Intermediate Filaments Diseases -Desminopathy L6 PDF

Presentation by: Dr Temba Mudariki Intermediate Filaments- Desminopathy Molecular Medicine XY3121 2024  Learning Outcomes  Understand the genetic basis and inheritance patterns associated with desminopathy, focusing on mutations in desmin and a...

Presentation by: Dr Temba Mudariki Intermediate Filaments- Desminopathy Molecular Medicine XY3121 2024  Learning Outcomes  Understand the genetic basis and inheritance patterns associated with desminopathy, focusing on mutations in desmin and alphaB- crystallin.  Recognize the clinical manifestations of desminopathy, including the onset, progression, and variability of muscle weakness, and the potential complications involving skeletal and cardiac muscles.  Identify the types of DES gene mutations found in desminopathy patients and their impact on desmin assembly, filamentous network disruption, and muscle fiber pathology.  Evaluate the diagnostic approaches and genetic testing methods used to confirm DES mutations, distinguishing desminopathy from other neuromuscular disorders.  Analyse the current therapeutic interventions for desminopathy, including the management of cardiac manifestations, respiratory muscle weakness, and multidisciplinary care involving physical therapy and rehabilitation.  Examine case studies and patient perspectives to understand the impact of desminopathy on the quality of life, daily activities, and family dynamics.  Explore current research efforts, potential therapeutic targets, and emerging treatment modalities, as well as genetic counseling and family planning considerations for individuals with desminopathy. Introduction New England Journal of Medicine  Genetic Basis of Desminopathy  Mutations in Desmin and AlphaB-Crystallin  The DES gene is located on chromosome 2q35 and encodes desmin  Expressed in striated muscles, including skeletal and cardiac muscles.  Disruption of normal assembly of desmin filaments, leads to the development of desminopathy.  The CRYAB gene is located on chromosome 11q22.3  Encodes alphaB-crystallin, a small heat shock protein.  AlphaB-crystallin acts as a chaperone protein  Mutations in the CRYAB gene can impair the chaperone function  Inheritance Patterns and Sporadic Cases  Desminopathy can be inherited in an autosomal dominant or autosomal recessive manner  Autosomal dominant desminopathy occurs when a single copy of the mutated gene is sufficient to cause the disorder.  Autosomal recessive desminopathy requires two copies of the mutated gene  Desminopathy can also occur due to sporadic or de novo mutations  Sporadic cases may result from new mutations  Occur during the formation of reproductive cells or early embryonic development. Clinical Manifestations of Desminopathy Pattern of muscle weakness in desmin-related muscle disorders Lower limb muscle weakness slowly spreading to involve truncal, neck- flexor, facial and bulbar  Clinical Manifestations of Desminopathy  Case History 1 Patient A, a 35-year-old male, presented with progressive muscle weakness and fatigue. Symptoms initially appeared in the lower limbs, leading to difficulty in walking and frequent falls. Over time, muscle weakness spread to the upper limbs, affecting activities of daily living. Cardiac involvement was also observed, with episodes of palpitations and shortness of breath.  Clinical Manifestations of Desminopathy  Case History 2: Patient B Patient B, a 50-year-old female, experienced muscle weakness and stiffness in her early forties. The weakness predominantly affected the proximal muscles, including the shoulders and hips. As the disease progressed, she developed difficulty in rising from a seated position and climbing stairs. Cardiac manifestations were absent in this case.  Clinical Manifestations of Desminopathy  Case History 3: Patient C Patient C, a 25-year-old male, had a family history of desminopathy. He started experiencing muscle weakness and cramps during his teenage years. The weakness primarily involved the distal muscles, such as the hands and feet. Cardiac abnormalities, including conduction blocks, were detected during routine cardiac evaluations.  Clinical Manifestations of Desminopathy  Onset of Disease  Progression and Variability  Muscle Weakness Patterns  Cardiac Involvement  Complications Genetic Mutations and Pathology of Desminopathy  Types of DES Gene Mutations mutations in the DES gene, which encodes the protein desmin Missense mutations, nonsense mutations, frameshift mutations, and splice site mutations.. Missense mutations, which result in a single amino acid substitution – common type Genetic Mutations and Pathology of Desminopathy  Impact of Mutations on Desmin Assembly  DES gene mutations disrupt the normal assembly of desmin filaments  Desmin is an intermediate filament protein  Mutations can impair the proper folding  Filamentous Network Disruption  Disorganization and loss of the filamentous network within muscle cells  Disruption weakens the structural integrity of the muscle fibers  Affects the connection between adjacent muscle fibers  Aggregates and Cytoskeletal Protein Involvement  Accumulation within muscle cells  Aggregates are composed of aggregated desmin / alphaB-crystallin and myotilin  Diagnostic Imaging  Magnetic resonance imaging (MRI)  Muscle atrophy  Fatty infiltration  oedema  Histopathology  Muscle biopsies are essential for confirming the diagnosis  Assessing the histopathological changes  Presence of abnormal desmin aggregates  Cytoskeletal protein accumulation  Myofiber degeneration and regeneration  Immunohistochemistry staining – identification of protein aggregates Diagnosis and Genetic Testing for Desminopathy  Diagnostic Approaches o Combination of clinical evaluation, imaging studies, muscle biopsies, and genetic testing.  Imaging Studies o Commonly used to evaluate muscle pathology in desminopathy  Muscle Biopsies o Confirming the diagnosis of desminopathy o Histopathology- identification of characteristic features  Genetic Testing o Confirming the diagnosis of desminopathy and identifying specific DES gene mutations Diagnosis and Genetic Testing for Desminopathy  Differential Diagnosis o Desminopathy shares some clinical features with other neuromuscular disorders o Limb-girdle muscular dystrophy, myofibrillar myopathy, and other forms of inherited muscle disorders. o Clinical evaluation, imaging studies, muscle biopsies, and genetic testing crucial  Distinguishing Desminopathy o Distinguishing desminopathy from other neuromuscular disorders can be challenging o Overlapping symptoms and pathological features o Presence of characteristic desmin aggregates and the identification of specific DES gene mutations key factors  Therapeutic Interventions for Desminopathy  Current Treatment Strategies o There is no cure for desminopathy o Treatment primarily focuses on managing symptoms and improving quality of life o Combination of pharmacological and non-pharmacological approaches.  Pharmacological Approaches o Specific symptoms and complications o Cardiac manifestations, medications such as beta-blockers or antiarrhythmics o Control conduction blocks and arrhythmias o Heart failure, diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) o Manage fluid retention and improve cardiac function.  Non-Pharmacological Approaches  Management of Cardiac Manifestations  Therapeutic Interventions for Desminopathy  Addressing Respiratory Muscle Weakness  Multidisciplinary Care  Physical Therapy and Rehabilitation Case Studies and Patient Perspectives on Desminopathy  Personal Accounts Personal accounts from individuals living with desminopathy provide valuable insights into the lived experience of the disease. These accounts offer a first-hand perspective on the challenges faced, coping strategies, and the impact on various aspects of life. Case Studies and Patient Perspectives on Desminopathy  Impact on Quality of Life Desminopathy can significantly impact the quality of life of affected individuals. Muscle weakness and fatigue can limit physical activities and mobility, leading to a loss of independence. Pain, discomfort, and the progression of the disease may affect emotional well-being and mental health. Case Studies and Patient Perspectives on Desminopathy  Impact on Daily Activities Desminopathy can affect various daily activities, including self-care tasks, mobility, and participation in recreational and social activities. Simple tasks such as walking, climbing stairs, or gripping objects may become challenging or require assistance. Fatigue and muscle weakness can cause difficulties in maintaining employment or engaging in hobbies. Case Studies and Patient Perspectives on Desminopathy  Impact on Family Dynamics Desminopathy can also have a significant impact on family dynamics. Family members may take on caregiving responsibilities, which can affect their own physical and emotional well-being. Adjusting to changes in family roles and routines may be necessary to accommodate the needs of the affected individual. Case Studies and Patient Perspectives on Desminopathy  Challenges in Managing Desminopathy Managing desminopathy presents various challenges for both patients and healthcare professionals. The progressive nature of the disease necessitates ongoing adjustments to treatment plans and care strategies. The complex nature of desminopathy requires a multidisciplinary approach, which may pose logistical challenges in accessing different healthcare professionals. Case Studies and Patient Perspectives on Desminopathy  Successes in Managing Desminopathy Despite the challenges, individuals with desminopathy can achieve successes in managing the disease. Physical therapy and rehabilitation programs can improve muscle strength, mobility, and overall well-being. Assistive devices and adaptive strategies may enhance independence and facilitate daily activities. Emotional support, education, and community engagement can empower individuals and promote a sense of control over their condition. Research and Future Directions for Desminopathy  Current Research Efforts  Molecular Mechanisms  Genetic Mutations  Biomarkers  Potential Therapeutic Targets  Emerging Treatment Modalities  Genetic Counselling and Family Planning Considerations End of Session