Access the assigned textbook viaClinical Key Studentusing the link below

Access the assigned textbook viaClinical Key Studentusing the link below

Purpose: The purpose of this assessment is to develop skills in applying key concepts covered in weeks 1-5. Written communication skills will also be developed in your responses to the case-based scenarios.

Instructions

Please read the case study carefully and ensure that you provide detailed answers that are clearly linked to the given scenario. Your responses MUST be written in your own words and material cited, referenced, and appropriately acknowledged. Your prescribed textbooks should be the primary source used in this assessment. However, you may choose to use other sources but please ensure that they are credible, recent and peer reviewed.

Word limit: 1250-1500 words. Citations are included but reference list is not included in word limit.

Weighting: 20% of unit grade.

Reference style: APA 7th style (see APA 7th style guide on Moodle), also see the Referencing module on Moodle for additional information about referencing.

Due date: Sunday 25th February 8 pm US ET 2024 (Monday 26th February 11 am AEST 2024).

How to submit: Turn-it-in submission link on Moodle (Week 6). You will need to accept the Academic Integrity statement stating that the work is entirely your own.

Grading: See rubric below.

Case - Duchenne muscular dystrophy

A four-year-old boy is brought into the GP by his parents because he is toe walking and falls frequently compared to other children his age. His parents also noted he was a little late to start walking but were not concerned at the time. On examination he exhibits muscle weakness, especially in the lower limbs and large appearing calf muscles (pseudohypertrophy). His mother had an uncle who had Duchenne muscular dystrophy and after genetic analysis it was discovered that the boy has the same mutation in the dystrophin gene. The patient was prescribed glucocorticoids to help slow the progression of the degenerative process of the disease.

Q1. Cells What is the dysfunctional protein in this condition? Describe the normal process of protein synthesis within the cell including the cellular locations and organelles involved. What part of the process is affected in DMD?

Q2. Tissues Which type of muscle tissue is predominantly affected in DMD? Describe the structure of this type of muscle tissue in terms of cellular arrangements, components, and connective tissue. How is it different in DMD? Describe the histopathology of muscle tissue affected in this patient.Q3. Genetics Explain the inheritance pattern of DMD and how it differs from other patterns of inheritance. If the patients parents were to have another child, what is the risk of that child being affected or a carrier of the DMD mutation? Use a Punnett square to show your answer.

Q4. Pathology Compare and contrast the two major cell death mechanisms - provide the two types of cell death and at least four differences comparing both.Which one would most likely be contributing to muscle tissue degeneration in DMD?

Q5. Pharmacology What receptor type do glucocorticoids act on?

Describe the process of this type of ligand interacting with a cell in order to cause a cellular response. What effect would this drug treatment have for DMD patients?

Level 4 Accurately discusses content related to all prompts (8) Applies knowledge to clinical case appropriately for all prompt (8) Well referenced, using appropriate sources and consistent referencing style (4)

Level 3 Mostly accurate discussion of content related to all prompts (6) Moderate application of knowledge to clinical case for all prompt (6) Clear and coherent writing with no language/expression errors (3) Mostly well referenced using appropriate sources and consistent referencing style (3)

Level 2 Discusses some content relevant to the prompts (4) Some application of knowledge to clinical case (4) Communicates message with some language/expression errors (2) Inconsistent application of reference style, some missing or inappropriate sources (2)

Level 1 Little relevant content discussed (2) Little application of knowledge to clinical case (2) Communication of message impacted by numerous English language/expression errors (1) Sufficient length (response within word limit) (1) Attempted to reference but many missing or inappropriate sources. (1)

Insufficient evidence (0) Insufficient evidence (0) Insufficient evidence (0) Insufficient length (response too long or too short) (0) Insufficient evidence (0)

Indicative behaviours Discuss relevant course content Applies course content knowledge to clinical case Clear and coherent communication of message Length of response Reference appropriately, use appropriate (peer-reviewed) sources, apply APA 7th referencing style.

Capabilities Understanding of relevant course content Application of course knowledge to clinical scenario Demonstrate clear written expression Ability to write within task limit Ability to reference accurately according to specified style

Q1. Cells

The dysfunctional protein in Duchenne muscular dystrophy is dystrophin. This dysfunctionality causes muscular dystrophy. The dystrophin protein plays an important role of ensuring the muscle fibers remains stable and intact. The instructions for creating dystrophin are provided by the dystrophin gene, that is positioned on the X chromosome. DMDdevelops when dystrophin is abnormally produced or not produced because of mutations in this gene, noted by Mendell et al., (2012).

One essential part of making proteins is translating genetic instructions into code. Transcription of DNA into messenger RNA (mRNA) takes place in the nucleus of a cell. After this messenger RNA leaves the nucleus and makes its way into the cytoplasm, the machinery responsible for production proteins in cells, called ribosomes, decode the code in the mRNA and translate the amino acids into a polypeptide chain, creating the protein. The Endoplasmic Reticulum (ER) and ribosomes are two biological components that are involved in this process, which mostly takes place in the cytoplasm (Berg et al., 2002).

Protein synthesis is disrupted in Duchenne muscular dystrophy (DMD) due to a mutation in the dystrophin gene, which either prevents the formation of functional dystrophin or results in a shortened and non-functional protein. Muscle fiber structural integrity is affected due to dystrophin's absence or malfunction, resulting in the gradual degradation seen in Duchenne muscular dystrophy patients (Monaco et al., 1988; Guiraud et al., 2015). A clear understanding of this molecular component is important for the growth of tailored therapeutics to reinstate or substitute dystrophin in order to ease signs of Duchenne muscular dystrophy.

Q2. TissuesThe skeletal muscle tissue which is under voluntary control is mostly impacted by DMD. This tissue consists of multinucleated muscle fibers of which each consists of myofibrils made up of sarcomeres. Muscle fiber structural integrity is maintained by dystrophin, which connects the intracellular cytoskeleton to the extracellular matrix. Damage to the sarcolemma is more likely to occur during muscular contractions and relaxations when dystrophin is absent (Mendell et al., 2012). A multi-step process takes place in several parts of cells, including the nucleus, the endoplasmic reticulum (ER), and the cytoplasm, when proteins are synthesized normally. In order to make proteins, the genetic code located in the nucleus is translated into messenger RNA (mRNA), which makes its way to the cytoplasm and is translated by ribosomes. Prior to their transportation to their ultimate destinations, proteins undergo folding and alteration in the ER (Alberts et al., 2014).

Mutations in the dystrophin gene, which is on the X chromosome, cause dystrophin deficiency or abnormalities in Duchenne muscular dystrophy. Degenerative musculoskeletal disease (DMD) is characterized by the gradual deterioration of skeletal muscle cells caused by a defect in protein synthesis (Hoffman & McNally, 2015).

Q3. Genetics

The recessive inheritance pattern of Duchenne Muscular Dystrophy (DMD) is X-linked. The dystrophin-encoding DMD gene is found on the X chromosome. Since males only have one X chromosome (XY), DMD develops when a mother passes on a defective X chromosome to her son. Carriers are usually females (XX), since a normal X chromosome may make up for a defective one. Homozygosity for the dystrophin mutation on both X chromosomes does, however, sometimes cause symptoms in females.

Because females possess two X chromosomes, which might constitute a healthy gene copy, X-linked recessive disorders mostly impact men, in contrast to autosomal inheritance patterns. Because a carrier mother may transmit on either a normal or a mutant X chromosome, the likelihood of an afflicted male kid increases when the mother is a carrier.

As the Punnett square shows,

Q4. Pathology

Apoptosis and necrosis are the two main ways in which cells die. Development and tissue homeostasis can't occur without apoptosis, or programmed cell death (Alberts et al., 2015). Alternatively, damage or infection may cause cells to die in a more disorderly and uncontrolled manner, a process known as necrosis (Galluzzi et al., 2018).

There is a notable distinction in their physiological functions; apoptosis is a controlled process that gets rid of damaged or undesired cells, while necrosis is linked to inflammation and pathological states. At the morphological level, apoptosis is characterized by the contraction of cells, blebbing of their membranes, and eventual fragmentation into apoptotic bodies that are subsequently consumed by nearby cells or phagocytes. However, inflammation results from necrosis, which causes cells to enlarge, organelles to be damaged, and subsequent contents of cells to be released (Alberts et al., 2015; Galluzzi et al., 2018).

The caspase family of protease enzymes is activated during apoptosis, which results in DNA breakage and cell disintegration on a molecular level. Damage to cell membranes that does not require caspases leads to inflammation and cellular content release in necrosis. In contrast to necrotic cells, which cause inflammation and immunological responses, apoptotic cells are quickly eliminated without triggering an immune response (Alberts et al., 2015; Galluzzi et al., 2018).

Muscle tissue deterioration is more likely to be caused by necrosis in the setting of Duchenne Muscular Dystrophy (DMD). Dystrophin deficiency myopathy (DMD) is characterized by impaired cell membrane integrity, which leaves muscle cells vulnerable to injury. Rather of apoptosis, necrosis occurs when cells lose their capacity to preserve structural integrity due to the inflammatory response triggered by this injury (Blake et al., 2002; Grounds et al., 2008).

Q5. Pharmacology

References

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2015). Molecular Biology of the Cell (6th ed.). Garland Science.

Berg, J. M., Tymoczko, J. L., & Stryer, L. (2002). Biochemistry (5th ed.). W H Freeman.

Bushby, K., Finkel, R., Birnkrant, D. J., Case, L. E., Clemens, P. R., Cripe, L., Tawil, R. (2010). Diagnosis and management of Duchenne muscular dystrophy, part 2: Implementation of multidisciplinary care. The Lancet Neurology, 9(2), 177189. https://doi.org/10.1016/S1474-4422(09)70272-8Blake, D. J., Weir, A., Newey, S. E., & Davies, K. E. (2002). Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiological Reviews, 82(2), 291329. https://doi.org/10.1152/physrev.00028.2001

Emery, A. E. H. (2002). The muscular dystrophies. The Lancet, 359(9307), 687695. https://doi.org/10.1016/S0140-6736(02)07815-7Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Kroemer, G. (2018). Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death and Differentiation, 25(3), 486541. https://doi.org/10.1038/s41418-017-0012-4Grounds, M. D., Radley, H. G., Lynch, G. S., Nagaraju, K., De Luca, A. (2008). Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiology of Disease, 31(1), 119. https://doi.org/10.1016/j.nbd.2008.03.008

Guiraud, S., Aartsma-Rus, A., Vieira, N. M., Davies, K. E., van Ommen, G. J., & Kunkel, L. M. (2015). The Pathogenesis and Therapy of Muscular Dystrophies. Annual Review of Genomics and Human Genetics, 16, 281308. https://doi.org/10.1146/annurev-genom-090314-025003Hoffman, E. P., & McNally, E. M. (2015). Dystrophinopathy. In GeneReviews [Internet]. University of Washington, Seattle.

Mendell, J. R., Shilling, C., Leslie, N. D., Flanigan, K. M., al-Dahhak, R., Gastier-Foster, J., Kneile, K., Dunn, D. M., Duval, B., & Aoyagi, A. (2012). Evidence-based path to newborn screening for Duchenne muscular dystrophy. Annals of Neurology, 71(3), 304313. https://doi.org/10.1002/ana.23528Monaco, A. P., Bertelson, C. J., Liechti-Gallati, S., Moser, H., & Kunkel, L. M. (1988). An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics, 2(1), 9095. https://doi.org/10.1016/0888-7543(88)90020-7Top of Form