An Exploration of Marfan Syndrome PDF

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An Exploration of Pleiotropy using Marfan Syndrome Marfan Syndrome (MFS) is a genetic disorder of the connective tissue, with a prevalence of approximately 1 in 5000 people1. The syndrome has no predilection for either sex or any race1. MFS is caused by a mutation in the Fibrillin-1 encoding gene (FBN1) and it is inherited in an autosomal dominant manner2. The most prominent manifestations of the syndrome involve the skeletal, ocular and cardiovascular systems3. Incidence of the MFS mutations are estimated to occur due to de novo mutations, 15-30% of the time4. These novel mutations in the FBN1 gene tend to result in severe forms of the syndrome such as neonatal MFS which has a survival rate of less than a year4. Pleiotropy describes the effect of one gene mutation on many aspects of the phenotype. Said mutations in these genes are referred to as pleiotropic as they are able to cause the development and variation of multiple unrelated phenotypic traits. Although pleiotropy is usually found in rare genetic mutations, it is not unusual to use it in order to diagnose and characterise certain syndromes3. Pleiotropy is considered to serve as the basis for multifactorial diseases such as Marfan Syndrome (MFS) 3. Nosology Diagnosis of MFS is currently based on Ghent nosology (a predefined clinical criteria). These criteria consist of major and minor manifestations, whether the patient has a family history and analysis of genetic mutation and phenotypic characteristics5. These criteria coupled with novel advancements in molecular techniques means diagnosis is possible in 95% of patients5. However, there are concerns with the current criteria. The nosology has not been sufficiently validated as it is solely based on opinion, it is not applicable to children and it requires expensive investigative work due to the possible 3000 different ways the FBN1 gene can mutate6. Currently, new guidelines are being explored which take children and alternative diagnosis methods into consideration. The FBN1 gene Located on the human chromosome 15 (15q21.1), FBN1 was identified as the locus for mutations that result in MFS in 19917. It is a large gene fragmented in 65 exons. FBN1 encodes Fibrillin-1, a cysteine rich, monomeric, extracellular glycoprotein which facilitates calcium binding to specific microfibril8. Said extracellular microfibril, consist of elastic and oxytalan fibres which provide stability and flexibility to tissues, play a role in tissue development and provide a reservoir for growth factor (TGF-β)8. A study8 in mice documented that a deficiency of Fibrillin-1 causes an excess of TGF-β. Mutations of FBN1 result in abnormal fibrillin which causes problems which often manifest in the musculoskeletal, ocular and cardiovascular systems where connective tissue is very prominent. As FBN1 encodes for a cysteine rich Fibrillin-1 (more than 360 residues), it has been assumed that many of the MFS causing mutations are due to cysteine mutations 9. Although there are over 3000 known mutations10 of the FBN1 gene, there are no known hotspots for the genetic mutations, which cause MFS to occur. However, it has been observed that mutations in the region of exons 24 to 32 are present in neonatal MFS and that exon skipping mutations tend to be associated with more severe phenotype expressions11. In addition expression of the FBN1 gene is highly variable both between

families and within families, so there is no known correlation between genotype and phenotype10. Pleiotropic Manifestations The most feared, and often the most common cause of death of MFS patients is aortic dissection or rupture following progressive aortic root dilation. Aortic dilation occurs due to degeneration of the aortic walls, which has often been linked to the heightened release of TGF-β8. This disorder of the aortic structure is present in the majority of MFS patients. In a study there was a higher prevalence of aortic aneurysms and mitral prolapse in patients with a cysteine substitution in comparison to patients with a cysteine introduction12. Therefore it appears that the disappearance of a conserved cysteine leads to more severe cardiovascular defects, compared to the addition of a new one. On the other hand, it has been observed that patients with a non-cysteine missense mutation had more severe cardiovascular manifestations13. This may be due to the belief that these missense mutations have a ‘dominant negative effect’ which leads to irregular folding of the protein and therefore disturbed interactions of Fibrillin-1 with other extracellular matrix protein. Ocular manifestations are one of the criteria of the Ghent nosology. From a study14 of 160 patients with MFS a variety of ocular abnormalities were observed. More than half of the group displayed ectopia lentis (dislocation of the lens) which could be attributed to the excessive stretching and subsequent rupture of the ciliary zonules which suspend the lens within the eye. Another study shows that ectopia lentis occurs in about 80% of MFS patients and is almost always bilateral15. Other conditions which may arise from said rupture of the ciliary zonules include exotropia and esotropia which are both forms of strabismus (misalignment of the eye). A study suggests that there is a correlation between cysteine mutations and increased occurrence of ectopia lentis13. The effects of Marfan Syndrome on the musculoskeletal are the most distinctive when looking at a patient. In the absence of regular Fibrillin-1, excess TGF-β can cause excessive growth in individuals. Persons living with Marfan tend to be very tall and slim (in comparison to their family members not the general population16), suffer from arachnodactyly (very long, slim fingers), have loose joints and a wingspan that exceeds their standing height. Other observed characteristics include scoliosis or kyphosis (an abnormal curvature of the spine) and pectus excavatum (a sunken chest) or pectus carinatum (a protruding chest). One study17 suggested that non-cysteine missense mutations result in more severe skeletal problems. Another study13 suggested that whole gene deletions led to more major involvement of the skeletal system. Conclusion With no known cure to date, treatment of Marfan Syndrome is limited to beta blockers, physical activity management and regular check-ups, particularly for monitoring of the heart. With these symptomatic treatments, life expectancy has increased significantly over the last few decades18. For the time being, Marfan Syndrome is only a clinical diagnosis. Mutations of the FBN1 are unique consequently there is no way of predicting the phenotypic manifestations on a molecular level. Hopefully, in the future, all aspects of MFS including its pleiotropic effects will become better understood, as the knowledge of its pathogenesis improves. (1058 words)

References 1. Von Kodolitsch,Y., Robinson,P.N. Marfan syndrome: an update of genetics, medical and surgical management. Heart, British Cardiac Society. 2007;93(6): 755–760. 2. Pepe, G., Giusti, B., Sticchi, E., Abbate, R., Gensini, G. F., Nistri, S. Marfan syndrome: current perspectives. The application of clinical genetics; 2016:9: 55–65. 3. Lobo, I. Pleiotropy: One Gene Can Affect Multiple Traits. Nature Education.2008; 1:1:10 4. Tiecke F., Katzke S., Booms P. Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Eur J Hum Genet; 2001:9(1):13-21 5. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47(7):476-485 6. Bonetti M. I. Microfibrils: a cornerstone of extracellular matrix and a key to understand Marfan syndrome. Italian journal of anatomy and embryology; 2009 4:201-224 7. Byers P,H J Clin Invest Determination of the molecular basis of Marfan syndrome: a growth industry; 2004: 114(2) 161-163. 8. Dietz H. C., Pyeritz R.E. Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Human Molecular Genetics; 1995 4:1: 1799–1809 9. Schrijver I., Liu W., Brenn T. Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet 1999;65(4):1007-1020 10. Downing AK, Knott V, Werner JM, et al. Solution structure of a pair of calcium-binding epidermal growth factorlike domains: implications for the Marfan syndrome and other genetic disorders. Cell 1996;85(4):597-605. 11. Robinson PN, Godfrey M. The molecular genetics of Marfan syndrome and related microfibrillopathies. Journal of Medical Genetics 2000;37:9-25. 12. Faivre L., Collod-Beroud G., Loeys BL. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007;81(3):454-466. 13. Franken, R. Marfan syndrome: Getting to the root of the problem; 2016: 5:73 14. Maumenee I.H. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc: 1981: 79: 684–733. 15. Robinson PN, Arteaga-Solis E, Baldock C, et al. The molecular genetics of Marfan syndrome and related disorders. J Med Genet. 2006;43(10):769–787. 16. Van de Velde S., Fillman R., Yandow S. Protrusio acetabuli in Marfan syndrome. History, diagnosis and treatment. The journal of bone and joint surgery. American volume; 2006 88:3:639-646 17. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352(6333):337-339 18. Judge D. P., Dietz H. C. The Lancet; 2005 366:9501: 1965-1976

1.

What was good about the essay? This essay gives a very clear introduction of MFS and easy to read and understand. Moreover, this essay introduces the definition of pleiotropy, MFS and the direct and indirect influences caused by the pleiotropy of the MFS by using solid data. The topic sentence in each paragraph is clear. And also including numerous researches. Overall, this essay let the reader understand the relationship between the disease and the pleiotropy easily and clearly.

2.

What was poor about the essay? However, there is no argument within the essay. There should be an argument after summarising these sources and the topic sentence should be topic sentence at the beginning of the paragraph. Moreover, most of the context are descriptive, there is no conclusion or thinking from sources. The result of the researches should be discussed or analysed. The overall structure is good and it could be better if you could add 'in conclusion' at the beginning of the last paragraph. I’ve tried to add an argument within the essay by including different studies on the genotype. Rather than linking each paragraph by a sentence, which I feel could be quite repetitive and boring, I’ve included subheadings so that the reader has a feel of what is being discussed in each section. I’ve tried to reduce the amount of descriptive context by including the studies, but I still want to demonstrate the pleiotropic effects. I don’t believe I need to add ‘in conclusion’ in the conclusion, as it clearly gives insight into what the future holds.

3.

How can the essay be improved? Firstly, it could be better that if you can have an argument from those scientific researches. That could be excellent if you could make your own argument in your essay, this will increase you mark. Secondly, summarizing and comparing several results from your source, which means try to analyse your sources. This will reduce your descriptive contexts and amplify more critical thinking in your essay. Thirdly, it could be better if you can use some linkers, for example, 'in conclusion'. This could emphasize your essay structure. Moreover, you could insert some relevant images or tables in your essays and they could become your solid evidence in your essay. As previously mentioned, I’ve tried to include different studies and how they demonstrate pleiotropy. I’ve tried to compare the results of different sources and what I believe, to show my critical thinking and analysing. I decided not to use ‘in conclusion’ and linkers but rather subheadings to emphasize the essay structure. I don’t think images or tables are necessary as they will be there for superficial purposes. They will not clearly demonstrate any of my points. Overall, the structure of the essay has been changed from the original, but some of the suggested improvements have still been taken on.

4.

What grade would you give the essay? 1 = 1st 70% and above ; 2 = 2.1 60-69% ; 3 = 2.2 5059% ; 4 = 3rd 40-49% ; 5 = FAIL below 40% 2 of 5...