DMD Lecture L2 PDF

P r e s e n t a t io n b y : D r T e m b a M u d a r ik i Diseases of The Nucleus M o le c u la r M e d ic in e X Y 3121 20 24  Introduction to Molecular Pathology  Definition and scope of molecular pathology.  Intersection of molecular biology, genetics, and classical pathology.  Rol...

P r e s e n t a t io n b y : D r T e m b a M u d a r ik i Diseases of The Nucleus M o le c u la r M e d ic in e X Y 3121 20 24  Introduction to Molecular Pathology  Definition and scope of molecular pathology.  Intersection of molecular biology, genetics, and classical pathology.  Role of biomarkers in disease analysis.  Personalized medicine through molecular insights.  Learning Outcomes Describe the nucleus’s function as the control centre of the cell, housing DNA and coordinating key activities such as gene expression and replication. Recognize and list diseases that arise from nuclear anomalies, including genetic disorders, chromosomal abnormalities, and nuclear envelope pathologies. Explain how alterations in genomic structure and function can lead to disease and appreciate the complexity of regulatory mechanisms within the nucleus. Understand the broad impact of nuclear diseases such as Duchenne Muscular Dystrophy (DMD) on individuals and their families, considering both the clinical manifestations and the psychosocial aspects. Grasp the pathogenesis of DMD at a molecular level, including the genetic mutations that lead to dystrophin deficiency and subsequent muscle degeneration. Describe the inheritance patterns of X-linked recessive diseases like DMD and the implications for carrier status, genetic counselling, and family planning.  Learning Outcomes Summarize the diagnostic methods for nuclear diseases, emphasizing the role of genetic testing and molecular diagnostics in DMD. Outline the current management strategies for DMD, highlight the importance of a multidisciplinary approach, and discuss emerging therapies aimed at addressing the underlying molecular defects. Appreciate the ethical considerations surrounding genetic testing, prenatal diagnosis, and treatment options for diseases of the nucleus like DMD. Acknowledge the importance of ongoing research in understanding and treating nuclear diseases and the role of patient advocacy groups in supporting affected individuals and promoting research funding.  Overview A. I ntroduction to M olecular Pathology B. Diseases Associated with the Nucleus C. Overview of Duchenne M uscular Dystrophy (DM D) D. Aetiology and I nheritance Pattern E. C linical M anifestations and Symptomatology F. Prevalence and Population Affected G. I mpact on Patients and Families H. M olecular B asis of DM D I. Genetic M utation R esponsible for DM D  Overview J. Pathophysiology of DM D at the M olecular L evel K. Diagnostic Approaches for DM D L. C linical C ases 1 and 2 M. L aboratory Tests and I maging Techniques N. R ole of Genetic Testing and M olecular Analysis O. I nterpretation of Test R esults P. M anagement and T reatment Strategies Q. Novel T herapeutic Approaches R. E thical C onsiderations  Diseases Associated with the Nucleus The nucleus as the cell's genetic command centre. Impact of nuclear anomalies on health. Spectrum of nuclear-associated diseases. Spotlight on Duchenne Muscular Dystrophy (DMD).  Overview of Duchenne Muscular Dystrophy Genetic basis and progression of DMD. Epidemiology - affecting young males. The role of dystrophin and genetic mutations. Clinical features and diagnostic approaches. Current management and emerging treatments.  Aetiology and Inheritance Pattern Genetic mutation specifics in DMD. X-linked recessive pattern and its implications. Carrier status and genetic transmission. The importance of genetic testing for family planning.  Clinical Manifestations and Symptomatology Symptom onset and progression in DMD. Common clinical signs to look for. Importance of early detection. Diagnostic methods and their significance.  Prevalence and Population Affected Global and regional prevalence data. Demographics of DMD - focusing on male prevalence. Significance for healthcare systems. The need for awareness and support structures.  Impact on Patients and Families The multifaceted impact of DMD. Physical limitations and medical complications. Psychological and social challenges. The importance of comprehensive care and community support. Respiratory failure Common cause of death Molecular Basis of Duchenne Muscular Dystrophy (DMD) Dystrophin's role in muscle cell integrity. Molecular consequences of dystrophin loss. Inflammatory response and muscle degeneration process. Insights into therapeutic target development. Molecular Basis of Duchenne Muscular Dystrophy (DMD) –Cont’d Dystrophin's role in muscle cell integrity. Molecular consequences of dystrophin loss. Inflammatory response and muscle degeneration process. Insights into therapeutic target development. Dystrophin Gene  Genetic Mutation Responsible for DMD & Pathophysiology of DMD at the Molecular Level  Mutation types and their prevalence.  Reading frame rule and its implications for dystrophin production.  Mutation detection techniques.  Role in diagnosis and personalized treatment approaches.  Disruption of the dystrophin-associated glycoprotein complex (DGC).  Muscle cell membrane vulnerability.  Chronic inflammation and fibrotic replacement.  Progressive loss of muscle function.  Diagnostic Approaches for DMD Step-by-step diagnostic framework. Importance of CK levels as a biomarker-Muscle damage. Genetic testing methodologies and their utility -Multiplex ligation-dependent probe amplification (MLPA) and next- generation sequencing (NGS) –Confirms diagnosis Role of muscle biopsy and immunohistochemistry.  Clinical Cases - Case 1 Case 1: A 7-year-old male with delayed motor milestones, progressive muscle weakness, calf muscle hypertrophy, and difficulty walking.  The clinical presentation, such as delayed motor milestones and muscle weakness, raises suspicion for Duchenne muscular dystrophy (DMD).  Diagnosis involves a comprehensive evaluation, including medical history, physical examination, measurement of creatine kinase (CK) levels, genetic testing, and potentially muscle biopsy or immunohistochemistry to confirm the diagnosis.  Clinical Cases - Case 2 Case 2: A 5-year-old male with difficulty running, muscle weakness, and no significant calf muscle hypertrophy.  The clinical presentation, such as difficulty running and muscle weakness, raises suspicion for Duchenne muscular dystrophy (DMD).  Diagnosis involves a comprehensive evaluation, including medical history, physical examination, measurement of creatine kinase (CK) levels, genetic testing, and potentially muscle biopsy or immunohistochemistry to confirm the diagnosis.  Laboratory Tests and Imaging Techniques  Role of laboratory tests in DMD monitoring.  Genetic testing for definitive diagnosis – MPLA/NGS  Use of imaging in assessing disease progression.  Integrating laboratory and imaging data for clinical decision-making. Role of Genetic Testing and Molecular Analysis Central role of genetic testing in DMD. Impact of molecular findings on prognosis and treatment. Mutation identification and its significance. Molecular analysis in the context of personalized medicine.  Interpretation of Test Results  Understanding and classifying genetic variants.  Implications of test results for patients and families.  The necessity of genetic counselling in result interpretation.  Informed decision-making based on test outcomes.  Management and Treatment Strategies Comprehensive care strategies for DMD. Importance of a multidisciplinary approach. Supportive and symptomatic treatments. Exploring the potential of gene-targeted therapies.  Novel Therapeutic Approaches Cutting-edge research in DMD treatment. Gene therapy and its potential for disease modification. Exon skipping and ASO technology. Future directions in DMD therapeutics.  Prenatal Diagnosis  Importance of genetic counselling in DMD.  The role of carrier testing for family members.  Guidance for family planning and reproductive choices.  Supportive role of genetic counsellors.  The significance of early detection through prenatal testing.  Available techniques: CVS and amniocentesis.  Exploring the foetal DNA for DMD mutations.  Decision-making and psychological impact.  Ethical Considerations & Research Advances  Ethical challenges in genetic testing for DMD.  Balancing confidentiality and family dynamics.  Informed consent and its complexities.  The need for ethical guidance in clinical practice.  The landscape of DMD research.  Translating basic research into therapeutic opportunities.  Current clinical trials and their scope.  The horizon of DMD research and patient impact.  Summary  Recap of DMD's molecular pathology and clinical impact.  The crucial role of genetic testing in managing DMD.  The promise of novel therapies for improved patient outcomes.  The ongoing need for research, patient advocacy, and support.  Ethical Considerations The End…