The underlying cause of Huntington’s disease, which is characterized by a progressive decline in movement, cognition, and mental stability, is a mutation in a gene called huntingtin (HTT).
Inheritance
The HTT gene is found on chromosome 4, of which every person has two copies, one inherited from each biological parent. Huntington’s is an autosomal dominant disorder, meaning that a mutation in only one of the two copies of the gene is sufficient to cause the disease. A person with one mutated copy of the gene also has a 50% chance of passing the mutation to his or her biological children.
In about 1-3% 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 — known as de novo — and has not been passed on from a parent.
Genetic defect
The defect in the HTT gene responsible for Huntington’s disease is known as a CAG trinucleotide repeat expansion.
Like other genes, the HTT gene is comprised of four DNA bases — referred to as A, C, G, and T — that are “read” in groups of three, called codons, to produce a protein. The CAG trinucleotide repeat, as its name implies, is a small section of the HTT gene in which the bases “CAG” are repeated multiple times in a row.
Normally, the HTT gene CAG trinucleotide repeat contains 10 to 35 repeats of this sequence. In people with Huntington’s disease, however, it may be repeated from 36 to more than 120 times. People with 40 or more repeats almost always develop Huntington’s, whereas for people with 36 to 39 repeats, the disease is incompletely penetrant — meaning an individual may or may not develop the disease. The reasons for this are still not completely understood.
The number of repeats inversely correlates with the age of onset of the disease. That means that the more repeats there are, the earlier in life a person is likely to develop symptoms. In juvenile Huntington’s disease, which affects children and young adults, the CAG trinucleotide is generally 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 neurons, or nerve cells.
The CAG trinucleotide repeat expansion in the gene results in a longer-than-usual huntingtin protein being produced. This abnormal protein is thought to form clumps in neurons, which disrupt the normal function of these cells and eventually cause their death.
The neurons that are most sensitive to the mutated huntingtin protein, called medium spiny neurons, are found in areas of the brain called the striatum, a structure of the basal ganglia, and receive input from the cortex. These regions of the brain help to coordinate movement, thinking, and motivation, among other processes.
When these neurons malfunction, those functions are disrupted, causing the signs and symptoms associated with Huntington’s disease.
Genetic testing
There are two types of genetic tests for Huntington’s disease: diagnostic and predictive. Both of these tests look for the same CAG trinucleotide repeat expansion.
Diagnostic testing is done in people who have clear symptoms of Huntington’s, particularly impaired movement, whereas predictive testing is typically performed in people with a family history of Huntington’s, to assess their likelihood of developing the disease.
Last updated: June 14, 2021
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