Illuminating Huntington’s Disease

Reviewed20 Apr 2023
Author Clinton Parks
Source BrainFacts/SfN

Shutterstock.com via Kateryna Kon

Huntington’s disease (HD) is a heritable disease that impairs voluntary movement and cognition. The disease afflicts three to twelve of 100,000 people of Caucasian descent but is less common among East Asian and African populations. The HD variant of the HTT gene is dominant; if one parent has a single copy of the HD gene variant and the other parent has normal HTT genes, a child has a 50 percent chance of inheriting the HD variant and developing the disease.

The most common form of HD begins earlier than most progressive brain diseases, becoming active when people are in their 30s and 40s. Death occurs 15 to 20 years after a patient becomes symptomatic. Juvenile HD begins in childhood or adolescence, occurring before the age of 20. Juvenile HD patients usually die 10 to 15 years after their symptoms appear.

Symptoms

Signs of HD begin with irritability, mood swings, depression, small involuntary movements (called chorea), poor coordination, and difficulty making decisions and learning new information. As the disease progresses, the chorea becomes more pronounced and patients have increasing trouble with voluntary movements like walking, speaking, and even swallowing. Their cognitive problems also worsen.

Around 90% of HD is adult onset. While juvenile HD onset displays the same symptoms as the adult form, it also includes slow movements, clumsiness, frequent falling, rigidity, slurred speech, drooling, and seizures. School performance declines as thinking and reasoning abilities become impaired, and seizures occur in 30 to 50% of children with this condition.

Clinical onset of HD is defined by motor symptoms because the psychiatric symptoms are heterogeneous and have high prevalence in the general population, so they are more difficult to link specifically with HD. However, mouse models of HD also display these changes, so we know they are really part of the disease rather than co-morbidities or a consequence of the stresses of being from an HD family. These symptoms can occur decades prior to motor onset.

Causes and Genetics

In 1993, Huntington’s disease was found to be caused by mutations in the HTT gene, which codes for the huntingtin protein located on chromosome 4. The protein likely interacts with other proteins involved in signaling, transport, binding to proteins and other structures, and protecting the cell from self-destruction.

The disease mutation involves an abnormal number of repeats of a three-part (trinucleotide or triplet) snippet of DNA in the HTT gene. This sequence of the nucleotides cytosine, adenine, and guanine (CAG) normally repeats 10 to 26 times but occurs more times in the mutation. Individuals with 27-35 repeats will not develop the disease but have a risk of passing it to their children through inter-generational expansion, and people with 36-39 repeats may or may not get HD and can have children with mutations that lead to disease onset. Repeats of 36-39 are found in around one in 400 people in the general population, and about 10% of HD cases have no family history. The disease continues across generations from both non-disease-causing and disease-causing sequence lengths. Individuals with 40 or more repeats will develop HD and have a 50% chance of passing it to children. In individuals with greater than 60 repeats, disease onset is typically before the age of 20 (juvenile onset HD).

This expanded huntingtin protein is susceptible to clumping and can disrupt functions associated with normal huntingtin. However, some research suggests the aggregation of huntingtin proteins may provide protective mechanisms for neurons, with oligomers or other intermediate species potentially driving neural toxicity. Brain areas most often affected are the basal ganglia (voluntary movement) and the cortex (cognition, perception, and memory).

Treatments

There currently is no cure for Huntington’s disease, but the U.S. FDA has approved two treatments for associated symptoms.

In August of 2008, tetrabenazine was the first drug approved for treating chorea — involuntary jerking or writhing movements — associated with Huntington’s disease. Tetrabenazine is a monoamine-depleting agent for oral administration. Monoamine depletors generally work by reversibly exhausting one or more monoamine neurotransmitters like serotonin, dopamine, adrenaline, and noradrenaline.

In April 2017, the FDA approved another similar monoamine-depleting agent, deutetrabenazine, also for treating chorea associated with Huntington’s. Other emerging therapies are aimed at slowing the progression of Huntington’s disease by targeting the mutated form of the huntingtin protein produced in HD patients.

Furthermore, there is now evidence for viable HD biomarkers. Studies have suggested that elevated levels of neurofilament light chain (a component of the neuronal cytoskeleton), and to a lesser extent tau (which turns up regularly in neurodegenerative diseases), in cerebrospinal fluid are biomarkers of HD. Interestingly, neurofilament light chain is also being investigated as a biomarker for ALS and other neurodegenerative diseases. In mouse studies, the amount of neurofilament light chain found in the animals’ cerebral spinal fluid and blood increased before neurological signs appeared, likely coinciding with the development of brain lesions.

Other treatments for Huntington’s focus on ameliorating symptoms and addressing quality of life. For example, physicians treat chorea with antipsychotic and other medications; psychiatric disorders are addressed with antidepressents, antipsychotics, and mood-stabilizing drugs; psychotherapy, speech therapy, physical therapy, occupational therapy, lifestyle changes, and generalized care and support can improve the quality of life for people with Huntington’s disease.

Adapted from the 8th edition of Brain Facts by Clinton Parks.

About the Author

Clinton Parks

Clinton Parks is a Washington, DC-based freelance science writer who writes for AAAS’ ScienceCareers, American Chemical Society’s Axial, and American Physical Society’s Physics Buzz, among others.

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