Huntington’s disease (HD) is a central nervous system disorder marked by a progressive loss of motor control; involuntary movements of the upper body (sometimes called chorea because these tics vaguely resembles dancing); followed by autonomic dysfunction, dementia, and eventually death.
In most cases, death occurs 10-15 years after the onset of symptoms. The age of disease onset varies but tends to occur after a person has reached reproductive age. HD is an autosomal dominant disorder. This means that anyone with a single copy of the abnormal gene responsible for HD has a 50% chance of passing the disease on to his or her offspring.
Although the hereditary pattern of HD has been understood for over a century, the genetic mutation underlying the disease was not identified until 1993. That year, researchers studying a large Venezuelan family with numerous cases of HD finally sequenced the stretch of DNA on chromosome 4 containing the abnormal HD gene. The gene in question encodes a protein named huntingtin, in honor of the physician who originally described the disease.
Soon after the huntingtin gene was identified, geneticists compared its sequence in HD patients to that of healthy controls. They discovered that healthy people have 35 or fewer repeats of a trinucleotide sequence called CAG in their huntingtin genes. CAG encodes the amino acid glutamine. In HD patients, however, the huntingtin gene contains an expansion of the CAG repeat to 36 or more copies, resulting in an unusually long stretch of glutamines in the resulting protein. These glutamines, in turn, seem to confer an abnormal gain of function on the huntingtin protein, ultimately disrupting cellular metabolism to the point of causing cell death.
Unlike autosomal recessive diseases like sickle cell anemia or Tay-Sachs, which result from two defective alleles, a single copy of the mutated huntingtin gene is sufficient to cause full blown Huntington’s disease. Apparently, one normal copy of the huntington gene cannot compensate for the presence of the mutant gene. Furthermore, the higher the number of CAG repeats, the earlier the onset of HD symptoms; in rare cases, HD can strike in childhood.
Several features of HD remain a mystery. First, no one has figured out what the normal physiological role of the huntingtin protein is in humans. When the corresponding gene is deleted in knock out mice, subtle behavioral changes result, but the mouse’s lifespan is not affected.
Secondly, it is unclear why HD strikes a specific region of the brain called the basal ganglia; after all, every cell in a person’s body, including the nervous system, contains the abnormal huntingtin gene. Finally, no one has offered a convincing explanation as to why the onset of HD, as well as other neurological diseases caused by CAG repeat expansions, is usually delayed until adulthood.
Treatment of HD is largely supportive. Antidepressants, mood stabilizers, and dopamine receptor blockers often alleviate psychiatric symptoms. Coenzyme Q10 may slow the course of the disease but its efficacy is still a matter of debate, as is its mechanism of action.
People with a family history of HD face the awful dilemma of undergoing genetic testing. Some prefer a definitive diagnosis years in advance. Proponents of genetic testing argue that if a test is done early enough, people with HD can use this knowledge to decide whether or not to have children. Opponents cite the emotional impact potentially devastating news can have on a person. They argue that people may regard an early diagnosis of HD as a virtual death sentence, leading to severe depression and even suicide. As with many other diseases for which genetic tests exist but effective treatments do not, there are no easy answers.
