Huntington's disease (or Huntington's disease)

Generality

Huntington's disease is a devastating, hereditary and neurodegenerative disease, for which there is currently no cure. Slowly but progressively, Huntington's disease reduces the ability to walk, talk and reason. Finally, those suffering from Huntington's disease become completely dependent on others for their care.

The disease is named after George Huntington who first described it in 1872, as a hereditary disorder. It is a monogenic pathology (the alteration affects only one gene), which cannot be diagnosed by chromosomal examination because the mutations of the genes are too small to be visualized through the microscope. Huntington's disease is the result of a protein misfolding, ie a failure to achieve the native conformation of the protein in question.

It is estimated that 3 - 10 individuals are affected per 100, 000 subjects in Western Europe and North America. Generally the age of onset varies between 30 and 50 years and death takes place 15-20 years after the onset of the disease. It can also affect children (juvenile Huntington); in this case the affected subjects rarely manage to reach adulthood.

Huntington's disease affects men and women equally and does not distinguish between races.

Symptoms

To learn more: Symptoms Huntington's disease

There are several symptoms that afflict patients with Huntington's disease; the early symptoms may involve cognitive or motor skills and include depression, mood swings, forgetfulness, clumsiness, involuntary contractions (còrea) and lack of coordination. With the progression of the disease, concentration and short-term memory diminish, while the movements of the head, trunk and limbs increase. The ability to walk, to speak and to swallow progressively regresses, until the individual with Huntington's disease is no longer able to take care of himself. Death often occurs as a result of complications such as shock, infection or heart attack.

Genetics

In 1993, the genetic mutation causing Huntington's disease was discovered, involving an autosomal dominant gene with incomplete but very high penetrance, which is located on chromosome 4. This gene codes for a protein, called huntingtin or HTT, whose function is still not well known and which is generally found in the cytoplasm. It has been observed that the mutated form of huntingtin contains a tract of chain formed by glutamine residues much longer than that present in the normal protein. In fact, in the non-mutated gene, the codon that codes for glutamine (CAG), is repeated 19-22 times, while in the mutated gene there is a repetition up to 48 times or even more. This would cause a lengthening of the glutamine residues located on the NH2-terminal portion of the huntingtin protein.

Furthermore, although the mutated protein is ubiquitously expressed in the body, cellular degeneration occurs more in the brain. In fact, Huntington's disease is characterized by the degeneration of the neurons of the caudate nucleus, a region of the ganglia (or nuclei) of the base responsible for regulating voluntary movement.

Deepening: Basal ganglia, Striatum functions and Neuropathology of Huntington's disease

Treatment

Pharmacological therapies have a purely symptomatic meaning and do not influence the evolution of the disease or its degenerative process. For example, dopamine antagonists can be used to relieve choreographed movements. However, their use is limited due to undesirable effects such as sedation and depression. Antiparkinson drugs, on the other hand, can positively influence youthfulness dominated by rigidity. Psychotic disorders may require adequate psychopharmacological treatment (neuroleptics, lithium salts), while depressive symptoms may be attenuated by the use of specific drugs (tricyclic antidepressants, serotonin).

Despite the numerous clinical studies conducted over the last ten years, to date no drug has been shown to be effective in a randomized placebo study in the treatment of Huntington's disease. The clinical phase is very demanding, mainly because the disease has a slow progression and a wide clinical heterogeneity. There are scales of evaluation of Huntington's disease and they are almost the same in all the clinics. The complete penetrance of the disease and the availability of predictive genetic tests, offers the opportunity to attempt treatment during the initial stages of the disease. Currently the studies are aimed at the search for biormarcators of change, sensitive and stable, in order to intervene in the first manifestations of the disease.

Currently, neuroimaging techniques have offered the best biomarkers during the prodromal phase (which precedes the clinical symptoms of the disease); they also provide a correlation between those that are therapies conducted on animal models and on humans. As mentioned, the atrophy of the striatum is early and progresses during the course of the disease. It has also been shown that other areas of the brain such as the subcortical and cortical structures of the white matter are affected in the prodromal period.

Through functional imaging it can also identify some abnormalities in individuals during the prodromal period. This technique could also be sufficiently sensitive to identify detectable structure irregularities or behavioral changes.

Finally, the identification of molecular biomarkers, such as lactate or other products of cellular stress, could be allowed thanks to magnetic resonance spectroscopy techniques.

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