Genetics: Huntington's Disease - Research Paper Example

?Huntington’s Disease Huntington’s disease is a hereditary disorder affecting the central nervous system. It usually presents with abnormal movements, psychiatric symptoms, and cognitive dysfunction. It is a rare disease that manifests only in 5-10 individuals in every 100,000 Caucasians, with much lower prevalence among Asian and other populations (Roos 1). Clinical symptoms usually begin to occur at a mean age of 30 to 50 years old. However, patients may be as young as 2 years old and as old as 85 years old at disease onset (Roos 2). Signs and symptoms can be grouped into motor, cognitive, and psychiatric disturbances. Motor symptoms manifest as involuntary and unwanted movements, which are called tics. These tics usually begin in the fingers and toes, but may also involve the muscles of the face. To other people, they can appear as nervousness. These tics gradually involve other muscles until they become big, abnormal movements called chorea. Patients eventually develop slowness in movement and difficulty initiating movements. Walking becomes drunk-like. This interferes with work and daily living, as patients become prone to falling and can no longer carry out their usual activities such as dressing and cooking (Roos 2). Behavior and psychiatric symptoms usually present early on in the disease, even before onset of motor signs. Irritability is usually the earliest sign, but only thought of in retrospect. The most frequently occurring symptom is depression. A study showed that 3 in 1000 individuals with major depression were found to carry an expanded huntingtin gene CAG allele. These patients suffering from depression were predicted to eventually develop full-blown Huntington’s disease (Perlis et al. 578). Apart from depression, patients may develop low self-esteem, guilt feelings, and anxiety. Patients may even commit suicide, with the likelihood higher among patients with early onset of the disease (Roos 2). Patients with Huntington’s disease also develop dementia, manifesting as the inability to plan or organize. Patients develop poor judgment and impaired memory, with drastic effects on other psychomotor processes (Roos 3). In animal studies, mice with mutated Huntington’s disease gene are found to have excitatory synapses that cannot sustain transmission during repeated stimulation. This causes defects in synaptic plasticity, which is theorized to play a role in memory (Usdin et al. 839). The diagnosis of Huntington disease is usually straightforward in a patient presenting with the motor, behavioral and psychiatric signs, with a family history of a parent with the disease. A thorough family medical history must be done if history of the disease is not elicited immediately. For testing, the current gold standard is DNA determination, which would show a CAG-repeat of 36 or more on the huntingtin gene on chromosome 4. Before doing a DNA test, patient must be counseled (Roos 5). Prenatal diagnosis may also be done for parents aware of whether or not they have Huntington’s disease. Chorionic villus is sampled between 10th and 12th weeks of pregnancy, and amniocentesis done between 15th and 17th weeks for DNA testing. The pregnancy may be terminated if the embryo is found to have the gene for Huntington disease, although the mother could decide otherwise (Roos 6). The symptoms of Huntington’s disease are brought about by the progressive neurodegeneration of the basal ganglia, which may also involve the cerebral cortex. It is an autosomal dominant inherited disease, which is characterized by an elongated CAG repeat on the short arm of chromosome 4p16.3 in the huntingtin gene. This gene codes for the huntingtin protein wherein the normal or wild-type variant has a series of CAG repeats which code for glutamine residues. Normally, there are 10-29 repeats of the CAG, which is expanded up to 121 in patients with Huntington disease (Kumar, Kalonia, and Kumar 2). The huntingtin protein is widely expressed in the central nervous system. Because of the mutation, it accumulates and triggers a cascade of oxidative injury, transcriptional dysregulation, mitochondrial dysfunction, and energy depletion which ultimately leads to increasing neuronal dysfunction (Kumar, Kalonia, and Kumar 2). Apart from these, newer studies also show that mutant huntingtin protein may also decrease affected tissues’ ability to maintain homeostasis, thus increasing risk of death of the neurons (Miller et al. 9). In animal models, motor deficits can be exacerbated and expression level of mutant huntingtin gene in the brain, particularly the striatum, can be increased with depletion of interleukin-1, a cytokine with both beneficial and harmful effects in inflammation. (Wang, Li, and Li 4) Signs and symptoms occur if the CAG repeats are more than 40. If the repeats number from 36 to 39, there will be incomplete penetrance or the disease will have a very late onset (Roos 4). If the CAG repeats number 27 to 35, patient is at risk of transmitting the disease to his or her children. Expanded CAG repeats are unstable and will tend to expand as it passes through the generations, especially if inherited from the father (Zuccato, Valenza, and Cattaneo 908). Apart from affecting the disease penetrance, studies have also shown that the longer the CAG repeat, the earlier the onset of the disease symptoms. With CAG repeats of 60 or more, a patient may have disease onset at childhood or adolescence, a condition known as Juvenile Huntington’s disease. The number of CAG repeats is also directly correlated with disease severity and progression (Zuccato, Valenza, and Cattaneo 908). A more expanded CAG repeat length has also been linked to weight loss, likely resulting from a hypermetabolic state (Aziz 1506). At present, despite multiple clinical trials, there is no cure for Huntington’s disease. There are, however, therapeutic options geared towards improving quality of life and offering palliative support. Most of the clinical trials on Huntington’s disease basically fall on the following categories: (1) symptomatic or palliative therapies, (2) anti-degenerative therapies, (3) restorative or reparative therapies, and (4) molecular targets in specific and radical therapies (Kanazawa 213). In controlling the motor signs such as chorea, current practice recommends the use of dopamine receptor blocking or depleting agents. The most common agents used are neuroleptics and tetrabenazine (Roos 6). The behavioral and psychiatric symptoms such as depression and aggression are also treated with neuroleptics, such as olanzapine, which is the preferred drug. Apart from these pharmacologic interventions, non-medical interventions are also employed. Patients undergo physiotherapy, occupational therapy, and speech therapy to aid them as they lose their ability to carry out activities of daily living. Patients may also consult with a dietician, psychologist, and social worker for help in the other aspects of the disease (Roos 6). Currently, research and clinical trials are exploring others approaches to intervention. Some studies and trials are targeting the mutant huntingtin gene, such as by degrading its alleles’ mRNAs. The huntingtin gene’s aggregation and protein homeostasis is also being looked into, as manipulating cellular mechanisms to ensure correct protein folding may prevent it from accumulation and causing its neurodegenerative effects. Basic researchers are also tracking transcriptional changes brought about by mutated huntingtin gene, and also looking into alterations in the neurotransmitters of patients, as these may be the culprits in the development of cognitive dysfunction (Munoz-Sanjuan and Bates 478-480). In summary, Huntington’s disease is a significant inherited disease. Though rare, it causes a debilitating illness, due to its drastic motor, behavioral, and psychiatric symptoms. Currently, there is no cure for it. It is an important area of research, especially for those in the field of genetics, as elucidating the factors that lead to its pathogenesis may provide clues on how to eventually cure it. Works Cited Aziz, NA, et al. “Weight Loss in Huntington Disease Increases with Higher CAG Repeat Number.” Neurology 71.19 (2008): 1506-1513. Print. Kanazawa, Ichiro. “Therapeutic Strategies in Huntington’s Disease.” Journal of Clinical Neurology 2 (2006): 213-224. Print. Kumar, Puneet, Harikesh Kalonia, and Anil Kumar. “Huntington’s Disease: Pathogenesis to Animal Models.” Pharmacological Reports 62 (2010): 1-14. Print. Miller, Jason, Montserrat Arassate, Benjamin Shaby, Siddharta Mitra, Eliezer Masliah, and Steven Finkbeiner. “Quantitative Relationships between Huntingtin Levels, Polyglutamine Length, Inclusion Body Formation, and Neuronal Death Provide Novel Insight into Huntington’s Disease Molecular Pathogenesis.” Journal of Neuroscience 30.31 (2010): 1-20. Print. Munoz-Sanjuan, Ignacio and Gillian Bates. “The Importance of Integrating Basic and Clinical Research toward the Development of New Therapies for Huntington Disease.” Journal of Clinical Investigation 121.2 (2011): 476-483. Print. Perlis, Roy, et al. “Prevalence of Incompletely Penetrant Huntington’s Disease Alleles among Individuals with Major Depressive Disorder.” American Journal of Psychiatry 167.5 (2010): 574-579. Print. Ross, Raymund. “Huntington’s Disease: A Clinical Review.” Orphanet Journal of Rare Diseases 5.40 (2010): 1-8. Print. Usdin, Martine, et al. “Impaired Synaptic Plasticity in Mice Carrying the Huntington’s Disease Mutation.” Human Molecular Genetics 8.5 (1999): 839-846. Wang, Chuan-En, Shihua Li, and Xiao-Jiang Li. “Lack of Interleukin-1 Type 1 Receptor Enhances the Accumulation of Mutant Huntingtin in the Striatum and Exacerbates the Neurological Phenotypes of Huntington’s Disease Mice.” Molecular Brain 3.33 (2010): 1-7. Print. Zuccato, Chiara, Marta Valenza, and Elena Cattaneo. “Molecular Mechanisms and Potential Therapeutic Targets in Huntington’s Disease.” Physiological Review 90 (2010): 905-981. Read More