The Fragile X Syndrome

The Fragile X Syndrome The fragile X syndrome is one of the most prevalent mental retardation problems that are inherited to generations. The clinical features of people with this syndrome are very subtle and hard to diagnose. Recent progress in the field of molecular biology and genetics has outlined the molecular mutation, that causes the syndrome was a triplet repeat mutation. Due to repetitive CGG repeat the respective proteins are not expressed. New molecular methods including direct probe analysis and PCR analysis, have simplified the process of diagnosis. The nature of the gene, their respective gene product and its function has not been yet found clearly. Inheritance may be found due to common ancestral flow of X chromosome at birth. Introduction Fragile S syndrome is a genetic disorder that affects the intellectual, physical and mental factors of a human being. It is also known to be martin-bells syndrome and the effects range widely from mild to severe. It is caused by the mutation on the X chromosome of the individual in a single gene called the Fragile X mental retardation gene (FMR1). Psychological problems such as mental retardation may be caused by two main factors, the physical environment or the genetic factor that is hereditary. As we mainly focus on the genetic factor, the FRAXA locus in xq27.3 is associated in causing fragile X mental retardation. Therefore based on molecular genetic testing of FMR1 gene, fragile X syndrome can be diagnosed. Women are only 50% affected by this syndrome when compared to males due to the fact that they have two X chromosomes where as males have one. Most common symptoms found are seizures, mood instability, attention deficit, sensory over stimulation, aggression, autism, speech diso rder and sleep differences. This syndrome also shows certain physical symptoms such as long narrow face, large ears enlarged testacles in males, flexible joints etc., various researches is being done across the world to find a solution for the disease. Various genetic techniques has been developed and handled to identify the fragility of the chromosome. There has been so much improvement in research but a definite solution has not been obtained. The treatment for this syndrome is usually a multidisciplinary approach which includes occupational therapy, medical managements, education and linguistics. The Fragile X Mutation: Genes are the precursors of specific protein molecules which in turn are specific for various functions of the body. The major cause for the fragile x syndrome is due to the mutation in one single gene called the fragile x mental retardation 1 (FMR1) gene which is the precursor for the fragile x mental retardation protein FMRP. This protein is responsible for the normal development and functioning of the brain. Men have only one x chromosome so presence of mutation in that chromosome will cause the disease whereas in females, they have two x chromosomes and hence full mutation in one copy makes them carriers of the syndrome and they may be affected partially according to the amount of mutation and number of cells expressing the FMR-1 gene copy. The inheritance found on the chromosomes is termed as x linked recessive inheritance which is more complex than the normal x linked genes. Fig.1 X chromosome with fragile site [1] Fig. 2 A photograph of X chromosomes showing a fragile site from both a male and a female [2] The number of CGG repeats on the FMR-1 gene determines the complexity of the syndrome. The repeats are classified as short, medium and long repeats. The short repeat of about six to fifty times which is found very common. These short repeats are mostly unstable and do not definitely cause the syndrome. Yet a genetic counseling along with certain tests is recommended. The medium repeat is about 50 to 200 times and is called permutation. The fragile x mental retardation protein (FMRP) has lower risk of the syndrome as short sequence repeats. The long repeats are usually more than 200 and are termed as full mutation where the complete FMR-1 gene is altered and production of the FMRP protein is totally stopped. Among the people with full mutation or long repeats, men will have the fragile x syndrome and women will be carriers. Fragile x mental retardation protein (FMRP) The FMRP protein is found in the ribo-nucleoprotein complex and is encoded by the FMR1 gene. The FMRP weighs up to 60-70 kD. This protein is associated with the polyribosome or polysomes. Two RNA-binding domains, KH domains or K homology domains are possessed by this protein and it binds to fetal human brain to 4% approximately. It also has the ability to bind to its own mRNA. Even a small amount of mutation in one of the KH domain could stop its interaction with the polysomes leading to the fragile x syndrome. Inheritance of fragile x syndrome Males have xy chromosome and hence have only one FMR-1 gene where as females have xx chromosomes and hence they have two FMR-1 genes. On the F1 generation each parent transfers one chromosome each to the offspring where the transfer of the FMR-1 gene is determined. Therefore the possibilities of their offsprings being affected are grouped under two conditions. Condition-1 [3] If a male has a mutated gene in his chromosome it can be transferred only to his daughter because only the Y chromosome can be transferred to his son by him. So if he was crossed with a female with normal genes all their sons will be normal and the daughters will have one fragile gene and remain as carriers. father à ¡Ã‚ ºÃ¢â‚¬ ¹ y mother x xà ¡Ã‚ ºÃ¢â‚¬ ¹ (carrier daughter) Xy (normal son) x xà ¡Ã‚ ºÃ¢â‚¬ ¹ (carrier daughter) Xy (normal son) à ¡Ã‚ ºÃ¢â‚¬ ¹ fragile x gene Condition-2 [4] If a female has one mutated gene in her chromosome and is crossed with a normal male then there is 50% chance of all the offsprings, be it male or female to have the syndrome. father x y mother à ¡Ã‚ ºÃ¢â‚¬ ¹ xà ¡Ã‚ ºÃ¢â‚¬ ¹ (carrier daughter) à ¡Ã‚ ºÃ¢â‚¬ ¹ y (fragile son) x xx(normal daughter) Xy (normal son) à ¡Ã‚ ºÃ¢â‚¬ ¹ fragile x gene Symptoms The symptoms of fragile x syndrome are categorized into : Physical Large eyes Prominent forehead Large testecles Seizures Cognitive development Social and emotional hyperactivity Behavioral Shyness Social anxiety Speech and language Rapid and repetitive Inability to adopt words Over-talkative Autism Flapping of hands Poor eye contact All these symptoms need not be necessarily seen. A combination of various symptoms may vary from person to person based on the amount of gene altered in their chromosome. Sometimes there may also be no visible symptoms making the chances of early diagnosis even worse. Molecular diagnosis [5] The chromosome associated with the syndrome is classified into three major types based on the number of CGG repeats as Normal allele the CGG repeat in FMR1 is 6-50 PCR analysis is sufficient to study all normal type genes Specific point mutations and mosaicism must be studied using specific types of pcr or other molecular methods Visualization is achieved either by radio-active labeling or auto radiography followed by automated sequencing Agarose gel electrophoreses may be used for simple separation analysis with stains such as ethidium bromide. Appropriate size markers and size controls are very important. Controls used for analysis mut approximately contain 50 repeats. Pre mutation The CGG repeat in FMR1 is 55-200 PCR analysis is not possible hence southern blot is always preferred. Since both premutation and full mutation have methylation status, specific methylation sensitive enzymes such as EagI or NreI is used to resolve the size of the fragment. Methylated alleles are cut only by one enzyme where as non methylated normal alleles are cut by both the enzymes. Prenatal diagnosis is very important for pre mutation carriers. Rather than normal PCR a radioactive PCR can be used to test for premutation and then the result can by confirmed using southern analysis. Full mutation The CGG repeats in FMR1 ranges from 200 to thousands This can be analysed only by a southern blot technique. At complications, if a confirmable result could not be obtained from a southern analysis then a radio active PCR can be run combined with a linkage analysis and the result can be confirmed with southern blotting. Intermediate alleles The CGG repeats in FMR1 gene is usually between 45-55 Since they are in the overlapping region between stable normal allele and unstable premutation alleles, diagnosis and interpretation is very difficult Diagnostic Tools and Methods With the advancement in technology DNA tests are always effective in diagnosis of fragile x syndrome. With the findings of Sutherland et al. that folic acid deficient cell culture medium was able to induce a fragile site at xg27.3 cytogenetics was the major way to determine the presence of the syndrome but after cloning of the FMR-1 gene direct methods for identifying the x linked gene has become possible. By using monoclonal antibodies specific to FMRP it is also possible to show the expression of FMR-1. The most common methods used for diagnosis in the genetic level are Polymerase Chain Reaction Southern Blotting Antibody test Denaturing gradient gel electrophoresis Single strand confirmation polymorphism Non-radioactive molecular diagnosis. Polymerase chain reaction Polymerase chain reaction may be defined as a technique where one copy of a DNA is amplified into numerous copies at a rate of 2n where n is the number of cycles. It is achieved under specific conditions of temperature, along with polymerase enzyme. PCR amplification is one of the preliminary methods in diagnosing fragile x syndrome. Since the syndrome is associated with CGG repeats PCR is not considered as the best method always, since the amplification across C-G composition could be unreliable for PCR technique. However now its very much possible for a PCR to identify CGG repeats in combination with various techniques. methylation specific PCR of the FMR1 locus fluorescent methylation specific PCR methyl-CpG-binding PCR Some of the major advantages of PCR are that it is less time consuming, a very small amount of the sample is enough to produce numerous copy and the tri-nucleotide repeat in the FMR-1 gene is accurately sized. There are also various disadvantages of this technique. When there are more than hundreds of tandem repeats it is impossible for the PCR to determine the complete mutation which may give a different result. Due to differential amplification PCR is incapable of detecting mosacism between pre mutation and normal alleles. Fig 3: fragile x analysis using PCR [6] Southern Blotting Southern blotting is one of the best methods of diagnosing fragile x syndrome. It is modtly used as the confirmatory test after PCR. The variations between the mutations and permutations along with the amount of methylation occurred can be clearly obtained by the southern blotting technique. The process can be summed up in two simple steps: Step 1: the patients DNA is digested using restriction enzymes. Step 2: southern hybridization is carried out along with specific radioactive probes after separation of FMRI region. Using southern Blotting, the differences in full mutation and pre mutation can be easily identified. Full mutations usually cause smearing of the band and are always unstable. The only advantage of this technique is that its accuracy whereas its labor intensive, time consuming. The major drawback of this method is its inability to determine the exact number of tandem repeats of the CGG nucleotides which is very much necessary in determining whether the patient is completely affected or a carrier. Fig 4: fragile x analysis by southern blot [7] N refers to normal Specific tools for analysis DNA probe A DNA probe can be defined as a single strand of DNA which act as a template to identify the target DNA molecule. To identify the fragility of chromosome on the DNA specific probes were designed which increases the accuracy rate of the diagnosis. Chemicon (Millipore) [8] has designed a special probe named The CHEMI probe which is labeled with dioxegenin to detect the CGG repeats in the FMR-1 gene. Markers There were special markers called the microsatelite markers used in linkage analysis. This came to an end with the advent of modern techniques. However these markers are now being used under special circumstances like prenatal diagnosis where southern blotting has failed. Some of the markers used are DXS548, FRAXAC1 and FRAXAC2 combined with PCR. They are considerably accurate and they undergo low recombination mechanism with CGG repeats. Treatments There are no gene therapies or genetic treatments available for fragile x syndrome though a lot of other therapies are available which include speech-language therapy, occupational therapy, physiotherapy and behavioral therapy. There are also a large number of medications available as listed in the table below: Symptoms Medications Seizures Mood instability à ¢Ã¢â€š ¬Ã‚ ¢ Carbamazepine (Tegretol) à ¢Ã¢â€š ¬Ã‚ ¢ Valproic acid or divalproex (Depakote) à ¢Ã¢â€š ¬Ã‚ ¢ Lithium carbonate à ¢Ã¢â€š ¬Ã‚ ¢ Gabapentin (Neurontin) à ¢Ã¢â€š ¬Ã‚ ¢ Lamotrigine (Lamictal) à ¢Ã¢â€š ¬Ã‚ ¢ Topiramate (Topomax), tiagabine (Gabitril), and vigabatrin (Sabril) à ¢Ã¢â€š ¬Ã‚ ¢ Phenobarbital and primidone (Mysoline) à ¢Ã¢â€š ¬Ã‚ ¢ Phenytoin (Dilantin) Attention deficit (With or without hyperactivity) à ¢Ã¢â€š ¬Ã‚ ¢ Methylphenidate (Ritalin, Concerta) and dexamethamphetamine (Adderall, Dexedrine) à ¢Ã¢â€š ¬Ã‚ ¢ L-acetylcarnitine à ¢Ã¢â€š ¬Ã‚ ¢ Venlafaxine (Effexor) and nefazodone (Serzone) à ¢Ã¢â€š ¬Ã‚ ¢ Amantadine (Symmetrel) à ¢Ã¢â€š ¬Ã‚ ¢ Folic acid Hyperarousal Sensory over-stimulation (Often occurs with ADD/ADHD) à ¢Ã¢â€š ¬Ã‚ ¢ Clonidine (Catapres TTS patches) à ¢Ã¢â€š ¬Ã‚ ¢ Guanfacine (Tenex) Aggression Intermittent explosive disorder Obsessive-compulsive disorder (Often occurs with anxiety and/or depression) à ¢Ã¢â€š ¬Ã‚ ¢ Fluoxetine (Prozac) à ¢Ã¢â€š ¬Ã‚ ¢ Sertraline (Zoloft) and citalopram (Celexa) à ¢Ã¢â€š ¬Ã‚ ¢ Paroxetine (Paxil) à ¢Ã¢â€š ¬Ã‚ ¢ Fluvoxamine (Luvox) à ¢Ã¢â€š ¬Ã‚ ¢ Risperidone (Risperdal) à ¢Ã¢â€š ¬Ã‚ ¢ Quetiapine (Seroquel) à ¢Ã¢â€š ¬Ã‚ ¢ Olanzepine (Zyprexa ) Sleep disturbances à ¢Ã¢â€š ¬Ã‚ ¢ Trazadone à ¢Ã¢â€š ¬Ã‚ ¢ Melatonin Table 2: symptoms and medications for FRAXA [9] (*these prescriptions have serious effects. DO NOT INTAKE ANY OF THESE WITHOUT CONSULTING A MEDICAL PRACTITIONER) Current Research Gene Therapy: studies are carried out on the recombination strategy of the target gene, whether removal or replacement of the defective gene with a recombinant gene would eliminate the syndrome. Protein Replacement Therapy: research is being carried out on the possibility of producing FMR protein and supplying to the patients through external sources like food or tablets. Psychopharmacology: research is being carried out in finding medications for all the symptoms of fragile x syndrome. Conclusion Fragile x syndrome is one of the genetic diseases that causes psychological problems due to the lack of FMR protein responsible for the mental behavior of the person. The protein is not expressed in the individual due to fragility of the FMR1 gene in the x chromosome. Though PCR and southern blotting are the only tools available for diagnosis they are considerably accurate and research is being carried out on various re-combinative tools for diagnosis. A complete cure has not been still devised for the syndrome though various behavioral and physical therapies help the patients gain psychological strength.

Describing The Obelisk :: Egypt Monuments Essays

Describing The Obelisk Whether you are driving past it on the freeway or it catches your eye as you leave the movie theater, the obelisk that stands in front of the Irvine Spectrum Center is a commanding sight to see. The 50-foot high fiber optic wonder is an impressive display of ancient shape and modern technology. During the evening hours, the needle rhythmically fades from one color to another, changing shades and hues. In daylight, it is a gleaming white beacon to all who look on. It is the identifying feature of a large business center know as the Irvine Spectrum. It is located where the 5 and 405 freeways connect in Irvine. This plaza contains a diversity of shops and restaurants, as well as commercial and business buildings. It is also the site if the Edwards 21 Cinema Complex and Edwards Imax 3-D Theater. Irvine Spectrum is surrounded by expanses of land that have yet to be developed, or are undergoing preliminary steps of development. This center is used by both young and old who shop, eat, and w ork there. Many people go to the Irvine Spectrum for the sole purpose of visiting the most technologically advanced movie theater in the world - the Edwards Imax 3-D Theater. I believe that this attraction is one of the main reasons the obelisk stands in front of the complex. When The Irvine Company, the development firm which built Irvine Spectrum, decided to have this one of a kind theater located at Irvine Spectrum, I think they were searching for something which would represent the grandeur of the new attraction. I believe the obelisk is that something. The stately shape is easily identifiable as one that has endured the test of time, while the advanced fiber-optics which cover the surface add new-age technology to ancient symbolism. The combination of these two factors into the structure of the obelisk parallels the theater because both are classics with a new twist. The obelisk, however, also parallels its counterparts from thousands of years ago. From the remains of great civilizations of the past, obelisks are found to be one of the most easily identifiable monuments of all.

Fundamentals of Speech Chapter 7 Assignment

Fundamentals of Speech (Stiefel) CHAPTER 7 ASSIGNMENT Student Name: Below are arguments based on faulty reasoning. Identify the fallacy used (use a fallacy only ONCE): 1. Loaded WordsIt’s ridiculous to worry about protecting America’s national parks against pollution when innocent people are being attacked by terrorists. 2. Red HerringThe proposal is likely to be resisted by the business-as-usual bureaucrats on Capitol Hill. 3. Celebrity EndorsementQueen Latifah promotes Cover Girl Cosmetics, so they must be good quality. 4. HearsayMy friend heard on the news the other day that the U. S. will declare war on Iran. . Question BeggingSince I'm not lying, it follows that I'm telling the truth.6. Slippery SlopeIf we allow the school board to spend money remodeling the gymnasium, next year they will want to build a new school and give all the teachers a huge raise. Taxes will soar so high that businesses will leave and then there will be no jobs for anyone in this town. 7. In valid AnalogyRaising a child is just like having a pet: you need to feed it, play with it, and everything will be fine. 8. Personal AttackI can’t support Senator Smith’s proposal for campaign finance reform because of all that time he spent in rehab back in the 1980s. . Hasty GeneralizationFred, the Australian, stole my wallet. Thus, all Australians are thieves. 10. False DillemaIf you don’t support the war in Iraq, then you don’t support the troops. 11. Authority FigureNoted psychologist Dr. Frasier Crane recommends that you buy the TurboSpa Hot Tub.12. Either OrWe must either increase tuition or cut back on library services. 13. Arguing From IgnoranceSince you cannot prove that ghosts do not exist, they must exist. 14. Complex QuestionHave you stopped using illegal sales practices? 15. Prejudicial LanguageA godly person would agree that social programs must be maintained. 6. CoercionOnly those employees who want to keep their jobs should show up to the Saturday morning work session. 17. Straw ManSome people claim the â€Å"War on Drugs† is a failure, but I say they are wrong. 18. Unnamed AuthorityHealthcare insiders estimate there are more than 2 million needless surgical procedures conducted every year. 19. BandwagonI don’t see any reason to wear a helmet when I ride my bicycle. None of my friends do. 20. Cause and EffectThe Great Depression was caused by the Hoover administration. Herbert Hoover became president in March 1929, and the stock market crashed just seven months later.

Imperialism - an Irony - Shooting an Elephant - 1255 Words

Imperialism  ­ an irony. Imperialism is a no ­win situation: ââ€"  ââ€"  ââ€"  Throughout the short text we see Orwell as a character torn between two completely juxtaposed ideals: that in support of the oppressed and the colonial. We are barely halfway through the opening sentence when Orwell declares how he was â€Å"hated by large numbers of people† and we quickly learn of the immense anger he has towards his tormentors. Initially, we learn of Orwell’s personal experience of power and how he is â€Å"hated by large numbers of people†. ââ€"  We quickly see how much of a struggle it is for Orwell to endure the bitterness of the locals. ââ€"‹ ââ€"‹ ââ€"  Orwell paints the â€Å"sneering yellow faces of young men† and talks of the insults â€Å"hooted† at his†¦show more content†¦This metaphor is then extended to the idea of a puppet. We see this image of the crowd pulling at Orwell’s strings, physically moving his limbs for him and forcing him to act against his will. We see the nature of the pupett having no will or mind of it’s own, not ability to decide in it’s fate but instead purely reliant on those who control it suggesting Orwell’s ultimate dependance upon the Burmese in his decision making process. The idea of performance suggests a nature of â€Å"playing up† to the locals. It suggests that the colonials are adhering to some sort of stereotype, trying to keep up appearances, to match the expectations of the people. He suggests this idea of an illusion of control, that the colonials think they have free will, power yet in fact they are lead by their own stereotype: ââ€"   ââ€"   ââ€"   ââ€"   ââ€"   ââ€"   ââ€"‹ We again see the will of those people is a stronger force that the threat of Orwell’s weapon. We see the gun is ultimately futile and so too is Orwell’s power. â€Å"He wears a mask, and his face grows to fit it†. This metaphor really hammers home the idea of acting up to stereotype. 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