Description of Huntington’s Disease
By Erica Metheny
Introduction
Huntington’s disease is a hereditary neurodegenerative disease that causes chorea
along with psychiatric and cognitive symptoms. The average age of symptom onset is 40
years and they typically last for 20 years before the disease becomes fatal. Some of the
more common symptoms include chorea, weakness, and depression. The area of the brain
that experiences the most damage is the basal ganglia in both direct and indirect pathways.
Normal huntingtin protein is involved in synaptic transmission, neuroprotective factors,
and BDNF production and transport. All of those functions are affected in people that have
Huntington’s disease.
The purpose of this document is to describe the neurodegeneration that occurs in
Huntington’s disease to students interested in neuroanatomy or brain disorders. Having a
basic background in neuroanatomy and genetics will help the reader better understand this
document.
Symptoms
As stated earlier, during all stages of the disease patients experience motor,
cognitive, and psychiatric symptoms. In the early stages patients develop fidgeting
movements, clumsiness, irritability, impulsivity, depression, and forgetfulness. Moderate
stage is characterized by a progression of motor symptoms such as chorea, dystonia
(sustained muscle contractions), and slow voluntary movements. Some late stage
symptoms include chorea in almost all patients, rigidity, swallowing problems, inability to
care for self, depression (50% of patients), mania, memory problems, inability to speak,
and comprehension issues. On average patients start to see symptoms around age 40 and
they last for approximately 20 years. Patients with Huntington’s disease typically die from
pneumonia, choking, or cardiovascular disease.
Genetics
Huntington’s disease is due to a mutation on a gene located on chromosome four
that codes for the huntingtin protein. It is autosomal dominant meaning that someone with
Huntington’s disease has a 50% chance of having a child with the disease. The huntingtin
gene (htt) has a sequence of 3 mRNA bases (CAG) that are repeated many times. People
that have over 40 CAG repeats are guaranteed to have Huntington’s disease. Those with
36-40 repeats fall under the category of reduced penetrance and have a possibility of
developing the disease and people with 35 or less repeats will not get Huntington’s. The
basic function of the huntingtin protein is cell structure, metabolism, and transport.
Mutant proteins stick together and cause the protein to fold into the incorrect shape. This
causes the protein to form abnormal clumps inside the neuron (neuronal intranuclear
inclusions). The altered form of the huntingtin protein cannot get broken down in the cell
and the cells die. Overall, Huntington’s is a genetic disease caused by having more than 40
CAG repeats on chromosome four. These repeats cause a mutant huntingtin gene resulting
in disruption of cell structure, metabolism, and transport.
Anatomy of Huntington’s Disease
The basal ganglia largely controls voluntary movement and undergoes the most
damage in Huntington’s. There is a significant amount of tissue damage done to the
structures in the basal ganglia before symptoms even start to show. Structures of the basal
ganglia include the striatum (including the caudate nucleus), nucleus accumbens, globus
pallidus, subthalamic nuclei, and the substantia nigra.
The striatum’s main function is to regulate and inhibit movement. The subthalamic nuclei
are responsible for inhibiting movement and action selection. The globus pallidus is
involved in voluntary movement such as walking and talking. Lastly, the Thalamus is the
relay station for sensory and motor signals to the cerebral cortex. The internal globus
pallidus has tonic inhibition on the thalamus, meaning that unless there is another signal,
the internal globus pallidus in inhibiting the thalamus.
There are 2 major pathways between the basal ganglia and the motor cortex that
are damaged during Huntington’s disease. The indirect pathway is damaged first and then
later the direct pathway. The indirect pathway inhibits movement so damage causes
movement. The indirect pathway starts with the striatum signaling the external globus
pallidus. From there the subthalamic nucelii gets signaled, which stimulates the internal
globus pallidus. Excitation of the internal globus pallidus decreases the inhibition on the
thalamus and as a result the thalamus over stimulates the motor cortex. This over
signaling to the motor cortex causes the chorea seen in most HD patients. Destruction of
the direct pathway and side effects from that are seen in later stage patients. The signal
again starts in the striatum, but then goes to the internal globus pallidus. This causes the
internal globus pallidus to increase inhibition of the thalamus so there is decreased
signaling to the motor cortex. The result of damage to this pathway is the rigidity that
occurs in late stage patients. The pathways that allow the basal ganglia to communicate
with the motor cortex are damaged and symptoms depend on the pathway that is damaged.
Cell death first occurs in the striatum, particularly at the head of the caudate
nucleus. Reduced activation of the striatum is also seen in most patients. Along with all
structures of the basal ganglia, the cerebral cortex also experiences neurodegeneration.
Extreme cases can show up to a 25% loss of brain tissue.
http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/the-basic-neurobiology-of-huntingtons-disease-text-and-audio/
Conclusion
Huntington’s is a genetic brain disease that results in motor, cognitive, and
psychiatric symptoms. Having more than 40 CAG repeats in a specific place on
chromosome four will guarantee that someone will get Huntington’s and it is a dominant
trait. Those that have Huntington’s have a mutation in the huntingtin protein that results
in abnormal clumping of proteins that leads to cell death. Damage to the pathways that
allow communication between the basal ganglia and the motor cortex are damaged
resulting in chorea and then rigidity. All structures of the basal ganglia show
neurodegeneration and this occurs before any symptoms show and then continues.