Class 11- Musculoskeletal system
what is the cause of the two forms of myotonic dystrophy ?
Both disorders are believed to result from 'toxic RNA' produced by the expansion which results in the binding of proteins such as muscle blind-like 1 (MBNL1) that leads to abnormal alternative splicing of several pre-mRNAs
what is denervation ?
Denervated muscle fibers atrophy. Fate of denervated muscle depends on: Severity, rapidity, extent of denervation Success of reinnervation
what is type 1muscle fiber type?
slow oxidative & resistant
who does Immune Mediated Necrotizing Myopathy affect ?
61% are men; mean age at onset is in the 5th decade for SRP-associated and 6th decade for HMGCR-associated
what is Inclusion Body Myositis ?
Most patients are men (2 or 3 times as often as women Age @ onset > 50 years Sporadic No effective treatment
what is Steroid Myopathy ?
Particularly with 9-α-fluorinated corticosteroids Rare with Prednisone, especially <30 mg qd
what does Critical Illness Myopathy look like microscopically?
Myosin loss in muscle fibers on ATPase stain diffuse or focal loss of myosin in scattered muscle fibers throughout muscle biopsy
What clinical signs does Mediated Necrotizing Myopathy show?
Myositis-specific autoantibodies against signal recognition particle (SRP) or 3-hydroxy- 3-methylglutaryl co-enzyme A reductase (HMGCR) can be detected in 60%
what part of the body does Polymyositis affect ?
Proximal, symmetrical weakness and myalgia evolving over several months
Immune Mediated Necrotizing Myopathy
Myalgia can occur in up to 80%; in severe cases, dysphagia and dysarthria can develop. Heterogeneous, includes autoimmune inflammatory mechanisms, paraneoplastic conditions, exposure to toxins or drugs as well as combinations of these mechanisms
what is Polymyositis ?
chronic inflammatory disease of muscle
what is type 2b muscle fiber type?
fast Glycolytic & fatigable
what is type 2a muscle fiber type?
fast oxidative/ glycolytic & resistant
What is Dermatomyositis ?
Humoral attack, primarily on the muscle microvasculature complement mediated
what are the 5 causes of acquired muscle diseases ?
1. Denervation 2. Idiopathic immune myopathies 3. Toxic/iatrogenic 4. Infections 5. Endocrine disorders
what are 4 Idiopathic Immune Myopathies ?
1. Dermatomyositis 2. Inclusion body myositis 3. Polymyositis 4. Immune mediated necrotizing myopathy
what are 4 Dystrophies (inherited myopathies) ?
1. Disorders of cytoskeletal proteins 2. Disorders of nucleosketal protein 3. Nucleotide repeat disorders 4. Myofibrillar myopathies
what are 5 Inherited Myopathies ?
1. Dystrophies 2. Inborn errors of metabolism 3. Mitochondrial myopathies 4. Channelopathies 5. Congenital myopathies
what are 2 Inborn errors of metabolism (inherited myopathies) ?
1. Glycogenoses 2. Lipid storage myopathies
What part of the body does Inclusion Body Myositis affect ?
Asymmetric, often distal
what are the clinical signs of Myofibrillar Myopathies ?
Abnormality results in excess amounts of a particular protein Desminopathy Alpha-B crystallinopathy Myotilinopathy Filaminopathy BAG3-related myofibrillar myopathy Zaspopathy
who does Polymyositis affect ?
Adults, from the 4th to 7th decade
what is Myotonic Dystrophy ?
An autosomal dominant disorder characterized by myotonia in association with muscle weakness & wasting, also affecting other tissues
what does Polymyositis look like microscopically ?
Biopsies show fiber size variability, scattered necrotic and regenerating fibers, perivascular & endomysial lymphocytes (CD4+ T-cells, CD8+ T-cells), dendritic cells, & macrophages
what else does Emery-Dreifuss Muscular Dystrophy affect ?
Cardiac Disease Almost invariable; Onset in early 2nd decade to 40's Bradycardia; Atrial fibrillation/flutter rhythm disturbances, A-V conduction defects
what are Lipid Myopathies ?
Carnitine deficiency, deficiency of carnitine palmitoyltransferases, or a defect in beta-oxidation of these fatty acids may lead to myopathies Long-chain fatty acids are the major source of energy for skeletal muscle during sustained exercise or fasting. Fatty acids are bound to carnitine for transport into mitochondria & oxidation. Carnitine is synthesized mainly in the liver & actively transported into the muscle against a concentration gradient.
Who does Dermatomyositis affect ?
Children & adults equally
what does Duchenne Muscular Dystrophy look like microscopically ?
Chronic,smoldering myopathy with fiber necrosis, fibrosis, & replacement adipose tissue
What are some clinical findings of Limb-Girdle Muscular Dystrophy Syndromes ?
Clinical findings depend on particular type: Common to all is progressive weakness of the pelvic and shoulder muscles Distal wasting in the lower limbs seen in some types Lordosis Variable progressive weakness, may be as severe as Duchenne Tightening of Achilles tendons (toe-walking) Inability to walk on toes Scapular winging
what are the associated factors of Critical Illness Myopathy ?
Corticosteroids at higher doses Lung, Liver transplants Systemic diseases: sepsis; myasthenia gravis; renal failure & dialysis Multiple organ failure
what are Mitochondrial Myopathies ?
Different clinical phenotypes: Isolated myopathy Chronic progressive external ophthalmoplegia (Kearns-Sayre syndrome) Encephalomyopathy of infancy and childhood Multisystem disease with myopathy Effects tissues with a high energy expenditure & dependency on oxidative metabolism: brain, heart & muscle
what are two kinds of Inborn Errors of Metabolism ?
Disorders of Carbohydrate Metabolism Disorders of Lipid Metabolism
what are Channelopathies ?
Disorders of skeletal muscle excitability caused by mutations in genes coding for voltage-gated ion channels Characterized by episodic failure of motor activity due to muscle weakness (paralysis) or stiffness (myotonia)
what are Muscular Dystrophies?
Diverse group of inherited disorders characterized by progressive muscle weakness and wasting
what causes Emery-Dreifuss Muscular Dystrophy ?
Emery-Dreifuss Muscular Dystrophy is X-linked and autosomal dominant Most are caused by defects in nuclear envelope proteins
What is the esterase stain ?
Esterase activity is demonstrated in denervated fibers as a red-brown color with normal fibers exhibiting pale yellow to brown color (sometimes two fiber types may be distinguished.) Neuromuscular junctions, when present, are demonstrated by a dark red-brown deposit on the edge of a muscle fiber
what is Myophosphorylase Deficiency (McArdle's Disease) ?
Gene mutations: 21 identified, most result in complete loss of protein production Impaired ATP generation from aerobic & anaerobic glycolysis & reduced production of pyruvate Exercise intolerance with cramping & Muscle swelling that may last for hours Subsarcolemmal vacuoles
what causes Mitochondrial Myopathies ?
Genetic defects may be due to mitochondrial or nuclear mutations Leigh syndrome (subacute necrotizing encephalomyelopath); due to mutations in one of over 30 different genes: nuclear or mitochondrial MELAS mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; due tomutations of mitochondrial DNA MERRF Myoclonic epilepsy with ragged red fibers (MERRF) characterized by myoclonus & associated with epilepsy, ataxia, and myopathy; due to mutations in mitochondrial DNA
Congenital Myopathies - Central Core Disease
Genetic features: > 250 mutations identified Most central core families linked to Ryanodine receptor mutations (chromosome 19q) Skeletal muscle Ca++ release channel Childhood or congenital onset Hypotonia; Proximal Weakness: Legs > Arms ;Face: Mild weakness Course: Non- or Slowly Progressive Malignant Hyperthermia: Onset in teens
Congenital Fiber Type Disproportion
Genetically heterogeneous disorder with relative hypotrophy of type 1 muscle fibers compared to type 2 fibers Diagnosis of exclusion: The findings are not specific & can be found in many different myopathic and neuropathic conditions Usually proximal muscle groups weakness; variable facial weakness; severe respiratory involvement. Majority have no family history Caused by mutations in one of different disease genes (genetic heterogeneity). Autosomal recessive or autosomal dominant
Centronuclear (Myotubular) Myopathy
Genetics: X-linked (MTM 1) Myotubularin, Chromosome Xq27.3-q28; Autosomal Recessive; Autosomal Dominant: myogenic factor-6 gene (MYF6)
what is the genotype of Duchenne Muscular Dystrophy ?
Genotype: X-linked with high mutation rate Severe dystrophin deficiency
what is Limb-Girdle Muscular Dystrophy Syndromes ?
Limb-girdle muscular dystrophy (LGMD) are a group of disorders affecting voluntary muscles around the hips and shoulders More than 25 different types with associated mutations Difficulties in classification arise because of allelic variations with clinical extremes or different phenotypes resulting from defects in the same gene
what is Acid Maltase Deficiency (Pompe's Disease) ?
Lysosomal storage disease: many different mutations identified Infantile form is systemic with cardiomegaly & congestive heart failure, weakness & hypotonia Juvenile form presents as proximal weakness Adult form may present as fatigue or proximal weakness
who does Critical Illness Myopathy affect ?
Mean 6th decade; men & women
what are the clinical signs of Duchenne Muscular Dystrophy ?
Most common and most severe muscular dystrophy Onset @ age 3 to 5 yrs Cardiomyopathy & mental retardation Failure to walk: 9 - 13 years; Death 15 - 25 years due to respiratory or cardiac failure
What proteins does Muscular Dystrophies involve?
Most dystrophies involve proteins of the subsarcolemmal cytoskeleton Sarcolemmopathies (Duchenne muscular dystrophy)
what does Acid Maltase Deficiency (Pompe's Disease) look like microscopically ?
Muscle fibers enlarged & contain glycogen filled vacuoles & enlarged lysosomes
what does Central Core Disease look like microscopically ?
Muscle pathology Variable muscle fiber size Marked type I muscle fiber predominance Internal zone, "core", in muscle fiber with reduced or absent oxidative enzyme activity Cores run whole length of muscle fiber Some cores also have loss of central myofibrillar structure
what is the muscle pathology of Nemaline (Rod Body) Myopathies ?
Muscle pathology: Thin filament disorders Rods Dark red-blue structures only visible on Gomori trichrome stain Composition: Contain a-actinin + Actin + other Z-line proteins Ultrastructure: Electron dense, Rod shaped
what type of muscle does Steroid Myopathy affect ?
Muscle pathology: Type 2 fiber atrophy Increased lipid
what muscle does Steroid Myopathy affect ?
Muscle weakness: Proximal Symmetric Legs > arms Wasting Myalgias
what are Myofibrillar Myopathies ?
Myofibrillar myopathies are a group of rare genetic neuromuscular disorders slowly progressive muscle weakness that can involve skeletal and smooth muscle. Distal muscle weakness is more common than proximal weakness Cardiomyopathy cardiomyopathy is common
Nemaline (Rod Body) Myopathies
Onset: Congenital (90%) to Adult Inheritance: dominant, recessive & sporadic Severe: Congenital; a-Actin, Nebulin & Troponin T1 mutations Mild: Childhood; a-Actin, Nebulin, a-tropomyosin 3, b-tropomyosin) mutations Adult onset: not known
what are the Pathological features of Myofibrillar Myopathies ?
Pathological features: Hyaline spheroid & granular structures containing compacted & degraded myofibrillar structures Ectopic dystrophin & γ-sarcoglycan Ectopic expression of lamin B & nuclear matrix protein in cytoplasm
What does Inclusion Body Myositis look like microscopically?
Pathology: inflammation, rimmed vacuoles, Congo red positive inclusions
What does Dermatomyositis look like microscopically?
Perimysial and perivascular CD4+ T-cells, B cells, plasmacytoid dendritic cells, & macrophages Tubuloreticular inclusions in intramuscular arterioles & capillaries on electron microscopy Atrophy of fibers at the periphery of some muscle fascicles
what part of the body does Critical Illness Myopathy affect ?
Progressive proximal > distal weakness over days to weeks; unexplained, persistent weakness after respiratory support or neuromuscular paralysis
what part of the body does Immune Mediated Necrotizing Myopathy affect ?
Progressive, symmetrical weakness of the proximal muscles of arms & legs, (Clinically indistinguishable from polymyositis)
What part of the body does Dermatomyositis affect ?
Proximal muscle weakness & erythematous rash over malar region of face
what is Critical Illness Myopathy ?
Rapidly evolving myopathy with myosin-deficient fibers Often associated with some rhabdomyolysis
what does Immune Mediated Necrotizing Myopathy look like microscopically ?
Scattered necrotic muscle fibers Sparse inflammatory cells Macrophages are predominant Few lymphocytes
what is the prognosis of Critical Illness Myopathy ?
Slow improvement in weakness (months) when steroids tapered High mortality (30% to 50%) from associated disorders History of paralytic treatment with NMJ blocking agents >1 week Inability to wean from respirator
what are some Muscular Dystrophies due to ?
Some muscular dystrophies due to: Abnormities nucleoskeleton proteins (Emery-Dreifuss muscular dystrophy) DNA repeat expansion (myotonic dystrophy) or reduction (facioscapulohumeral dystrophy)
what part of the body does Emery-Dreifuss Muscular Dystrophy affect ?
Striking wasting of the upper arms and lower legs is often apparent in both.
what part of the body does Duchenne Muscular Dystrophy affect ?
Symmetric weakness Proximal > Distal
what are three distinct forms of myotonias ?
Three distinct forms of myotonias: Paramyotonia congenita Potassium-aggravated Myotonia congenita
what are Costameres ?
Transverse structures organized in a rib-like pattern Lie at the sarcolemma over the Z and M lines of nearby myofibrils. Two sets of plasma membrane proteins connect the contractile apparatus to the costameres at the sarcolemma: * One set via the dystroglycan complex * other via the integrins (á7β1)
what are the two forms of Myotonic Dystrophy ?
Two forms of myotonic dystrophy (DM1 & DM2), caused by defects in two different genes: Both are caused by expansion of a nucleotide repeat DM1 by expansion of a CTG repeat in the 3′ untranslated region of a gene on chromosome 19q DM2 by a CCTG repeat expansion in the first intron of the ZNF9 gene on chromosome 3q
What are two forms of periodic paralyses based on changes in serum potassium levels ?
Two forms of periodic paralyses based on changes in serum potassium levels during the attacks: Hypokalemic periodic paralysis Hyperkalemic periodic paralysis
What is the underlying pathogenic process of Nemaline (Rod Body) Myopathies ?
Underlying pathogenic process Rod formation 2° to contractile dysfunction Load-dependent processes probably involved Often increase in number with age
What causes Polymyositis ?
Unknown but May be associated with a number of different serum autoantibodies & other autoimmune disorders: "overlap syndrome" (Mixed connective tissue disease (MCTD), Scleroderma-myositis overlap syndrome, Antisynthetase syndrome) Cell-mediated: cytotoxic T-cells (CD 8+) inducing myofiber necrosis by releasing perforin-1 and granzyme B
