Huntington's Disease

Huntington's disease is an autosomal dominant neurodegenerative disease, which is characterized by a progressive cognitive impairment beginning in middle age, involuntary movements and coordination of movements. The diagnosis is confirmed by genetic testing. Treatment is predominantly symptomatic. Blood relatives can be recommended to undergo genetic testing. George Huntington was the first to describe this condition in 1872, after examining a familial case of the disease from residents of Long Island.

The prevalence of Huntington's disease is about 10 cases per 100,000 population, and, given its late onset, about 30 people out of 100,000 have a 50% risk of getting it in their lifetime. Although most often the disease manifests itself at the age of 35-40 years, the age range of its onset is quite wide: the earliest onset is noted at the age of 3 years, and the most recent - at 90 years. Although initially it was believed that the disease is characterized by 100% penetrance, it is now believed that this is not always the case. In persons who inherited the gene for the disease from the father, the disease appears on average 3 years earlier than comfort, who inherited the pathological gene from the mother. At the same time, in about 80% of patients who inherited the pathological gene from the father, the disease manifests itself up to 20 years. The phenomenon of an earlier manifestation of a genetic defect in the offspring is called anticipation.

[1],

What causes Huntington's disease?

Huntington's disease has no tender preferences. Atrophy of the caudate nucleus is shown, where small neurons degenerate and the level of neurotransmitters - gamma-aminobutyric acid (GABA) and substances P. Decreases.

A mutant gene with an increased number (“expansion”) of CAG DNA sequences (cysteine - alanine - glycine), encoding the amino acid glutamine, is responsible for the development of Huntington's disease. The product of this gene - large protein gatinging - contains an excess amount of polyglutamine residues, which leads to the disease by an unknown mechanism. The more repeats CAG, the earlier the disease debuts and the heavier its course. From generation to generation, the number of repetitions may increase, which over time leads to an aggravation of the family phenotype.

Despite considerable interest in genetic and biochemical changes in Parkinson's disease, the search for the disease gene was unsuccessful until the late 1970s. At this time, Nancy Wexler and Allan Tobin (A. Tobin) organized a workshop sponsored by the Hereditary Disease Foundation in order to discuss the strategy for searching for the Huntington's disease gene. David Houseman (D. Housman), David Botstein (D. Votstein) and Ray White (R. White) who participated in the meeting suggested that the newly developed DNA recombination techniques can help achieve this goal. The key task in the project under development was to search for a large family, whose members suffered from Huntington's disease in many generations, to obtain DNA samples. In 1979, a joint project of scientists from Venezuela and the United States was launched, which included a survey of a large family with Huntington's disease living on the coast of Lake Maracheibo (Venezuela). In 1983, the gene of the Huntington's disease was located at the end of the short arm of the 4th chromosome (Gusella et al., 1983), and a decade later it was revealed that the mutation of this gene is an increase in the number of repetitions of the cytokine-adenine-guanine trinucleotide (CAG) (Huntington's Disease Collaborative Research Group, 1993). The methodology developed by this scientific group is currently considered standard for the positional cloning of new genes.

While the wild-type gene has a stretch of 10-28 CAG repeats, the mutant form of the gene that causes Huntington's disease has a stretch increased from 39 to more than 100 CAG repeats. Identification of the expansion of trinucleotide repeats allowed us to explain many clinical features of the disease. In particular, an inverse correlation was found between the age of onset and the length of the site with repeated trinucleotides. Anticipation of paternal inheritance can be explained by the fact that an increase in the number of repetitions often occurs in men during spermatogenesis. The analysis of new mutations showed that they usually arise when one of the parents, usually the father, had a number of repeats of CAG higher than 28; in this case, the number of repetitions increased in the next generation. It is now established that if the number of repetitions is no more than 28, then it is stably transmitted from generation to generation. If the number of repetitions is from 29 to 35, then the symptoms of Huntington's disease do not appear, but when transferred to the offspring, the length of this area may increase. If the number of repetitions is from 36 to 39, then in some cases (but not always) the disease may manifest itself clinically (incomplete penetrance), and by transmitting to the offspring, an increase in the number of trinucleotide repeats may occur. If the number of repetitions exceeds 40, then the disease occurs in almost all cases, and with the transfer to offspring, further expansion of repetitions is possible. The reasons for the increase in the number of repetitions remain unknown.

Pathomorphology of Huntington's Disease

Huntington's disease is characterized by the death of neurons predominantly in the caudate nucleus and the shell, to some extent also in the cortex and other structures of the brain. The total weight of the brain in Huntington's disease is reduced not only by reducing the number of neurons, but due to the loss of white matter. In the cerebral cortex, cells in layers V and VI are most affected. The severity of micro- and macroscopic degenerative changes (with age correction at the time of death) correlates with the number of CAG repeats. A detailed pathological analysis of changes in several hundred cases of Huntington's disease showed that the striatum degeneration begins with the dorsomedial portion of the caudate nucleus and the dorsolateral portion of the shell, and then propagates in the ventral direction. Different groups of neurons of the caudate nucleus and the shell do not suffer to the same extent. Inserted neurons in the striatum remain relatively intact, but some projection neurons are selectively affected. In the juvenile form of Huntington's disease, pathological changes in the striatum are more pronounced and more common, involving the cerebral cortex, the cerebellum, the thalamus, the pale ball.

[2], [3], [4],

Neurochemical changes in Huntington's disease

GABA. A neurochemical study of the brain in patients with Huntington's disease revealed a significant decrease in the concentration of GABA in the striatum. Subsequent studies confirmed that the number of GABAergic neurons is reduced in Huntington's disease, and showed that the concentration of GABA is reduced not only in the striatum, but also in its projection zones - the outer and inner segments of the pale globe, as well as the substantia nigra. In the brain of Huntington's disease, a change in GABA receptors was also revealed using receptor binding and in situ hybridization of mRNA. The number of GABA receptors was moderately reduced in the caudate nucleus and shell, but increased in the reticular part of the substantia nigra and the outer segment of the pale globe, which is likely, due to denervation hypersensitivity.

Acetylcholine. Acetylcholine is used as a neurotransmitter for large non-visible intercalary neurons in the striatum. In early post-mortem studies in patients with Huntington's disease, a decrease in cholinecetyltransferase (HAT) activity was detected in the striatum, which could indicate a loss of cholinergic neurons. However, in comparison with a significant decrease in the number of GABAergic neurons, cholinergic intercalated neurons remain relatively intact. Consequently, the density of acetylcholinesterase-positive neurons and the activity of HAT in the striatum are actually relatively elevated compared to controls that are age-balanced.

Substance R. Substance P is contained in many medium styloid neurons of the striatum, which are mainly projected onto the inner segment of the pale ball and the substantia nigra and usually also contain dorforph and GABA. The level of substance P in the striatum and the reticular part of the substantia nigra is reduced in Huntington's disease. At the terminal stage of the disease using immunohistochemical studies revealed a significant decrease in the number of neurons containing substance R. At earlier stages, neurons containing substance P and projected onto the inner segment of the pale ball are relatively preserved compared to neurons projecting onto the reticular part of the black substance.

Opioid peptides. Enkephalin is found in the medially styled projection GABAergic neurons of the indirect pathway, projecting onto the outer segment of the pale ball and carrying D2 receptors on themselves. Using immunohistochemical studies, it was shown that at the early stage of Huntington's disease, there is a loss of enkephalin-containing neurons projecting onto the outer segment of the pale ball. These cells, apparently, die earlier than cells containing substance P and projecting onto the inner segment of the pale ball.

Catecholamines. Neurons containing biogenic amines (dopamine, serotonin) and projected onto the striatum are located in the compact part of the substantia nigra, ventral lid and suture nuclei. While noradrenergic projections into the striatum of humans are minimal, the levels of serotonin and dopamine (in terms of grams of tissue) in the striatum are elevated, indicating the safety of these afferent projections against the background of pronounced loss of striatal neurons of their own. Dopaminergic neurons of the substantia nigra remain intact in both the classical and juvenile forms of Huntington's disease.

Somatostatin / neuropeptide Y and nitric oxide synthetase. Measuring the level of somatostatin and neuropeptide Y in the striatum in Huntington's disease revealed their 4-5-fold increase compared with normal tissues. Using immunohistochemical studies, absolute safety of interstitial striatum neurons containing neuropeptide Y, somatostatin and nitric oxide synthetase was stated. Thus, these neurons are resistant to the pathological process.

Exciting amino acids. It has been suggested that selective cell death in Huntington's disease is associated with a glutamate-induced neurotoxic effect. The levels of glutamate and quinolinic acid (endogenous neurotoxin, which is a byproduct of serotonin metabolism and an agonist of glutamate receptors) in the striatum for Huntington's disease are not significantly altered, but a recent study using MR - spectroscopy revealed an increase in glutamate in vivo. The level of glial enzyme responsible for the synthesis of quinolinic acid in the striatum in Huntington's disease is increased by about 5 times compared with the norm, while the activity of the enzyme that provides degradation of quinolinic acid is increased in Huntington's disease only by 20-50%. Thus, quinolinic acid synthesis in Huntington's disease can be enhanced.

Investigations of excitatory amino acid receptors (HAC) in Huntington's disease revealed a significant decrease in the number of NMDA-, AMPA-, kainate and metabotropic glugamat receptors in the striatum, as well as AMPA- and kainate receptors in the cerebral cortex. At the late stage of Huntington's disease, NMDA receptors were practically absent, at the preclinical and early stages there was a significant decrease in the number of these receptors.

Selective sensitivity. In Huntington's disease, certain types of striatal cells selectively die. The middle styloid neurons projecting onto the outer segment of the pale ball and containing GABA and enkephalin already die at a very early stage of the disease, as well as neurons containing GABA and substance P and projecting onto the reticular part of the substantia nigra. The loss of neurons containing GABA and enkephalin and projecting onto the outer segment of the pale ball disarms this structure, which, in turn, leads to active inhibition of the subthalamic nucleus. The decrease in the activity of the subtalamic nucleus can apparently be explained by the choreiform movements that occur in Huntington's disease. It has long been known that focal lesions of the subtalamic nucleus can be the cause of chorea. The loss of neurons containing GABA and substance P and projecting onto the reticular part of the substantia nigra can probably be the cause of oculomotor disorders observed in Huntington's disease. This path normally inhibits neurons of the reticular part of the substantia nigra, projecting onto the upper hillocks of the quadrilateral, which, in turn, regulate saccades. In the juvenile form of Huntington's disease, the paths mentioned above suffer more severely and, in addition, the striatal projections to the inner segment of the pale ball are lost early.

The huntingtin protein encoded by the gene, the mutation of which causes Huntington's disease, is detected in various brain structures and other tissues. Normally, huntingtin is predominantly found in the cytoplasm of neurons. Protein is detected in most neurons of the brain, but, as recent data show, its content is higher in matrix than in striosome neurons, and in projection neurons is higher than in intercalated neurons. Thus, the selective sensitivity of neurons correlates with the content of huntingtin in them, which is normally represented in certain populations of neurons.

As in the brain of patients with Huntington's disease, in mice transgenic for the N-terminal fragment of the Huntington's disease gene with an increased number of repeats, huntingtin forms dense aggregates in the nuclei of neurons. These intranuclear inclusions are formed in striatal projection (but not in intercalary) neurons. In transgenic mice, inclusions form several weeks before the onset of symptoms. These data indicate that the huntingtin protein, which contains an increased number of glutamine residues, the inclusion of which encodes trinucletide repeats, or its fragment accumulates in the nucleus, as a result, the control of cellular functions that it carries out may suffer.

[5], [6], [7], [8], [9], [10], [11]

Symptoms of Huntington's Disease

The age at which the first symptoms appeared, in patients with Huntington's disease, is difficult to determine with precision, since the disease manifests itself gradually. Changes in personality and behavior, minor coordination disorders can occur many years before the appearance of more pronounced symptoms. By the time the diagnosis is established, the majority of patients are found to have choreic movements, incoordination of subtle movements, and a slowdown in the generation of arbitrary saccades. As the disease progresses, the ability to organize its activities is impaired, memory is reduced, speech becomes difficult, oculomotor impairments and impaired performance of coordinated movements increase. Although at the early stage of the disease there are no changes in muscular and posture, due to its progression, dystonic postures may develop, which over time can turn into the dominant symptom. At a late stage, speech becomes unintelligible, swallowing becomes much more difficult, walking becomes impossible. Huntington's disease usually progresses within 15–20 years. In the terminal stage, the patient is helpless and needs constant care. Fatal outcome is not directly linked to the primary disease, but to its complications, for example, pneumonia.

[12], [13], [14]

Dementia in Huntington's Disease

[15], [16], [17]

ICD-10 code

Р02.2. Dementia in Huntington's disease (G10). 

Dementia develops as one of the manifestations of the systemic degenerative-atrophic process with a primary lesion of the striatal system of the brain and other subcohecal nuclei. Inherited by autosomal dominant

As a rule, the disease manifests itself in the third or fourth decade of life with choreiform hyperkinesis (especially in the face, arms, shoulders, gait), personality changes (excitable, hysterical and schizoid types of personality anomalies), psychotic disorders (particular depression with gloominess, gloominess, dysphoria; paranoid mood).

Of particular importance for the diagnosis is the combination of choreoform hyperkinesis, dementia and hereditary burden. The following are specific to this dementia:

• slow progression (average 10–15 years): dissociation between the persistent ability to discuss oneself and apparent intellectual inconsistency in situations requiring productive mental work (conceptual thinking, learning new things);
• severe irregularity of mental performance, which is based on gross violations of attention and inconstancy of the patient’s attitudes (“abrupt” thinking, by analogy with hyperkinesis);
• atypicalness of obvious violations of higher cortical functions;
• inverse relationship between the increase in dementia and severity of psychotic disorders.

Taking into account the high proportion of psychotic (paranoid delusions of jealousy, persecution) and dysphoric disorders in the clinical picture of the disease, treatment is carried out using various neuroleptics that block dopaminergic receptors (phenothiazine and butyrophenone derivatives) or reduce the level of dopamine in the tissues (reserpine).

Haloperidol (2–20 mg / day), tiaprid (100–600 mg / day) for not more than three months, thioridazine (up to 100 mg / day), reserpine (0.25–2 mg / day), anticonvulsant clonazepam (1, 5-6 mg / day). These drugs contribute to the reduction of hyperkinesis, smoothing of affective tension, compensation of personality disorders.

In the hospital, the treatment of mental disorders is carried out taking into account the leading syndrome, age and general condition of the patient. In outpatient treatment, the principles of therapy are the same (continuous maintenance therapy of movement disorders, periodic replacement of the drug). Outpatient use of lower doses of neuroleptics.

Rehabilitation activities for mild to moderate dementia include employment therapy, psychotherapy, and cognitive training. It is necessary to work with family members, psychological support of people caring for the sick. The main method of preventing the disease is medical and genetic counseling of the patient’s close relatives with a referral to DNA analysis in deciding whether to give birth.

The prognosis is generally unfavorable. The course of the disease is slowly progressive, the disease usually leads to death in 10-15 years.

[18], [19]

Diagnosis of Huntington's Disease

The diagnosis is made on the basis of typical symptoms, family history and data of genetic testing. Atrophy of the head of the caudate nucleus, MRI and CG in the late stage of the disease reveal the expansion of the ventricles of the brain.

[20], [21], [22], [23], [24], [25], [26]

Treatment of Huntington's Disease

Treatment of Huntington's disease is symptomatic. Chorea and anxiety can be partially suppressed by neuroleptics (for example, chlorpromazine 25-300 mg orally 3 times / day, haloperidol 5-45 mg orally 2 times / day) or reserpine 0.1 mg orally 1 time / day. Doses are increased to the maximum tolerated (until side effects appear, such as drowsiness, parkinsonism; for reserpine, hypotension). The goal of empirical therapy is to reduce glutamatergic transmission through Nmethyl-O-aspartate receptors and to support energy production in mitochondria. Treatment aimed at increasing GABA in the brain is ineffective.

Genetic testing and counseling are important because the symptoms of the disease manifest themselves at the end of the childbearing age. Persons with a positive family history and those interested in testing are sent to specialized centers, taking into account all the ethical and psychological consequences.

Symptomatic treatment of Huntington's disease

An effective treatment that can stop the progression of Huntington's disease has not yet been developed. Repeatedly conducted tests of various drugs, but to obtain any significant effect was not possible. Neuroleptics and other dopamine receptor antagonists are widely used to correct mental disorders and involuntary movements in patients with Huntington's disease. Involuntary movements reflect an imbalance between the dopaminergic and GABAergic systems. Accordingly, antipsychotics are used to reduce excess dopaminergic activity. However, these drugs themselves can cause pronounced cognitive and extrapyramidal side effects. Moreover, with the exception of those cases when a patient develops a psychosis or arousal, their effectiveness has not been proven. Neuroleptics often cause or aggravate dysphagia or other movement disorders. Neuroleptics of the new generation, such as risperidone, clozapine and olanzapine, may be particularly useful in the treatment of Huntington's disease, as they cause extrapyramidal side effects to a lesser extent, but can weaken paranoid syndrome or increased irritability.

Tetrabenazine and reserpine also weaken the activity of the dopaminergic system and can reduce the severity of involuntary movements at an early stage of the disease. However, these remedies can cause depression. Since the disease itself often causes depression, this side effect significantly limits the use of reserpine and tetrabenazine. At the late stage of the disease, the cells bearing dopamine receptors die, therefore the effectiveness of dopamine receptor antagonists weakens or is lost.

Neuroleptics, antidepressants, and anxiolytics are used to treat psychosis, depression, and irritability in patients with Huntington's disease, but they should be prescribed only for the period when the patient does have these symptoms. Drugs that may be useful at one stage of the disease, as it progresses, may become ineffective or even have an adverse effect.

In patients with Huntington's disease, GABA receptor agonists were tested, because Huntington's disease revealed a significant decrease in GABA levels in the striatum, as well as hypersensitivity of GABA receptors in its projection zones. Benzodiazepines have proven effective in cases where involuntary movements and cognitive impairment are aggravated by stress and anxiety. Low doses of these drugs should be prescribed to avoid undesirable sedation. In most patients with Huntington's disease, none of the drugs leads to a significant improvement in the quality of life.

With the early onset of Huntington's disease, which occurs with parkinsonian symptoms, dopaminergic agents can be tried, but their effectiveness is limited. Moreover, levodopa can cause or strengthen myoclonus in these patients. At the same time, baclofen can reduce the rigidity in some patients of Huntington's disease.

[27], [28], [29], [30]

Preventive (neuroprotective) treatment of Huntington's disease

Although the genetic defect in Huntington's disease is known, it is still unclear how it leads to selective degeneration of neurons. It is believed that preventive therapy aimed at reducing oxidative stress and excitotoxic effect is potentially capable of slowing or suspending the progression of the disease. The situation may in some ways resemble hepatolentic degeneration, in which the genetic defect remained unknown for many years, however, preventive therapy aimed at a secondary effect — accumulation of copper — led to a “cure”. In this regard, the hypothesis that Huntington's disease is associated with a disorder of energy metabolism and cell death due to an excitotoxic effect attracts special attention. The disease itself can cause cell death due to the intranuclear aggregation of N-terminal fragments of the gouting, disrupting cellular and metabolic functions. This process can affect some groups of neurons to a greater extent than other groups, due to their higher sensitivity to excitotoxic damage. In this case, preventive therapy with excitatory amino acid receptor antagonists or means of preventing free radical damage will be able to prevent or delay the onset and progression of the disease. In laboratory models of amyotrophic lateral sclerosis, it has been shown that antioxidant agents and receptor antagonists (HAC) can slow the progression of the disease. Similar approaches can be effective in Huntington's disease. Currently, clinical trials are underway on glutamate receptor antagonists and agents that enhance the function of complex II of the mitochondrial electron transport chain.

[31], [32], [33], [34], [35], [36], [37], [38], [39], [40]