Huntington Disease

In 1993, scientists discovered the genetic defect that causes Huntington disease. A gene located on the chromosome 4 normally contains a sequence of three nucleotide bases (the alphabet of the genetic code) that repeats several times. The sequence is cytosine, adenine, and guanine, or CAG, which codes for the amino acid glutamine that is a building block for protein synthesis. In Huntington disease, patients have too many repeats. While unaffected individuals normally have 11-24 repeats, a person with Huntington disease may have anywhere from 36-100 or more repeats. Clinical research studies have demonstrated that the greater the number of repeats, the earlier the disease will develop and the clinical manifestations will be more severe. If the expanded trinucleotide sequence is passed from the father to the offspring, the offspring that inherit this expansion can have an earlier age of onset of the disease. This phenomenon is called anticipation and is paternal in origin if the father inherited the disease gene from his mother. There are also other diseases characterized by expansion of a repetitive sequence in the DNA and developmental delay, such as fragile X.

Despite the discovery of the Huntington disease gene, scientists were baffled by how this genetic defect produces such a devastating disease course. The Huntington disease gene codes for a large protein with no similarities to known proteins. It has been named the huntintin protein. It is important for normal development of the nervous system and interacts with many other proteins. Through autopsy, it was shown that an abnormality in the huntingtin protein caused the destruction of brain cells in the basal ganglia, a region of the brain with unknown functions. Using genetic engineering, scientists have developed strains of mice that express the Huntington disease gene. These mice display the symptoms of the disease. It has been found that the huntington protein, normally present in the cytoplasm (internal fluid-like content) of cells, collects in the brain cell nuclei, forming masses that kill the cell. This dominant-negative effect explains why clinically asymptomatic patients develop progressive neurodegeration of the brain in the fourth decade of life.