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More Is Not Always Better, in the Case of Huntington's Disease


“Driving with my father through a wooded road leading from Easthampton to Amagansett, we suddenly came upon two women: mother and daughter. Both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean? My father paused to speak with them, and we passed on. Then my Gamaliel-like instruction began; my medical instruction had its inception. From this point, my interest in the disease has never wholly ceased.

The boy who described this scene in 1858 was only eight years old at that time. Today, we know him as George Huntington, the physician whose name is given to the insidious illness: Huntington's disease.

Symptoms of Huntington's disease

Symptoms of Huntington's disease are quite diverse and include motor, cognitive, and psychiatric disorders. Mental disorders include:

  • Antisocial behavior.
  • Depression.
  • Apathy.
  • Bipolar disorders.
  • Schizophrenia-like disorders.

The patient develops irregular, jerky, erratic, chaotic, sometimes sweeping, aimless movements that occur mainly in the limbs, which a person cannot control. The type of such movement is called chorea, hence the other name of the disease: Huntington's chorea.

Manifestations can occur both in adulthood (usually at about 30 to 50 years old) and in childhood (most often at 7 to 10 years old). Worldwide prevalence of Huntington's disease is 2.7 per 100,000 individuals. However, it is known that western populations such as the United States, Canada, the United Kingdom, and Australia have higher prevalence (5.7 per 100,000) than in Asian countries (0.4 per 100,000), including Japan, Korea, Taiwan, and Hong Kong.

Genetics and biology behind Huntington's disease

Huntington's disease is a genetic autosomal dominant disease. A gene with a mutation is located on the autosomal chromosome and one mutated gene is enough for the disease to manifest itself.

This means that if one of the parents is sick, the probability of inheritance is 50%. Both human sexes can be affected by this insidious disease, but it is more common in men.

Huntington's disease develops because of an increase in the number of cytosine-adenine-guanine (CAG) trinucleotides in the huntingtin (HTT) gene.

Normally, the number of these trinucleotides ranges from 6 to 26. If the number rises from 27 to 35, patients rarely exhibit the clinical phenotype. However, since the number of CAG triplets of mutated HTT gene tends to increase in descendants, the disease may appear in the next generation.

The threshold in 36 repeats is considered curtailed for developing Huntington's disease. Although, patients with 36 to 40 CAG trinucleotides face mild Huntington’s disease form. Higher numbers of CAG trinucleotides repeats are associated with faster rate of clinical progression, earlier onset and increased disease severity.

As a result, organisms start to produce a large huntingtin protein containing an elongated chain of glutamine amino acids. The function of the huntingtin protein has not been entirely revealed. However, it can be found in various human body parts including throughout the central nervous system (CNS) and is involved in protein trafficking, transport of vesicles, and selective autophagy.

Autophagy is defined as the consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases, including Huntington’s.

The lengthened chain of amino acids disrupts the structure of the protein. It sticks together with other proteins, which leads to the death of neurons and disruption of the central nervous system.

Diagnosing Huntington's disease

The most accurate and fastest diagnostic method is a genetic test of the HTT gene using a blood sample. Genetic testing is usually combined with deep medical history and other neurological tests, such as computed tomography, electroencephalography, and magnetic resonance imaging (MRI).

First-line relatives should be offered genetic tests as well. If a borderline number of trinucleotides is detected in one of the parents, a consultation with a geneticist is necessary before planning a pregnancy.

On MRI, a decrease in the density of the substance of the brain, expansion of the lateral ventricles, atrophy of the heads of the caudate nuclei could be seen. Pathological anatomical examination reveals a decrease in the mass of certain anatomical formations in the brain, the appearance of peculiar "scars" in its various departments.

Treatment prospects

Today, treatment of Huntington's disease focuses on symptomatic management of symptoms, as unfortunately, there is no US Federal Drug Administration-approved disease-modifying treatment for Huntington's disease.

However, scientists are working on discovering new approaches for treatment. Moreover, some of the newest therapeutics currently are at stage three of clinical trials. Therapies under investigation include two major approaches aimed at managing:

  • HTT gene or its product: mRNA.
  • Downstream pathways.

Therapies based on targeting HTT gene or its product

Using the first approach, researchers are trying to silence the mutated gene with zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR/Cas9 system.

All these methods aim to destroy the DNA chain of the HTT gene and not allow the synthesis of mutant mRNA, which are a source of information for protein synthesis.

Since all these therapies have limitations of difficulty in design, off-target effects, and require invasive administration of DNA, targeted therapies still are in preclinical phases.

Another approach is to reduce the amount of HTT gene product, mRNA. For that purpose, scientists are using antisense oligonucleotide and microRNA.

Short sequences of nucleotides bind to mRNA and degrade it, preventing the formation of an irregularly structured protein.

Two approaches of oligonucleotides usage are possible: selective and non-selective. The advantage of selectivity is the generalizability and the possibility of using this approach by all Huntington's disease patients.

However, the disadvantage of this approach is that the synthesis of the normal, non-mutant protein is also suppressed in this way. Although studies on non-human primate and rodents did not reveal significant association of low normal HTT protein concentration and motor function, long-term consequences are still unexplored.

Therapies based on targeting downstream pathways of HTT protein

Most processes in our body present in cascade form. From the beginning, one protein binds to receptors and stimulates another protein, which, in turn, acts on receptors to stimulate another protein, and so on.

In the case of Huntington's disease, the normal cascade of such events is disrupted. Therefore, the non-genetic downstream HTT protein pathway approach includes the use of proteins or other molecules that bind to certain receptors of the HTT cascade and restore its normal operation.

Other new methods of therapies

One of new methods for Huntington's disease therapy is gene therapy conversion.

This method includes technology of reprogramming glial cells (non-neuronal cells that do not produce electrical impulses) into neurons by introducing special molecules (transcription factors) that force cells to change their structure and function.

Studies in rodents and monkeys showed partial recovery of motor deficits and increased survival.

Moreover, mutated HTT protein stimulates inflammation through the synthesis of cytokines.

Therefore, there are also approaches to reduce this process as well. Preclinical studies in mouse models have shown that immunization against mutant HTT protein using antibodies improves the life of patients. These approaches include antibodies that do not allow the mutant protein to fold incorrectly or suppress its pathways.

Key takeaways

Even though the cause of Huntington's disease has been known for a long time, it is not so easy to defeat this genetic disorder.

It is important not to neglect genetic analysis if there are Huntington's disease cases in your family.

Active research in this area and several dozen clinical trials inspire hope that one day there will be a confirmed cure for Huntington's disease.

Resources

Huntington’s Disease Society of America. Overview of Huntington’s Disease.

Johns Hopkins. Huntington’s Disease.

Mayo Clinic. Huntington’s Disease.

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