Huntington Disease - Essay Example

? Huntington Disease of the of Huntington Disease Introduction HD or Huntington's disease is a neurodegenerative hereditary disease that impacts muscle coordination and contributes to psychiatric problems and cognitive decline. It generally becomes detectable in mid-adult life. It is the most usual genetic reason of abnormal involuntary twisting motions called chorea, that’s why it is often referred as Huntington's chorea. Huntington’s disease is very much common in Western European descendents than in those of African or Asian ancestry. Autosomal dominant alteration (mutation) in any of the tow copies of an individual’s gene known as Huntington. Thus each child of the affected person usually has 50% chances of inheriting the Huntington’s disease. The physically apparent Huntington’s disease may develop at any age from birth to the death, but commonly they show up between the period of 35 to 44 years of age (Purdon et al., 1994). Clinical features Physical examination of an individual often in combination with psychological examination may help in the determination of the beginning of the onset of the Huntington’s disease. Extreme unplanned movements of body part are frequently the grounds for attempting medical consultation. Moreover, if these movements are disconnected and have haphazard distribution and timing, they propose the diagnosis of Huntington’s disease. Psychiatric or cognitive symptoms are seldom the initial diagnosed but they are commonly only distinguished in apprehension or when they grow further. The level of progression of disease can be gauged using a unified HD rating scale which renders an overall scoring system based on behavioral, motor, functional and cognitive assessments. Medical imaging, like MRI (magnetic resonance imaging) and CT (computerized tomography), can reveal caudate nuclei’s atrophy in the earlier stages of the disease but these alterations does not provide diagnostic of the disease. Cerebral atrophy is evident in the progressed stages. Functional neuroimaging methods such as PET and fMRI can reveal alterations in brain activity prior to the onset of symptoms (physical) but are used for experimental purposes and thus are not employed clinically (Jang-Ho Cha and Young, 2000). Huntington’s disease is characteristically a grownup onset disorder qualified by insidious onset of psychiatric as well as neurologic symptoms (Harper, 1996; Ranen et al., 1996). Within the U.S., about 25,000 individuals are impacted by HD (almost 10 out of 100,000 population) and roughly 150,000 individuals have 50% risk for the Huntington’s disease because of bearing an affected parent (Jang-Ho Cha and Young, 2000). The symptoms typically commence in the period between 35 to 45 years of age while disease onset may range from as immature as 2 years or as aged as 80 years. Early symptoms consist of personality change and the continuing emergence of small spontaneous movements (Harper, 1996). Symptoms develop, with chorea turning more incapacitating and obvious. Over existence, motor symptoms deteriorate such that difficulty in walking increases as do eating and speaking. Weight loss is general, to some extent because of the extra energy needed for extrinsic movements but also to heightened expenditures of quiescent basal energy. the majority HD patients ultimately surrender to aspiration pneumonia, due to swallowing difficulties (Purdon et al., 1994). Around 10% cases of HD initiate prior to the age of 20. The Westphal variant (juvenile form) exhibits more parkinsonian nature. Instead of chorea, the eminent features are rigidity, bradykinesia and tremor. The juvenile onset may contain seizures. Juvenile onset typically consequences from transmission from father (Nance and Myers, 2001). Among individuals who produce symptoms prior to 10 year’s age, it has been seen that greater than 90% possess father with the same disease (Ranen et al., 1996). This propensity for anticipation of onset in younger age within following generations is particularly prominent in instances of paternal transmission. Interestingly, the adult onset as well as the juvenile onset phenotypes may be there within the individuals belonging to one family. Novel mutations have been accounted, typically from one of the parents containing “intermediate allele”. Thus, Huntington’s disease seems to be a genuinely dominant disease (Nance and Myers, 2001). Genetic Association All human beings possess two copies of gene associated with the Huntington disease named as HTT (Huntingtin gene), which codifies the protein Htt (Huntingtin). This gene is also referred as IT15 or HD, where IT15 represents 'interesting transcript 15'. A fraction of this gene is a repeated section known as trinucleotide repeat, with varying in length among individuals and may also reveal variations among generations. Upon reaching a certain threshold of growth of the repeated section’s length, it develops a modified protein form, referred as mHtt (mutant Huntingtin protein). The contradictory operations of these proteins lead to pathological changes which consecutively reason the symptoms of HD. The mutation of Huntington's disease is heritably dominant and approximately fully penetrating, as mutation of one of an individual’s HTT genes consequences the disease. Since its inheritance is unaffected by sex but by the variation in the length of repeated section, so its severity may be impacted by the sex of the transmitting parent (Harper, 1996). Huntington’s disease is one of the various trinucleotide repeat disarrays which are induced by the repeated portion of a gene’s length beyond a normal range. The gene involved is situated on the shorter arm of the chromosome 4. HTT possesses a three DNA bases sequence i.e. CAG (cytosine-adenine-guanine) recurring multiple times (such that .CAGCAGCAGCAG ...), referred as a trinucleotide repeat. CAG provides the genetic code for the production of glutamine; an amino acid. So a chain of them consequences in the construction of a sequence of glutamine called as a PolyQ tract (polyglutamine tract), while the repeated gene’s section is known as the PolyQ region. The trinucleotide repeat classification, the consequential disease’s status depends upon the number of repeat of CAG. If the repeat count is less than 26, it is classified as normal and the disease will not result in the individual as well as the offspring will not be carrying any risk. If it is between 27 to 35, the repeat is classified as intermediate, it will also now produce disease in the individual but does inherent a risk of much less than 50% to the offspring. If the repeat count is between 36 to39, it is classified as reduced penetrance and may probably affect an individual along with posing a risk of 50% to offspring. If the repeat count is more than 40, it is classified as full pentrance, affecting an individual along with posing the risk of 50% to offspring (Harper, 1996). Usually, people possess less than 36 repeated glutamines within the polyQ region which induces the production of the Huntingtin; a cytoplasmic protein. But a sequence of more than 36 glutamines repeats consequences in the development of a protein having different characteristics. This distorted form, known as mutant Htt (mHtt), enhances the rate of decay of specific neurons type, thus impacting the portions of human brain possessing various amounts and dependence on such neurons. Normally, the amount of CAG repeats is connected to the level of process affected, and explains approximately 60% of the fluctuation of the age at which the symptoms onset takes place. The residual variation is accredited to other genes that transform the mechanics of HD, and environment. The reduced-penetrance often results in a too later onset as well as slower development of symptoms. In few cases, the onset may be as later thus not resulting in any noticeable symptoms during life. However, in full penetrance the disease onset is evident at the age below 20 years, known as Westphal variant, akinetic-rigid or juvenile HD and this leads to around 7% carriers of the disease (Zuhlke, 1993). The CAG repeats of more than 28 are not stable throughout replication and this unstableness enhances with the present repeats number. This typically directs to new extensions as generations pass going through dynamic mutations rather than developing an exact trinucleotide repeat’s copy. This consequences the number of repeats to alter in succeeding generations, thus an unaffected individual with an intermediate repeat count, or with reduced penetrance, may inherit a gene with an enhance in the repeat count that develops full penetrance in the offspring. This phenomenon of increased repeat counts and thus earlier onset and severity of HD in sequential generations is referred as genetic anticipation (Teisberg, 1995). Instability is lesser in oogenesis than in spermatogenesis; hence alleles inherited from mother usually show similar lengths while those from father possess increased length (Zuhlke et al., 1993). Conclusion HD is transmitted in an autosomal dominant manner. Its inheritance is not dependent upon gender, as well as the phenotype is present in each generation. Due to autosomal dominant pattern of inheritance of HD, any affected individual usually inherits a single copy of the mutant allele (gene having an extended trinucleotide repeat) from either of the affected parent. The repeat count as evident from their pattern of increase show variation in meiosis while remain stable mitotically, as they vary in length upon inheritance but not within the same individual. The age of onset of the disease is found to be negatively correlated with the length of the CAG repeat and the strength of this correlation is more evident in the high number of repeats such as in full penetrance. References Harper, P. (1996). Huntington's Disease. London, W.B. Saunders Company Ltd. Jang-Ho Cha, J., and Young, A. B. (2000). Huntington's Disease. Retrieved from http://www.acnp.org/g4/gn401000151/ch.html Nance, M. and Myers, R. (2001). Juvenile onset Huntington's disease--clinical and research perspectives. Ment Retard Dev Disabil Res Rev. 7(3): 153-157. Purdon, S., Mohr, E., Ilivitsky, V. and Jones, B. (1994). Huntington disease: Pathogenesis, Diagnosis and Treatment. J Psychiatr Neurosci. 19(5): 359-367. Ranen, N., Stine, O. C., Gross, R., Bylsma, F. W., and Brandt, J. & Ross, C. A. (1996). Trinucleotide Repeat Length and Clinical Progression in Huntington’s Disease. Neurology 46:527-531. Teisberg, P. (1995). The genetic background of anticipation. J R Soc Med. 88(4): 185-187. Zuhlke, C., Riess, O., Bockel, B., Lange, H., and Thies, U. (1993). Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. Hum Mol Genet 2(12):2063-7. Read More