Huntington’s Disease
Huntington’s Disease (HD) is a neurological condition characterized by uncontrolled movements, psychological and emotional problems, and decreased cognition. This disease affects 3-7 per 100,000 people of European ancestry, although people of other ancestries, such as African and Asian descent, are less affected. (3). Due to the nature and symptoms of the disease, various treatment plans can be enacted to help with everyday managing of the disease effects, along with new research that also helps shed light on the root causes.
Signs and Symptoms
Patients present with a variety of symptoms related to the malfunctioning of various neurons in the central nervous system. Onset of symptoms usually begin with patients complaining of clumsiness, tremor, “balance trouble”, or jerkiness. These movements, which develop into Huntington’s Chorea, is characterized by continuous, jerky, irregular, and writhing limb movements, which also can affect the trunk. Other areas also affected include the respiratory system, larynx, pharynx, and oral cavity. Along with spontaneous movements, voluntary actions are usually impaired, slow, and uncontrolled. (1) (2). Symptoms can also begin with cognitive impairments. Cognitive speed and efficiency tends to lessen, and over time, dementia will become more global. Behavioral changes include irritability, hallucinations, moodiness, paranoia, and psychosis. As dementia sets in, disorientation, loss of judgment and memory, and personality changes will become more apparent. There are two populations of patients in which the disease can present. Adult-onset Huntington’s Disease is the most common form where life expectancy is usually about 15-20 years after presentation of signs and symptoms. A juvenile form will develop during childhood or teenage years, and include additional symptoms such as frequent falling, drooling, rigidity, declining school performance, and seizures. Life expectancy is generally 10-15 years after onset of symptoms. (1) (2) (3).
Causes
Huntington’s Disease is a autosomal dominant-inherited disorder. The primary cause for the disease is the production of an abnormal protein called Huntingtin, controlled by the gene HTT, on Chromosome 4. While the exact functioning of this protein is largely unknown, it is probable that it plays a variety of necessary roles for the proper functioning of the neuron, including chemical signaling, transporting materials, attaching to proteins and other structures, and protecting the cell from destruction. A mutation in the HTT gene, caused by an increase in the size of the CAG repeat sequence on a specific segment of chromosome 4 by 36-120 repeats, will create an elongated protein that functions abnormally and will disrupt the normal functioning of a neuron through interactions with other proteins. Huntingtin plays the biggest role in the brain, specifically in area that control movement and emotions, such as the caudate, putamen, and certain areas of the cerebral cortex that affect emotion and personality. The caudate and putamen is collectively called the striatum, which is part of the basal ganglia, a section of the brain responsible for coordinating movement. In MRI studies this area becomes atrophied in Huntington’s Disease, with medium spiny neurons specifically becoming most vulnerable to change. (3) (4) (1).
Risk Factors
For most cases Huntington’s Disease is passed on to children from parents. As the gene is passed down through family members, the repeated CAG segment is expanded, until there are enough repeats to cause classical symptoms of the disease. There is a 50% chance that the child will have Huntington’s Disease if one of the parents has Huntington’s mutation. In some special and rare cases, the child can develop Huntington’s Disease from sperm mutation during the father’s sperm development. (5) (2).
Diagnostic Tests
There are number of test performed to verify the presences of HD gene mutation. One of the more common genetic tests is PCR, where a sequence of a gene is taken to check for the repetition of the CAG sequence. The test will check for reoccurrences for abnormal CAG gene sequence of more than 10-35 repeats. Other neurological tests include the MRI and CT scans to check for reduced blood flow to certain areas of the brain and to look for areas which have reduced mass. PET scans use radioactive substances to check which area of the brain have become affected or damaged. Various psychological tests will check whether any changes in personality or occurrences of hallucinations are present in the individual. A test for dementia will check for disorientation, lack of judgment, or any other cognitive impairment. Finally, some basic physical tests will indicate presence of abnormal movements, reflexes, "Prancing" and wide walk and hesitant speech or poor enunciation. (2).
Treatments
There is no definite cure nor a definite way to reverse the progression of Huntington ’s Disease. However, there are various current treatments available that can help alleviate symptoms. Some drugs offered can lessen some symptoms and prolong the normal functioning of the patient. In most individuals, a specialized treatment plans is drawn up and regularly monitored and updated to screen for any side effect of such drugs. An example of a treatment plan may include drugs such as Tetrabenazine to aid with the “jerky movements” associated with the affected areas of the basal ganglia, anti-psychotic drugs, anti-seizure drugs, and anti-anxiety drugs to help with the psychotic symptoms. Anti-depressants and mood stabilizers are also prescribed due to the side effects from the previous drugs. A treatment plan also includes physical therapy, occupational therapy, speech therapy, and psychotherapies to help an individual cope with HD and relearn old and new skills for daily functioning. The only form of prevention for HD is for a carrier parent to get genetic testing done and meet with a genetic counselor. Genetic counseling can help figure out alternative forms of conception such as vitro fertilization with donor sperm or eggs. (2) (5).
Current Research
There is a variety of research associated with finding ways to help alleviate symptoms of Huntington’s Disease. According to one study conducted by Chel, -et al., a correlation between low Vitamin D levels and increased fall risks among Huntington’s Disease patients is explored. The researchers conducted studies that tried to find a correlation between the increased tendencies of HD patients for falls and balance problems with the observation that institutionalized patients tend to receive less vitamin D in their bodies from lack of sunlight, and thus produce weaker bones. In the study, 28 patients in an institution which houses HD patients were tested to Vitamin D3 levels throughout a week long period. The results showed that while most patients were in the sunlight at least once a week, along with a few others who used vitamin D supplements, the mean serum Vitamin D levels in the patients in this study was 33 nmol/L, which was lower compared to patients from a separate study who did not have HD, at 64.5 nmol/L. The results of the study did not find a conclusive correlation; however, is it clear that it is a valuable pursuit as further related studies can help with identifying novel ways to lessen the negative consequences from increased imbalances and falls among HD patients. (7).
Another study conducted by Steffan, -et al., explores the effects of the abnormal Huntintin protein and its interactions with p53 and CREB-binding protein. The researchers discovered that a mutated segment of the htt protein, called httex1p, is responsible for aggregation, protein-protein aggregation, and other interactions within a cell. P53 is a tumor suppressor gene/protein within cells which control whether a cell will undergo differentiation, growth or apoptosis. The httex1p segment was found to especially interact with p53 in vitro and in cell culture to create inclusions within the cell, similar to those found in Huntington’s Disease patients. Such an interaction would cause lack of function of p53 and aberrant transcriptional regulation associated with growth of the cell. The httex1p segment was also found to interact with CBP and mSin3a, two other proteins that interact with p53. This study is important because it highlights the importance of finding the causes for Huntington’s Disease and its molecular basis and mechanism. (6)
A third study conducted by Ferrante, -et al., explores the neuroprotective effects of creatinine on neurons which are affected by the HTT mutation. Using transgenic mice, the researchers were able to insert an exon of a mutated HD gene into the mice and reproduce similar symptoms as would a human HD patient, such as abrupt shuddering, resting tremors, and seizures. In addition, neuronal inclusions were found in the striatum of the mice, as would be normally found in a human HD patient. It is seen that the HTT mutation will affect normal energy metabolism of a neuron, which causes lactate and other mitochondrial toxins to be formed among the cells, causing damage to the tissue. Creatine and Phosphocreatine, along with creatine kinase which act on those two substrates, show neuro-protective effects by buffering energy production and consumption. The researchers show that administration of creatine induces protective changes in the cells which reduce the amount of toxins and helped creatine kinase perform better. Furthermore, it helped with better functioning of motor neurons in certain areas of the brain, such as the anterior horn and Substantia Nigra. This study is important because it is another possible novel way to deal with and potentially alleviate syptoms associated with Huntington’s Disease. The discovery of new drugs and pharmaceuticals, even as something as simple as creatine, can help open doors to creative ways to positively affect damaged neurons and the respective areas of the brain. (8).

Works Cited

1. Margolis, R. L., & Ross, C. A. (2014, January 1). Diagnosis of Huntington Disease. . Retrieved July 19, 2014, from http://www.clinchem.org/content/49/10/1726.long

2. Board, A. (2013, May 28). Huntington Disease. Huntington disease. Retrieved July 19, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001775/

3. Huntington disease. (2013, June 1). Genetics Home Reference. Retrieved July 19, 2014, from http://ghr.nlm.nih.gov/condition/huntington-disease

4. HTT gene. (2008, October 1). Genetics Home Reference. Retrieved July 19, 2014, from http://ghr.nlm.nih.gov/gene/HTT

5. Huntington's disease. (2011, May 5). Definition. Retrieved July 19, 2014, from http://www.mayoclinic.org/diseases-conditions/huntingtons-disease/basics/definition/con-20030685

6. Joan S. Steffan, Aleksey Kazantsev, Olivera Spasic-Boskovic, Marilee Greenwald, Ya-Zhen Zhu, Heike Gohler, Erich E. Wanker, Gillian P. Bates, David E. Housman, and Leslie M. Thompson
The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription
PNAS 2000 97 (12) 6763-6768; published ahead of print May 23, 2000, doi:10.1073/pnas.100110097. http://www.pnas.org/content/97/12/6763.full

7. Chel, V., Ooms, M., der Bent, J. v., Veldkamp, F., Roos, R. A., Achterberg, W. P., et al. (2013, August 15). High prevalence of vitamin D deficiency and insufficiency in patients with manifest Huntington disease. . Retrieved July 19, 2014, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908964/

8. Ferrante, R. J., Andreassen, O. A., Jenkins, B. G., Dedeoglu, A., Kuemmerle, S., Kubilus, J. K., et al. (2000, June 15). Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease. . Retrieved July 19, 2014, from http://www.jneurosci.org/content/20/12/4389.full