Huntington’s disease (HD) is an inherited neurodegenerative diseases with an estimated 250,000 people in the United States either diagnosed with, or at risk for, the disease. The typical age of HD onset is between the ages of 30 and 50, with very rare juvenile onset as young as two years old and the average lifespan once diagnosed with HD is 10-20 years. HD causes progressive motor disturbances, cognitive disability, and emotional disorders. Motor symptoms include involuntary writhing movements called chorea as well as coordination problems, rigidity and slowness of movement (bradykinesia). HD-associated cognitive defects include learning, emotion recognition and decreased attention; emotional disorders may include depression and apathy. These symptoms tend to progress slowly and vary even among individuals in the same family.

The progress in our understanding of HD is a laudable example of the power of large genetic studies. The huntingtin gene, HTT, whose mutant form, mHTT, encodes a product that causes HD was identified in 1993 with the help of a detailed genetic study on a large Venezuelan family affected by the disease. HD is inherited in an autosomal dominant fashion. This means that if either parent is affected, then their child has a 50% chance of developing HD.

HTT is expressed most highly in the brain, where the huntingtin protein appears to have an important function in neurons. The gene contains a series of repeats of the DNA sequence CAG in the first part of the gene that encodes the protein. In the normal HTT gene there are 9-35 of these CAG repeats but in the HD-causing version the repeats are typically greater than 40, with the greater number of repeats correlated with earlier disease onset and greater severity of symptoms. CAG is the DNA sequence that encodes the amino acid glutamine (single letter abbreviation Q) in the resultant huntingtin protein and HD is one of several “PolyQ” diseases associated with protein folding problems due to abnormally long glutamine repeats.

mHTT is most lethal to a type of neuron called medium spiny neurons in the region of the brain known as the striatum. HD patients' brains contain inclusion bodies of mHTT as well as clumps of mHTT. The mutant protein deleteriously affects neurons in a number of ways including interfering with normal neuronal gene expression, affecting the release of chemical messengers called neurotransmitters by disrupting intracellular transport, restricting the energy-producing chemical reactions in the neuron’s mitochondria, as well as disrupting the normal protein degradation pathways. mHTT may also interfere with the metabolism and reuptake of neurotransmitters in the space between neurons, thereby altering cell-to-cell communications. 

There is currently no cure for HD and its treatment is focused on slowing the progression of its symptoms. HD patients may be prescribed drugs that block the effects of the neurotransmitter dopamine to control motor symptoms, such as tetrabenazine; and antidepressants, antipsychotics, and mood stabilizers to manage the emotional symptoms of the disease. A genetic test is available to determine if an individual carries the mHTT gene. Since there is currently no known cure for HD, it is often a personal dilemma whether or not to take the test; many individuals who may be at risk opt to not take it.

Researchers are actively engaged in finding a cure for HD. One area that is being explored is looking for small molecules that can enhance protein folding, thereby reducing the pathological mHTT misfolding effects. mHTT appears to be cleaved into fragments that are highly pathogenic. Another therapeutic approach is to find a means to prevent this cleavage in the first place or to remove the smaller, resultant fragments. A third line of investigation is looking at ways to eliminate expression of the mHTT genes using a variety of molecular strategies, or to provide support for the neurons that are under attack.

Despite the clear genetic basis for Huntington’s disease, its complexity has rendered a cure still a work in progress. Numerous clinical trials are pursuing a wide variety of treatments. Visit for a comprehensive listing.