BMS150 Pathology 4.02 Skeletal Muscle PDF

Pathology 4.02 Skeletal Muscle Pathology Dr. Hurnik BMS 150 Week 10 Video Links – Toronto Video 1 (23 minutes) https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.a spx?id=4d8aaaea-b7ed-4be2-85d8-afc20044457c Video 2 (24 minutes) https://ccnm.ca.panopto....

Pathology 4.02 Skeletal Muscle Pathology Dr. Hurnik BMS 150 Week 10 Video Links – Toronto Video 1 (23 minutes) https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.a spx?id=4d8aaaea-b7ed-4be2-85d8-afc20044457c Video 2 (24 minutes) https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.a spx?id=a9558845-4770-4b54-9e15-afc20044452b Video 3 (11 minutes) https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.a spx?id=75418d90-654d-4c89-b515-afc2004444a4 Outline Video 1 Duchenne muscular dystrophy Becker Muscular dystrophy Myotonic dystrophy Video 2 Statin myopathy Myasthenia Gravis Muscle tumours: rhabdomyosarcoma, synovial cell sarcoma Video 3 Fibromyalgia Chronic Fatigue Syndrome Learning Outcomes Describe the etiology, epidemiology, pathogenesis, pathophysiology, clinical features, prognosis, and diagnosis of: Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Myotonic Dystrophy Statin myopathy, Myasthenia gravis Describe the epidemiology and clinical features of: Rhabdomyosarcoma, Synovial cell sarcoma Fibromyalgia, Chronic fatigue syndrome Muscular dystrophies - intro Group of inherited muscle disorders leading to progressive weakness and muscle wasting § Characteristic muscle fiber necrosis and regeneration We will discuss the three types: § Duchenne Muscular dystrophy § Becker Muscular dystrophy § Myotonic dystrophy Duchenne Muscular dystrophy – Etiology & Epidemiology Etiology: X-linked, loss-of-function mutation of a structural protein call dystrophin. Typically associated with deletion or frameshift mutations result in total absence of dystrophin resulting in a severe, progressive phenotype. Female carriers of the mutation can be mildly symptomatic due to unfavourable X- chromosome inactivation Epidemiology: Kumar et. al., Robbins and Cotran Pathologic Basis of Most common muscular dystrophy: Disease 9th ed Figure 27.11, page 1233 1 per 3500 live male births Duchenne Muscular dystrophy – Pathogenesis Pathogenesis: Dystrophin is a key component of the dystrophin glycoprotein complex This complex spans the plasma membrane, linking the cytoskeleton of the muscle fiber with the basement membrane. As a result provides mechanical stability to the muscle fiber and it’s cell membrane (sarcolemma) during muscle contraction Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed Figure 27.10, page 1232 Duchenne Muscular dystrophy - Pathophysiology Remember cell necrosis? Pathophysiology: Dystrophin is a key component of the dystrophin glycoprotein complex Defects in the complex can lead to sarcolemma tears: § Calcium influx from ECF à ultimately triggering muscle fiber necrosis Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-19, p. 47 Duchenne Muscular dystrophy - Pathology Pathology Ultimately the disease is marked by chronic muscle damage that outpaces the capacity for repair: In young boys muscle biopsies show segmental muscle fiber degeneration and regeneration + atrophic muscle fibers As the disease progresses muscle tissue is replaced by collagen and fat cells. Remaining muscle fibers vary from small atrophic fibers to large hypertrophied fibers Muscle fascicular architecture is preserved initially but will become abnormal over time with muscle remodelling.  Duchenne Muscular dystrophy - Pathology Muscle biopsy in two brothers, both with Duchenne Muscular dystrophy 3 year old brother: 9 year old brother: Variable muscle Significant fiber size disease Cluster of progression regenerating compared to muscle fibers younger Slight brother endomysial Extensive fibrosis variation in Fascicular muscle fiber muscle size architecture Significant fatty Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed Figure maintained 27.11, page 1233 replacement and endomysial fibrosis Duchenne Muscular dystrophy – Clinical Features Gower’s sign Clinical Features: Normal at birth with early motor milestones met, but walking is often delayed Clumsiness and inability to keep up with peers are first indications of muscle weakness Weakness begins in pelvic girdle muscles and extends to shoulder girdle (+) Gower’s sign: patient often have to push off the thighs in order to stand from sitting Pseudohypertrophy of lower leg Cognitive impairment and learning disability are common Not well understood, presumably due to a function role for dystrophin in the brain Sheffield, Herman Bernard, 1871- [from old catalog], No restrictions, via Wikimedia Commons Duchenne Muscular dystrophy – Clinical Features & prognosis Clinical feature progression & prognosis: Eventual progression to wheelchair dependance Average age ~9.5years § Patients develop joint contractures, scoliosis, worsening respiratory reserve and sleep hypoventilation § Development of cardiomyopathies and arrhythmias can occur in older patients due to impact of dystrophin in cardiac muscle Female carriers have increased risk of cardiomyopathy § Mean age of death – 25-30 years of age Commonly from respiratory insufficiency, pulmonary infection, or heart failure Duchenne Muscular dystrophy – Diagnosis Diagnosis: Based on history, physical exam and laboratory studies: Creatine kinase: remarkedly elevated in first decade of life then decreases as diseases progresses § Initially high due to ongoing muscle damage § Levels decrease with loss of muscle mass Genetic testing offers a definitive diagnosis Muscle biopsies can also be used in diagnosis Becker Muscular dystrophy – Etiology & Epidemiology Etiology: X-linked mutation in dystrophin Results in truncated dystrophin protein that retains partial function Milder phenotype than Duchenne muscular dystrophy and later age-of-onset Epidemiology: Less common than Duchenne muscular dystrophy: 1 per 30,000 live male births Becker Muscular dystrophy – Clinical Features & Prognosis Clinical Features: Onset later in later childhood, adolescence, or adulthood Generally similar but less severe than Duchenne Muscular dystrophy and has slower progression Patients are still at risk of developing dilated cardiomyopathy, but this is very rare compared to Duchenne Muscular dystrophy Prognosis: § Near-normal life expectancy  Review at home Etiology Epidemiology Pathogenesis Pathology Diagnosis Clinical Prognosis & patho- Features & physiology Progression Duchenne Muscular Dystrophy Becker Muscular Dystrophy Myotonic dystrophy Myotonia: sustained involuntary muscle contractions Etiology Autosomal dominant disorder caused by expansion of triplet repeats Type I: expansion of CGT trinucleotide repeat within the myotonic dystrophy protein kinase (DMPK) gene Type II: CCTG repeat expansion within the gene nucleic acid- binding protein (CNBP) gene Both types affect voluntary muscles, type I also affects involuntary muscles Epidemiology Affects 1 in 8,000 individuals Myotonic Dystrophy Pathogenesis – not well understood § Type I: Skeletal muscle phenotype may result of “toxic” gain-of- function effect by CGT triplet repeat expansion within the DMPK that disrupts splicing of mRNA transcripts of other proteins, including the transcript of a chloride channel (CLC1) § Lack of CLC1 may explain myotonia § Type II: CNPB gene codes for a zinc-finger DNA binding protein Myotonic Dystrophy – Clinical Features Clinical Features Onset begins in adolescence or young adulthood § Type I Myotonia, weakness, and wasting of peripheral muscles and facial muscles § Weakness of the hands, ptosis Can also include: cardiomyopathy, intellectual disability, cataracts and endocrine disorders (abnormal glucose tolerance, male hypogonadism) Patients with type I will also experience myotonia of involuntary muscles (eg. GI tract, uterus) § Dysphagia, constipation, uterine muscle abnormalities § Type II Generally less severe with fewer extra-muscular symptoms Tends to affect more proximal-located muscles (thigh and hip) § Often causing myalgic pain Myotonic Dystrophy – Diagnosis & Prognosis Diagnosis: Diagnosis is made based on history (characteristic clinical findings, age of onset, and family testing) Confirmation with genetic testing Prognosis § Reduced life expectancy - mean age of death: 54 years Death most commonly due to respiratory and cardiac disease (cardiomyopathies and arrhythmias) Review at home Etiology Epidemiology Pathogenesis Diagnosis Clinical Prognosis & patho- Features & physiology Progression Myotonic dystrophy type I Myotonic dystrophy type I Drug-induced myopathies: Statin myopathy Statin myopathy Most-common drug-related myopathy Estimated to affect in 9 – 17% of those who are on statin therapy § Pathophysiology: Myopathy is thought to result from: Decreased cholesterol concentrations may impact sarcolemma Depletion of Coq10 (Ubiquinone) § Clinical Features Myalgias and muscle weakness after exercise are the prominent clinical features; often severe enough to discontinue or switch medication § typically affects the thigh muscles § CoQ10 seems to help, may improve exercise tolerance  Drug-induced myopathies: Statin myopathy Cholesterol Remember the Cholesterolsynthesis review synthesis pathway? olesterol synthesis review 3 X Acetyl CoA 3 X Acetyl CoA Rate limiting step catalyzed To ketogenesis HMG CoA by HMG-CoA reductase HMG-CoA Blocked by high cholesterol Rate limitingreductase step catalyzed levels and the cholesterol- enesis HMG CoA by HMG-CoA reductase Mevalonate lowering “statin” drugs such as Blocked by high cholesterol atorvastatin (Lipitor®) levels and the cholesterol- Mevalonate lowering Isopentenyl “statin” drugs such as pyrophosphate atorvastatin (isoprene units) (Lipitor®) To CoQ10 synthesis Isopentenyl pyrophosphate Squalene Cholesterol (isoprene units) Squalene Cholesterol Myasthenia Gravis (MG) – Etiology & Epidemiology Etiology: Autoimmune condition associated with autoantibodies directed against acetylcholine receptors There is a strong association between anti-Ach receptor autoantibodies and thymic abnormalities (thymoma or thymic hyperplasia) Thymoma = tumour of thymic epithelial cells § May contribute to immune dysregulation and development of auto-antibodies Epidemiology Prevalence of 150-200 per 1 million In young adults, it is more commonly found in females, in older adults in males. MG – pathogenesis & pathophysiology Pathogenesis and pathophysiology: The majority of patients have auto-antibodies to the post-synaptic acetylcholine receptors (ie. Nicotinic receptors) FYI - A smaller subset (~15%) have auto-antibodies against a receptor tyrosine kinase (RTK) specifically found on muscle sarcolemma. Neuromuscular junction: Acetylcholine (Ach) Ach receptor (Nicotinic receptor) MG – pathogenesis & pathophysiology continued Pathogenesis and pathophysiology: § Ab-Ach receptor complexes lead to a variety of problem ultimately limit the ability of the myofiber to respond to Ach at the neuromuscular junction: Impact turnover of Ach receptors leading decrease in overall number of receptors Blocks activation of the Ach receptors Can damage the neuromuscular junction due to complement fixation MG – Clinical Features Clinical Features: Fluctuating proximal muscle weakness Ptosis and diplopia are common initial findings § Levator palpebrae, extraocular muscles often initially involved § In 15 – 25%, disease is exclusively extraocular Proximal muscle involvement: § diaphragm, neck, facial muscles (snarling smile, difficulty chewing foods) § Dysphagia may develop to both solids and liquids Usually worse with activity/ exercise and improves with rest (fatiguability) Weakness seems to come and go initially (but eventually symptoms become more consistent) MG – Diagnosis & Treatment Diagnosis: Based on clinical history, physical exam findings, (+) antibody screen, and electrophysiologic studies Prognosis: § Prognosis has improved significantly with current therapies Complications can include pneumonia, falls, and myasthenic crisis § Myasthenic crisis – RED FLAG Respiratory weakness becomes severe enough to necessitate intubation Treatment § Acetylcholinesterase inhibitors (first line of treatment) – increase half- life of Ach in the neuromuscular junction § Plasmapheresis & immunosuppressive drugs § Thymectomy for patients with a thymoma Skeletal Muscle Tumours Nearly all skeletal muscle tumours are malignant Occur in younger patients (usually onset is before age 20) We will discuss some common types: Rhabdomyosarcoma Synovial Cell sarcoma Skeletal Muscle Tumours - Rhabdomyosarcoma Malignant mesenchymal tumour with skeletal muscle differentiation 4 subtypes: Alveolar, Embryonal, Pleomorphic, Spindle cell/sclerosis Malignant cell is rhabodomyoblast – rich in myosin and actin filaments, typically with round or elongated shapes Epidemiology: § Alveolar and embryonal rhabdomyosarcoma are most common soft tissue sarcoma of childhood Incidence of 6/1,000,000/ year in children under 15 years Etiology: Chromosomal translocations commonly found, typically involving transcription factor (FYI – PAX) involved in skeletal muscle differentiation Skeletal Muscle Tumours - Rhabdomyosarcoma Clinical Features: Tumour is detected as a mass, sometimes painful – metastases tend to cause respiratory difficulties, bone pain, and bone marrow failure Tumours can occur anywhere in the body: § Head & neck, extremities, genitourinary tract Embryonic type often tumours in mucosal cavities (bladder, vagina, nasopharynx, middle ear) Alveolar type often results in tumours in the extremities Treatment & Prognosis: Tumours are aggressive, with a poor survival rate in older children/adults and those with metastatic disease However, younger children with localized disease have a survival rate of about 80% 5 years after diagnosis Skeletal Muscle Tumours – synovial cell sarcoma Epidemiology: Most common soft tissue tumour in adolescents and young adults (represents 5-10% of all soft tissue sarcomas) FYI - Mean age of diagnosis: 30 years old Incidence: 2.75 per 100,000 Etiology: § Chromosomal translocation has been found in >90% of cases (FYI – fusion of SYT and SSX genes) § Origin and pathophysiology is unclear Skeletal Muscle Tumours – synovial cell sarcoma Clinical Features: Usually history of long-standing nodule Present for years → increases rapidly in size over few months Sometimes overlooked before growth Tumor spreads along fascial planes - much more widespread than apparent on initial evaluation § Mass often is painless and deep Usually situated around knee, hands and feet Malignancy can affect any part of appendicular skeleton Distal extremity tumors have a better prognosis than proximal or truncal tumors Fibromyalgia Syndrome of persistent widespread pain, stiffness, fatigue, disrupted sleep, and cognitive difficulties. It is often accompanied by anxiety/depression and impairment of activities of daily living. Epidemiology: Can occur in patients of either sex or any age, but most commonly presents in young-adult to middle age females. Etiology & Pathogenesis: Not known Now considered a neurosensory disorder characterized in abnormalities in pain processing by the CNS Considered a central sensitivity syndrome Fibromyalgia – Diagnostic criteria Diagnosis is based on widespread pain index (WPI) and self-administered patient questionnaire Widespread pain index – score of 0-19 Patients are asked if they have had pain or Manual tender- tenderness in 19 different body regions points survey over the past week. § shoulder girdle, hip, jaw, upper arm, upper leg, lower arm, and lower leg on each side of the body, as well as upper back, lower back, chest, neck, and abdomen § Each region scores 1 point Manual tender-points survey is also used during physical exam (though not required for diagnosis) Fibromyalgia – Diagnostic criteria Diagnosis is based on widespread pain index (WPI) and self- administered patient questionnaire § Self-administered patient questionnaire – score of 0-12 (section 2 & 3) Section 1: Assess distribution of bodily pain as above (score of 0- 19; analogous to WPI) Section 2: Asseses severity of problems with: daytime fatigue, nonrestorative sleep, and cognitive dysfunction § Each is scored out from 0-3 (0=no problem, 3=severe problem) Section 3: Asses pain or camps in lower abdomen, depression, or headache in past 6 months § 1 point for each positive symptoms WPI/ Section 1 is combined with total points for sections 2 & 3 to yield a score out of 0-31 (aka Polysymptomatic distress scale) § A score of 13 or greater, with symptoms being present at similar level or severity for at least 3 months, and not explained by another disorder is diagnostic of fibromyalgia. Chronic Fatigue syndrome Also called Myalgic encephalomyelitis (ME) Characterized by unexplained and profound fatigue that is worsened by exertion Accompanied by cognitive dysfunction and impairment of daily functioning that persists for at least 6 months Etiology & Pathogenesis: § Cause is unknown, although implications of a number of viruses have been studied § Environmental factors have also been suspected as a trigger Epidemiology: § True prevalence is unknown § Most common in young to middle-aged adults and more common in females. Chronic Fatigue syndrome Diagnostic Criteria Presence of 3 or more of the following symptoms for at least 6 months and symptoms severity must be moderate or severe at least 50% of the time Fatigue - unrelated to exertion and not relieved by rest Post-exertional malaise (PEM) Unrefreshing sleep – fatigue despite a night’s sleep § AND at least 1 of the following: Cognitive impairment Orthostatic intolerance References Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed Roberts, J. (2020). Chronic Fatigue Syndrome. Medscape. Retrieved from:https://emedicine.medscape.com/article/235980-overview Boomershine, C. (2021). Fibromyalgia. Medscape. Retrieved from: https://emedicine.medscape.com/article/329838-overview Drake, A. (2019). Pathology – Rhabdomyosarcoma. Medscape. Retrieved from:https://emedicine.medscape.com/article/873546- overview?_ga=2.60275499.787809189.1678487970-485005295.1678468874 Vargas, B. (2022). Synovial Sarcoma. Medscape. Retrieved from: https://emedicine.medscape.com/article/1257131-overview Rubin, M. (2022). Myotonic Dystrophy. MERCK MANUAL. Retrieved from: https://www.merckmanuals.com/en-ca/professional/pediatrics/inherited-muscular- disorders/myotonic-dystrophy?query=myotonic%20dystrophy Images: Betts et al. Anatomy and Physiology (2ed). OpenStax Sheffield, Herman Bernard, 1871- [from old catalog], No restrictions, via Wikimedia Commons. Retrieved from: https://upload.wikimedia.org/wikipedia/commons/c/c3/Modern_diagnosis_and_treatme nt_of_diseases_of_childern%3B_a_treatise_on_the_medical_and_surgical_diseases_of_in fancy_anf_childhood_%281911%29_%2814801659623%29.jpg