Abstract:

Huntington’s disease (HD) is an autosomal dominant, monogenic,rogressive, neurodegenerative and rare disease with a frequency of 10 per 100,000 in the Caucasian population and occurring more rarely in other races. HD is, nevertheless, one of the most frequently and extensively studied diseases of those caused by a dynamic mutation. The HD mutation is located on the short arm of the 4th chromosome within the HTT gene. This mutation consists of cytidine, adenosine and guanosine (…CAG CAG CAG…), namely trinucleotide repetition exceeding 35 repeats, with a higher CAG expansion leading to disease onset at a younger age. It also results in a stronger manifestation of HD symptoms and faster clinical progression. Although the mutation is present in each cell from conception, HD symptoms usually appear between 30 and 50 years of age. HD symptoms were first precisely described by George Huntington in a paper titled “On Chorea”, published in the Medical and Surgical Reporter in 1872. Huntington was the descendant of 2 generations of physicians who had been treating HD patients living in the vicinity of East Hampton on Long Island, USA. Earlier, HD had been known as St. Vitus’ Dance; in Huntington’s times it was called chorea. The term “Huntington’s chorea” is still used today but was recalled as a “Huntington’s disease” when other symptoms were identified, including other movement disturbances such as dystonia, stiffness (most prevalent in later stages), oculomotor disturbances, slowness, psychiatric symptoms such as irritability,aggression, apathy and depression, obsessive-compulsive disorders or impulsive suicidal attempts, cognitive disturbances (subcortical dementia), e.g., thinking stiffness and slowness, and attention and executive function disturbances. Both the sequence and intensity of symptoms constitute unique features of every patient, although diagnosis can be established when typical motor symptoms appear. Psychiatric symptoms or isolated cognitive disturbances might preclude HD diagnosis for many years  There are also specific HD presentations such as juvenile HD with onset age before 20 years of age, faster disease progression with frequent symptoms such as stiffness and severe oculomotor disturbances (Westphal variant), or senile HD that usually appears after 60 years of age with a display of predominantly choreic movements. Although the CAG repeats number might indicate the severity of symptoms as well their progression with age, additional modifying factors play a crucial role and often might result in a shift of disease onset for a few or even over a dozen years (Genetic Modifiers of Huntington’s Disease (GeM-HD).