Diseases of skeletal muscle Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University Email: ali.alkhader@bau.edu.jo

Lecture outline Skeletal muscle atrophy Inflammatory myopathies: - Dermatomyositis Polymyositis Inclusion body myositis Muscular dystrophies: Duchenne muscular dystrophy Becker muscular dystrophy

Skeletal muscle atrophy …a common feature of many disorders Causes: -Loss of innervation (neurogenic injury) -Disuse -Cachexia -Old age -Primary myopathies (inflammatory or others) Certain patterns of atrophy are suggestive of specific underlying etiologies: -Cluster/Group atrophy …neurogenic disease…see next slide -Perifascicular atrophy …dermatomyositis -Type II fiber atrophy …corticosteroids and disuse

Cluster/Group atrophy neuron normal checkerboard appearance (enzyme stain) In a normal muscle, some of the fibers are of type 1 and others are of type 2…each neuron gives branches to a group of fibers of the same type (for example: the fibers supplied by neuron X must be of type 1, while those supplied by neuron Y must be of type 2) *neuron + its branches + fibers supplied by its branches = motor unit If denervation occurs, group atrophy is the result This is called: type grouping …as you see, the type of fibers is converted now according to which neuron is now supplying

Perifascicular atrophy Normally: …note the presence of lymphocytes…this is a case of dermatomyositis

Inflammatory myopathies Dermatomyositis Because there is damage in the muscle here (myopathy), we will find the following: -Elevated serum creatine kinase -EMG (electromyography) will show: myopathic changes A systemic autoimmune disease Proximal myopathy + skin manifestations The most common inflammatory myopathy in children In 15-24% of adult cases, it is associated with malignancy and manifests as a paraneoplastic disorder Typically associated with skin manifestations May have systemic manifestations such as interstitial lung disease Prognosis in adults is worse than in children

Dermatomyositis, pathogenesis Autoimmune damage to small blood vessels contributes to muscle injury As with some other autoimmune diseases such as SLE, type 1 interferon- induced gene products are strongly upregulated in affected muscles…this signal increases with disease activity Some patients have autoantibodies that are relatively specific for dermatomyositis; these include antibodies against Mi-2 (a nuclear helicase), anti-Jo1 and anti-p155 and anti-p140 …role in disease not proven yet

Dermatomyositis, morphology in the affected muscle Perivascular & perimysial mononuclear cell infiltrates with plasma cells “Dropout” of capillaries The presence of so-called “tubuloreticular inclusions” in endothelial and inflammatory cells…an ultrastructural feature Myofiber damage in a perifascicular pattern Fibrosis and fat replacement may occur late

Dermatomyositis, clinical picture Slowly progressive muscle weakness and muscle pain…Which muscles?? Telangiectasias (dilated capillary loops) in the nail folds, eyelids, and gums…because this disease is mainly caused by small vessel damage Gottron papules (scaly eruptions rash on the knuckles, elbows or knees) & heliotrope rash (blue-purple discoloration around the eyes along with swelling, mainly upper eyelids)…anti-Mi2 antibodies are especially associated with these features and can be detected in blood Other rashes: mechanic’s hand (rough, crackled skin at tips and lateral aspects of  the fingers resulting in irregular, dirty appearing lines), V neck sign (above breasts) & Shawl sign (upper back) Also interstitial lung disease, arthritis, dysphagia & cardiac involvement can occur Raynaud phenomenon also may accompany the disease…What is Raynaud phen.??

Inflammatory myopathies Polymyositis An adult-onset inflammatory myopathy that shares myalgia, weakness and other manifestations of dermatomyositis but lacks its distinctive cutaneous features As in dermatomyositis, patients typically develop symmetric proximal muscle involvement …autoantibodies similar to those of dermatomyositis may also be present …manifestation such as lung & heart involvement, Raynaud phenomenon and dysphagia may also be present Also has an immunologic basis Unlike dermatomyositis, vascular injury is not believed to have a major role in polymyositis

Polymyositis, morphology Mononuclear inflammatory cell infiltrates are present, but in contrast to dermatomyositis, these are usually endomysial in location Degenerating necrotic, regenerating, and atrophic myofibers typically found in a random or patchy distribution The perifascicular pattern of atrophy that is characteristic of dermatomyositis is absent Fibrosis and fat replacement may occur late

Inflammatory myopathies Inclusion body myositis These are cytoplasmic inclusions The morphologic hallmark is the presence of rimmed vacuoles…these contain aggregates of hyperphosphorylated tau, Aβ-amyloid, TDP-43 & ubiquitin It does not respond well to immunosuppressive agents, a feature suggesting that inflammation is a secondary event Laboratory studies usually show modestly elevated creatine kinase levels Most myositis-associated autoantibodies are absent…However, antibody to cN1A has recently been described A disease of late adulthood that typically affects patients older than 50 years The most common inflammatory myopathy in patients older than age 65 years Slowly progressive muscle weakness that tends to be most severe in the quadriceps and the distal upper extremity muscles Dysphagia from esophageal and pharyngeal muscle involvement is not uncommon

Muscular dystrophies (in general) Several inherited disorders of skeletal muscle that have in common progressive muscle damage that typically manifests itself between childhood and adulthood With the exception of congenital muscular dystrophies, these diseases do not present in infancy We will discuss the X-linked muscular dystrophies with dystrophin mutation (mainly Duchenne and Becker Muscular Dystrophy)

Duchenne and Becker Muscular Dystrophy (X-Linked Muscular Dystrophy with Dystrophin Mutation) The most common muscular dystrophies Mutations that disrupt the function of a large structural protein called dystrophin Sometimes referred to as dystrophinopathies The most common early onset form is referred to as Duchenne muscular dystrophy Becker muscular dystrophy is a second relatively common dystrophinopathy that is characterized by later disease onset and a milder phenotype As with many X-linked diseases, female carriers of dystrophin mutations may be mildly symptomatic due to unfavorable X-chromosome inactivation

Duchenne and Becker Muscular Dystrophy, pathogenesis Loss-of-function mutations in the dystrophin gene on the X chromosome Dystrophin, is a key component of the dystrophin glycoprotein complex (DGC) Dystrophin is thought to provide mechanical stability to the myofiber and its cell membrane during muscle contraction …it also has a role in signal transduction Many mutations, so variable phenotypes (Duchenne, Becker, other dystrophinopathies) Mutations in Duchenne are more severe (deletions, frame shift mutations) DGC

Duchenne and Becker Muscular Dystrophy, morphology Changes are similar, but more pronounced in Duchenne Degenerating necrotic, regenerating, and atrophic myofibers, usually no inflammation except for the presence of myophagocytosis Both are marked by chronic muscle damage that outpaces the capacity for repair…so: fibrosis and fatty replacement Immunohistochemical studies for dystrophin show absence of the normal sarcolemmal (= membrane of muscle fiber) staining pattern in Duchenne muscular dystrophy and reduced staining in Becker muscular dystrophy abnormal normal

Duchenne muscular dystrophy, clinical course Normal at birth Walking is often delayed The first indications of muscle weakness are clumsiness and inability to keep up with peers Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle Enlargement of the muscles of the lower leg associated with weakness, termed pseudohypertrophy, is often present The mean age of wheel chair dependence is around 9.5 years Worsening respiratory reserve, and sleep hypoventilation Heart (cardiomyopathy and arrhythmias, particulary in older patients) & CNS (may cause mental retardation) are also affected The mean age of death for patients with Duchenne muscular dystrophy is 25 to 30 years of age…due to resp. failure, pulmonary infections or heart failure

Becker muscular dystrophy, clinical course Presents in later childhood, adolescence or adult life Its course is more slowly progressive Often with a near normal life expectancy

Duchenne and Becker Muscular Dystrophy, lab investigations Serum creatine kinase is markedly elevated during the first decade of life due to ongoing muscle damage …then falls as the disease progresses and muscle mass is lost The presence of a dystrophin mutation can be confirmed by genetic studies

Positive Gower sign in Duchenne and Becker muscular dystrophy …due to proximal lower limb muscle weakness …not only in Duchenne & Becker It describes a patient that has to use his hands and arms to "walk" up his own body from a squatting position

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