Huntington’s disease, Genetics, Pathology and Symptoms, with animation

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Huntington’s disease, or HD, is an INHERITED neurodegenerative disorder in which brain cells are damaged and die over time, leading to progressive loss of mental and physical abilities.
The disease is caused by an ABnormal version of the gene huntingtin, or HTT. The normal HTT gene has a stretch of 10 to 35 repeats of C-A-G nucleotide triplets, which encode for the amino acid glutamine. In people with HD, the HTT gene has MORE than 36 CAG repeats. The ABnormally LONG stretch of poly-glutamine ALTERS the structure of HTT protein, causing fragmentation and aggregation, forming a MIS-folded protein that is TOXIC to nerve cells. The resulting neuronal cell death is most prominent in the basal ganglia of the brain, especially in the striatum. Because the striatum’s function in motor control is to INHIBIT unwanted movements, its degeneration results in UNcontrollable dance-like movements, known as Huntington’s CHOREA, characteristic of the disease.
A person has 2 copies of the HTT gene but ONE ABnormal copy is sufficient to cause the disease. Children of an affected parent have a 50% chance of receiving the abnormal copy, hence a 50/50 chance of inheriting the disease. This pattern of inheritance is known as autosomal dominant.
The onset and progression of the disease depends on the number of CAG repeats – the greater the number of repeats, the earlier the age of onset and the faster the progression.
The high degree of sequence repetition also INcreases the likelihood of INaccurate DNA replication. Repeating sequences may form loops which cause the DNA polymerase to add more repeats as it replicates the DNA. This means a phenotypically-NORMAL father with 30-35 repeats MAY give his child a 40-repeats gene that would produce the disease. As the size of the polyglutamine stretch INcreases from generation to generation, the onset of symptoms gets earlier with each generation. This phenomenon is known as genetic ANTICIPATION.
An average person with a 40-50 CAG repeats in the HTT gene usually develops symptoms in their 40s. People with more than 60 repeats may start to show signs of the disease in their childhood. The first signs are SUBTLE mental and cognitive disturbances that may go unnoticed. As the disease progresses, chorea becomes prominent, followed by motor speech disorders, rigidity, swallowing difficulty, dysphagia, personality changes, memory loss, and other cognitive and psychiatric impairments.
Diagnosis is by genetic testing. Genetic counseling is available for people with family history of HD.
Life expectancy in HD is generally around 10 to 20 years following the onset of symptoms. Most life-threatening complications result from problems in muscle coordination, of which pulmonary aspiration is the most common cause of death. Currently there is no cure for Huntington’s disease, but treatments can relieve symptoms and improve quality of life.

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