events and is therefore an important tool for studying interneuronal connections.

The combined use of optogenetics and classical electrophysiology techniques allows us to benefit from the positive qualities of each of these approaches. The precision of electrophysiological recording is combined with the ability to use light stimuli of varying durations and intensities to help scientists study the workings of neural connections in detail.

The electrical activity of neurons is expressed in sharp voltage surges on the cell membrane and the resulting appearance of an electric current. These sudden jumps are called spikes or action potentials and last a few milliseconds (Figure 8). We found that the longer a neuron is illuminated with blue light, the more spikes it creates during this time. If the illuminated neuron is connected by a synaptic contact with another neuron, then response activity can be recorded on the second neuron, also in the form of individual spikes.

Figure 8. An example of a recording obtained from electrophysiological recording of neuron activity. Spikes (action potentials) are reflected in the recording as vertical lines showing sharp jumps in membrane current.

In our experiments, we used a pair of young (14 days) cortical and striatal neurons connected by synaptic contact. The cortical neuron was activated with blue light, and the response activity was recorded on the striatal neuron. It turned out that for a response to occur on a striatal neuron, a certain duration of illumination (activation threshold) is required. If the duration of illumination was below the threshold value, then a spike on a striatal neuron did not occur in response to every flash of light. And most importantly, the activation threshold for neurons from the brains of healthy mice was different from YAC128 mice (with a mutation in the huntingtin gene). This difference was most clearly visible at 50% activation of the striatal neuron, i.e. the duration of illumination at which a spike occurs in response to every second flash of light. The threshold for 50% activation of a striatal neuron in response to irradiation of a cortical neuron for the YAC 128 cell culture was approximately two times (more precisely 2.3 ± 0.8) higher compared to the positive control [10].

It turns out that a mutation in the huntingtin protein leads to the fact that synaptic transmission deteriorates even in young neurons, and the disturbances occur at the functional level (without morphological changes). Could it be that it is these functional disorders that subsequently lead to the appearance of morphological changes, such as the disappearance of spines in old striatal neurons?

To answer this question, we again turned to optogenetics for help, but now with its help we suppressed the activity of neurons with light (Fig. 9a). If our assumption is correct, then the temporary absence of the activating influence of the cortex should lead to the disappearance of spines on striatal neurons in the YAC128 culture. Indeed, after the experiment, the number of spines in the positive control remained unchanged, but in the YAC128 culture it decreased significantly (Fig. 9b, c). It turns out that neurons modeling HD are especially sensitive to weakening the activating influence of cortical neurons , therefore, long-term weakening of the synaptic connection between these neurons leads to a decrease in the number of spines on the 20th day of cultivation [10].

Figure 9. Influencing neurons using optogenetics. a — suppression of cortical neuron activity using optogenetics. When a neuron is illuminated with yellow light (orange stripe), it becomes inactive—there are almost no spikes in the electrophysiological recording during this period of time. b — influence of long-term optogenetic inhibition on the morphology of neurons. Micrographs show a decrease in the number of spines on the dendrite of the YAC128 neuron. c — change in the density of dendritic spines after optogenetic inhibition. In the wild-type culture, the number of spines does not change, but in the YAC128 culture, spine density is significantly reduced.

In summary, we found that in our HD model there is a disruption of synaptic transmission that develops in two stages. At an early stage (young neurons, on day 14 of neuron culture), a functional weakening of the synaptic connection occurs, which at a later stage (old neurons, on day 20 of culture) leads to morphological disturbances of synaptic contacts.

Symptoms of Huntington's chorea

Most often, the onset of symptoms occurs in adults over 30 years of age, but there are always exceptions and the disease may begin to develop earlier. All symptoms appear mild at the very beginning of the disease and begin to progress over time. The main symptoms of Huntington's chorea are as follows:

1. It is very difficult to diagnose a specific disease for an ordinary person or a relative of the patient, since during the first 6-12 months chorea may simply resemble a person’s increased fussiness or restlessness.
2. After the development of the first symptoms, the intensity of disturbances in the functioning of the musculoskeletal system gradually begins to increase.
3. Even in a calm state and without physical activity, a person can experience sudden cramps in the upper and lower extremities of the body. One of the symptoms is spasms of the facial muscles, which appear during conversation or look like grimacing. Over time, increased gesticulation begins to appear, becoming out of place. Attention and thinking become scattered, confused and difficult.
4. At an advanced stage of the disease, an unsteady gait, reminiscent of a person in a strange dance, is added to the symptoms. This occurs due to impaired coordination of the musculoskeletal system under load.

Mental changes

The psyche in HD undergoes gradual pathological changes. A decrease in a person’s ability to fully think is characterized, first of all, by problems with memory and a decrease in the critical threshold for perceiving one’s own state. The patient becomes anxious, irritable or, conversely, apathetic. In severe cases, hallucinatory or delusional syndromes develop. Suicidal behavior is also common in the context of severe depression.

Also, the following mental symptoms may appear:

• aggressive outbursts;
• insomnia;
• impulsiveness and spontaneity in behavior;
• social alienation.

Delusions and hallucinations are much less common. As for mental disorders, as the disease progresses, patients gradually lose memory acuity, logic and concentration. They find it difficult to make independent decisions and give clear answers to even the simplest questions. Over time, they learn new information worse and worse, which is an obvious sign of progressive dementia.

Signs of Huntington's chorea

Unlike the symptoms of the disease, the signs of Huntington's chorea can only be recognized by a professional doctor. In medical practice, to make a diagnosis, it is necessary to identify 3 groups of characteristic signs of nervous and mental disorders in a patient. They are the most common, and begin to appear after a person’s motor reflexes are impaired. Neuropsychiatric signs are conventionally divided into 3 subgroups:

• signs of impaired cognitive function, which most often affect orientation in space and visual touch of objects. Emerging problems prevent the sick person from seeing normally the image or picture happening around him. Every day it becomes more and more difficult to recognize any schematic drawings, elements on a TV screen or letters in a newspaper;
• signs associated with impaired consciousness or impaired intellectual function of the patient. Memory failures appear, but this does not affect the ability to remember information from the past, but the performance of the brain. A person can no longer, as before, be productively engaged in several things. The patient experiences difficulties when planning his time or organizing activities;
• signs manifested in violation of emotional and behavioral functions. The patient may notice sudden outbursts of aggression or irritability that were not caused by anything. Almost half of patients suffer from depression, but they themselves do not realize it.

Consequences and complications

After 15-20 years, patients develop complications:

• Dysphagia , in severe cases of which the possibility of percutaneous endoscopic gastrostomy (installation of a feeding system in the stomach) is considered.
• Loss of body weight up to cachexia , which is associated not only with impaired swallowing, but also with cognitive impairment, when the patient loses the skills of eating or forgets to take it.
• Aspiration pneumonia due to dysphagia.
• Heart failure.

Diagnosis of Huntington's chorea

If a person complains of the above symptoms, and relatives or friends observe the development of all signs of the disease in the patient, then the diagnosis of Huntington’s chorea first begins with a trip to the doctor and prescribing a genetic test for the patient.

Diagnostics will allow us to identify a pathological gene in a person that led to the development of Huntington's chorea. Only in this case can we talk about confirming this diagnosis. In addition to genetic research, computer and magnetic resonance imaging of the cerebral cortex are used as types of disease diagnosis in medical practice.

A complex genetic study consists of DNA analysis, based on the results of which a doctor can judge whether a person has an abnormal gene. The disease can be inherited, since with a probability of more than 50% repeated genes are passed on to children from one of the affected parents.

Treatment of Huntington's chorea

The disease is a genetic disorder of a person, so there is currently no specific treatment for it. All the efforts of doctors can be aimed at maintaining a person’s mental balance, as well as eliminating movement and behavioral disorders. Thanks to special medications, it is possible to minimize problems with a person’s gait or being in society.

To treat and prevent the development of Huntington's chorea, complex treatment is used, but only after a deoxyribonucleic acid test and medical genetic counseling. The mutant gene cannot be treated, and it is important in the initial stages of the disease not to confuse it with schizophrenia, hereditary ataxia or Alzheimer's disease. This is precisely why DNA analysis is performed, since in other mental disorders the number of trinucleotide repeats does not increase.

Medicine to treat Huntington's chorea

Until now, there is no medicine in the world that could completely cure a person from Huntington’s chorea. But the whole essence of treatment in modern medicine comes down to reducing the symptoms of the disease. Medicine for the treatment of Huntington's chorea, more precisely for the elimination of disorders associated with behavioral and motor functions, can be selected from 3 main pharmacological groups of prescription drugs:

1. Phenotosians help block dopamine receptors in the human body. Most drugs from this group, for example, Promethazine or Fluorophenazine, suppress the functioning of human histamine and serotonin receptors.
2. The haloperidol group of drugs is aimed at reducing behavioral disorders. The drugs have antipsychotic properties, help block dopamine receptors in the human body and partially restore behavioral functions. However, while taking potent drugs, the patient very often develops side effects such as constant drowsiness, sudden motor movements that are beyond the patient’s self-control, and a decrease in the muscles of the whole body.
3. A group of benzodiazepines as part of medications is prescribed to patients to reduce the body’s convulsive reactions. In addition, benzodiazepine-based drugs help the patient sleep better. The effect of such drugs is achieved by inhibiting GABA (aminobutyric acid) receptors, which are stimulated by the nervous system.

List of sources

• Shtok V.N., Ivanova-Smolenskaya I.A., Levin O.S. Extrapyramidal disorders: Guide to diagnosis and treatment. - M.: Medpress inform, 2002. - 700 p.
• Shtok V.N., Levin O.S. Drug-induced extrapyramidal disorders //In the world of drugs. - 2000. - No. 2. - P. 3-7.
• Seliverstov Yu.A. and others // Nervous diseases. 2014. No. 3. P. 24.
• Tyurin N.A., Artamonova V.A., Alexandrova K.A. and others. Features of the modern course of minor chorea in children. Pediatrics. 1987; 2:20–23.
• Pediatric rheumatology (Guide for doctors) / Ed. Baranova A.A., Bazhenova L.K., 2002; 49.

Huntington's Chorea Clinic

Treatment of the disease should be carried out only under the guidance and supervision of doctors at a psychiatric clinic. A genetically complex disease can manifest itself differently at any time, so it is important not to miss the moment when symptoms begin to appear. A Huntington's chorea clinic should specialize in neurological disorders in humans.

A slowly progressing disease of the nervous system and cerebral cortex is incurable, but a person with such a diagnosis must be constantly under the supervision of a specialist who can correctly calculate and apply a medication in an emergency. Sick people require careful care, as well as the supervision of doctors such as psychiatrists, neurologists, psychologists, ophthalmologists and orthopedists.

Clinical guidelines for Huntington's chorea

The list of basic recommendations should be compiled individually after examining the sick person by a psychiatrist and neurologist. The main clinical recommendations for Huntington's chorea are highlighted, which must be followed while in the hospital or when the patient is at home. The patient should regularly receive drugs that reduce the activity of dopamines in the cerebral cortex, the dose being increased every 3 days.

Parents, one of whom has been diagnosed with a genetic disease, are not recommended to have children. The probability of inheriting Huntington's chorea exceeds 50%; if pregnancy occurs, a DNA test is required for the unborn child. Statistically, people with Huntington's chorea most often die from pneumonia, cardiac activity, or other congestive processes in the body, so it is important to promptly treat any secondary diseases.

Prevention

There is no prevention for Huntington's disease because it is a genetically determined disease. It is impossible to prevent the disease in mutation carriers. People of childbearing age who have relatives with this disease must undergo genetic testing. If a carrier of a mutation is detected, it is recommended to avoid childbearing. As for rheumatic chorea, the following measures are the prevention of rheumatism and, accordingly, its complications in the form of hyperkinesis:

• hardening;
• good nutrition;
• rational physical education;
• walks in the open air;
• carrying out sanitary and hygienic measures that reduce the risk of streptococcal infection of children in the team;
• timely and effective treatment of sore throat and pharyngitis ;
• year-round bicillin prophylaxis for rheumatism .

The standard antibiotic treatment regimen for sore throat should be 10 days. The optimal penicillin drug is Flemoclav Solutab (amoxicillin/clavulanate). In case of poor intolerance to β-lactam antibiotics, macrolides ( Azithromycin , Clarithromycin , Josamycin ) are prescribed. Secondary prevention of repeated attacks of rheumatism involves year-round administration of long-acting penicillins ( Extencillin , Retarpen , Bicillin 5 and Bicillin 1 ).

The duration of secondary prevention can be 5 years to lifelong use (for patients with heart disease). An effective dosage form is Extensillin , which has advantages over Bicillin-5 . Of the domestic drugs, Bicillin-1 (injections once a week).