Huntington's Disease

Introduction:

Huntington's disease (HD), also known as Woody Guthrie Disease, is a brain disorder that destroys cells in the basal ganglia. The basal ganglia's main function in the brain is to help control movement, emotion and cognitive ability. Therefore, patients with HD tend to have mood swings or depression, poor memory, lack of coordination, and uncontrollable movements. HD is caused through a mutation in someone's genetics where patients have an abnormally large amount of repeats of the nucleotide CAG in chromosome 4. Normal people have about 9-35 repeats of this nucleotide while patients with HD tend to have about 40 or more repeats. Parents who contain the mutated gene have a 50% chance of giving it to their offspring because it is an autosomal dominant mutation. Most patients usually develop the disease around middle age and survive for about 10-15 years after the onset of the disease until about the average age of 50-57 years. Patients with HD die from an intercurrent illness, not necessarily from the disease itself. One study showed that the main cause of the death from patients with HD is typically pneumonia or cardiovascular disease.

Functional Anatomy:

The basal ganglia is comprised of the caudate, putamen, globus pallidus (GP), substantia nigra (SN) and the subthalamic nucleus (STN). Collectively, the caudate and putamen are referred to as the striatum. The basal ganglia is located on both sides of the thalamus but outside and above the limbic system. If you look just behind the frontal lobe you will see the caudate curving back towards the occipital lobe. The function of the caudate is to inform us when something is going wrong. A highly active caudate may result in OCD while an underactive caudate may be involved in ADD. The putamen lies underneath the caudate and it is involved in coordinating behaviors like riding a bike. The GP is located inside the putamen and it receives input from the striatum and sends its output to the SN. The SN is located in the upper portions of the midbrain and beneath the thalamus.
Basal Ganglia.jpg
Image One


Input and Output:
The striatum receives somatopically organized projections from the cerebral cortex and intralaminar nuclei of the thalamus. The caudate head also receives information mainly from the premotor cortex and supplementary motor area while the putamen receives information from primary motor cortex and primary somatosensory cortex. The major output structures that comprise of the basal ganglia are the globus pallidus internal segment (GPi), Substantia Nigra pars reticulata (SNr), The GPi sends its efferent projections to the thalamus through two tracts: ansa lenticularis and lenticular fasciculus. The SNr projects its efferent fibers to the superior colliculus which is involved in the control of eye movements as well as the ventral anterior and ventral lateral nuclei.

Pathways:

  • Direct Pathway: It is hypothesized that the direct pathway functions to help initiate movement. Cells in the striatum make inhibitory connections with the GPi through the neurotransmitters GABA and substance P. When the GPi is active, its connections with the thalamus are inhibited thus preventing movement. Therefore, when the striatum inhibits the GPi it can no longer inhibit the thalamus which allows movement to occur.
  • Indirect Pathway: Its role is the opposite of the direct pathway which is to prevent movement. It does this by having the striatum send inhibitory synapses with the globus pallidus externus (GPe) through the neurotransmitters GABA and enkephalin. Then the GPe uses the neurotransmitter GABA to make more inhibitory connections to the STN which then makes excitatory connections through glutamate in the GPi. This then allows the GPi to send its inhibition to the thalamus via the neurotransmitter GABA, thus not allowing the thalamus send a signal to the motor cortex allowing the movement. People with HD have problems with the indirect pathway which is the reason why they have uncontrollable movements.

basal ganglia pathways.png
Image Two

Etiology:

People who have HD have neural cell loss throughout the basal ganglia, mainly in the striatum but also in GP, thalamus, STN, SN and cerebellum. There are several proposed mechanisms that result in the cell death of the basal ganglia.
  1. Excitotoxicity refers to the neurotoxicity that causes cell death from the presence of excessive activation of postsynaptic receptors.
  2. Oxidative stress can cause cell death from the presence of a large amount of free radicals. Free radicals may appear due to exictotoxicity or mitochondrial malfunction which can trigger apoptosis.
  3. In impaired energy metabolism, the threshold for glutamate toxicity is reduced which can lead to the activation of excitotoxic membranes.
  4. Apoptosis is programmed cell death. Patients with HD appear to have apoptosis in a subset of neurons and glia in the neostriatum. One theory is that the expansion of polyglutamine causes neuronal cell death through the interactions with other proteins. Another study shows the polyglutamine may interfere with the binding protein CBP which is a major mediator of survival signals in mature neurons.

Degrees of HD:

  • Grade 0: no detectable histologic neuropathology.
  • Grade 1: There is no gross atrophy but there are neuropathologic changes that can be detected microscopically.
  • Grade 2: There is striatal atrophy but the caudate remains nucleus remains convex.
  • Grade 3: The caudate remains flat and the striatum atrophy is even more severe.
  • Grade 4: The most severe atrophy in the striatum. The medial surface of the caudate nucleus is concave.

HD brain vs normal.jpg
Image Three

Treatment:

Treatments cannot slow the progression of the disease but it can help make the patient feel more comfortable. Medications can help reduce a patient's depression, anxiety and even help control some of their movements. It is best to not treat HD with drugs unless it is disabling. It is also a good idea to educate one's family about the disease to try to develop a better support system for them. Future therapies may include engineering neuronal cells to produce specific genes such as growth factors or enzymes. This therapy would be effective if the HD allele represents a loss in function and the new cell would replace the missing constituent. Alternatively, if the HD allele causes an increased or inappropriate expression of a specific structural gene a possible therapy would be to reduce the expression of that gene. This can be done by producing synthetic nucleic acids with a complementary sequence to the messenger RNA. This can essentially reduce the level of gene product.

Conclusion:

HD is a disease that is caused by a mutation in chromosome which results in an abundant amount of repeats of the nucleotide CAG. Oftentimes people with disease have problems with uncontrollable movements, memory, cognitive functioning and emotion regulation. The disease results in the atrophy of the basal ganglia, more specifically, the neo-striatum, which is one of the reasons why we see these symptoms in patients with HD. HD effects the indirect pathway of the basal ganglia which has a role in inhibiting certain movements. That is why patients with HD show uncontrollable and involuntary movements. There currently is not anything you can do to slow down the disease but there are a few things to help make the patient feel more comfortable.



Glossary of Terms:

  • Apoptosis: programmed cell death
  • Basal Ganglia: region of the brain that functions in regulating movements and some emotion.
  • HD: Huntington's disease, causes atrophy of the basal ganglia which results in a difficult time regulating emotions, lack of coordination and uncontrollable movements.
  • Nucleotide: one of the structural blocks of DNA.
  • Oxidative Apoptosis: cell death caused by the lack of oxygen.
  • Striatum: part of the basal ganglia that features the caudate and putamen.

Further Readings:

https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_8C.html
http://www.dystonia.org.uk/index.php/about-dystonia/dystonia-and-the-basal-ganglia
http://hdsa.org/
http://www.mayoclinic.org/diseases-conditions/huntingtons-disease/basics/definition/con-20030685
http://www.movementdisorders.org/MDS/About/Movement-Disorder-Overviews/Chorea--Huntingtons-Disease.htm

Quiz:

True and False
  1. HD affects the direct pathway of the basal ganglia (T/F)
  2. HD is caused by having too few of the nucleotide CAG in chromosome 4 (T/F)
  3. Neuronal atrophy occurs within the neostriatum (T/F)
  4. The Indirect pathway's job is to inhibit unwanted movement (T/F)
  5. GABA and substance P are two common neurotransmitters seen in the indirect pathway of the basal ganglia (T/F)
  6. GABA and enkephalin are two common neurotransmitters seen in the direct pathway of the basal ganglia (T/F)
  7. The putamen and caudate are collectively known as the striatum (T/F)
  8. Patients with HD are often seen having problems with unwanted movements (T/F)
  9. Sine the basal ganglia is also has a role with balance, patients with HD have trouble balancing (T/F)
  10. There is nothing you can do to slow down the progress of HD but there are ways to make the patient feel more comfortable (T/F)
Short answer
  1. Illustrate how the indirect pathway works.
  2. Describe two out of the four potential causes of neuronal cell loss.
  3. Give a brief description of each grade of HD atrophy.
Answers
F, F, T, T, F, F, T, T, F, T

Sources:

Basal Ganglia (Chapter 4) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy – The University of Texas Medical School at Houston. Retrieved December 12, 2015. http://neuroscience.uth.tmc.edu/s3/chapter04.html
Boeree, Dr. George C. "Basal Ganglia." Basal Ganglia. N.p., 2006. Web. 12 Dec. 2015. http://webspace.ship.edu/cgboer/basalganglia.html
Brain, W. Russell Brain, and John Nicholas. Walton. Brain's Diseases of the Nervous System. Oxford: Oxford UP, 1985. Print.
Disorders of the Motor System (Section 3, Chapter 6) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy – The University of Texas Medical School at Houston. Retrieved December 12, 2015. http://neuroscience.uth.tmc.edu/s3/chapter06.html
"Huntington's Disease." Huntington's Disease. University of Utah Health Sciences, n.d. Web. 12 Dec. 2015. http://learn.genetics.utah.edu/content/disorders/singlegene/hunt/
Pearlman, Alan L., and Robert C. Collins. Neurobiology of Disease. New York: Oxford UP, 1990. Print.
Revilla, Fredy J. "Huntington Disease." : Background, Pathophysiology, Etiology. Medscape, 9 July 2015. Web. 12 Dec. 2015. http://emedicine.medscape.com/article/1150165-overview#a3

Image References:

  1. http://scienceblogs.com/purepedantry/wp-content/blogs.dir/454/files/2012/04/i-05b9f20e65a3464654059e6249f4e016-basal-ganglia.jpg
  2. http://forums.studentdoctor.net/proxy.php?image=http%3A%2F%2Fi50.tinypic.com%2F2096jaq.jpg&hash=d2670b892b61a258c7f00e7abfa2141f
  3. http://ucsdnews.ucsd.edu/news_uploads/2015_05_26_huntingtons_mri.jpg