The HTT gene is found on chromosome 4, of which everyone has two copies, one inherited from each parent. Huntington’s is an autosomal dominant disease meaning that a defect in only one of the two copies of a gene is sufficient to cause the disease. So, if either parent has the defect, half of his or her offspring is likely to inherit the disease.
In about three percent of cases, there is no previous family history of the disease. This could be because an affected parent may have died before the symptoms of Huntington’s became apparent. In some very rare cases, the mutation causing the disease can occur on its own (de novo) and has not been passed on from a parent.
The defect in the HTT gene responsible for Huntington’s disease is known as a CAG trinucleotide repeat expansion. This is a very small stretch of DNA, made of three building blocks, called C, A, and G, that is repeated multiple times in a row. Healthy people normally have the CAG trinucleotide repeated 10 to 35 times in their HTT genes. In people with Huntington’s disease, it may be repeated from 36 to more than 120 times. The number of repeats inversely correlates with the age of onset of the disease, or the longer the repeat region the earlier the onset. For example, people with 36-39 repeats may or may not develop Huntington’s disease during their lifetime, while people with 40 or more repeats almost always develop the disorder. In juvenile Huntington’s disease, the CAG trinucleotide is repeated more than 60 times.
Effect on the body
The HTT gene contains the instructions for cells to produce the Huntingtin protein. The exact function of this protein in the body is not fully understood, but it is thought to play an important role in nerve cells. The defect in the gene results in a longer-than-usual huntingtin protein being produced. This abnormal protein is cut into smaller toxic pieces, which stick together and accumulate inside the nerve cells. This disrupts the normal function of the nerve cells and eventually causes their death.
Nerve cells that are most sensitive to defective huntingtin protein are found in areas of the brain called the basal ganglia and the cortex. Messages to control movement, thinking, and motivation go through the basal ganglia and the cortex. When these neurons malfunction, those functions are disrupted, causing signs and symptoms associated with Huntington’s disease.
There are two types of genetic tests for Huntington’s disease: diagnostic and predictive. A person who consults a doctor for symptoms of the disease first will be referred to a neurologist. A diagnostic genetic test is done when a patient has clear symptoms of Huntington’s, particularly of impaired movement. Predictive testing is done if requested by a genetic counseling unit in the case of people older than 18 years who have a family history of Huntington’s.
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