Morales, Reina Lyria C. C1 Group 6 1. WHAT IS MYASTHENIA GRAVIS?

Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. The name myasthenia gravis, which is Latin and Greek in origin, literally means "grave muscle weakness." With current therapies, however, most cases of myasthenia gravis are not as "grave" as the name implies. In fact, most individuals with myasthenia gravis have a normal life expectancy. In myasthenia gravis, antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle contraction from occurring. These antibodies are produced by the body's own immune system. Myasthenia gravis is an autoimmune disease because the immune systemwhich normally protects the body from foreign organismsmistakenly attacks itself. 2. WHAT IS THE CHEMICAL STRUCTURE AND NATURE OF ACETYLCHOLINE AND THE ACETYLCHOLINE RECEPTOR? Acetylcholine (ACh) is a simple molecule synthesized from choline and acetylCoA through the action of choline acetyltransferase. Neurons that synthesize and release ACh are termed cholinergic neurons. When an action potential reaches the terminal button of a presynaptic neuron a voltage-gated calcium channel is opened. The influx of calcium ions, Ca2+, stimulates the exocytosis of presynaptic vesicles containing ACh, which is thereby released into the synaptic cleft. Once released, ACh must be removed rapidly in order to allow repolarization to take place; this step, hydrolysis, is carried out by the enzyme, acetylcholinesterase. The acetylcholinesterase found at nerve endings is anchored to the plasma membrane through a glycolipid.

ACh receptors are ligand-gated cation channels composed of four different polypeptide subunits arranged in the form [( 2)( )( )( )]. Two main classes of ACh receptors have been identified on the basis of their responsiveness to the toadstool alkaloid, muscarine, and to nicotine, respectively: the muscarinic receptors and the nicotinic receptors. Both receptor classes are abundant in the human brain. Nicotinic receptors are further divided into those found at neuromuscular junctions and those found at neuronal synapses. The activation of ACh receptors by the binding of ACh leads to an influx of Na+ into the cell and an efflux of K+, resulting in a depolarization of the postsynaptic neuron and the initiation of a new action potential.

3. HOW WOULD YOU DESCRIBE THE VOLUNTARY SKELETAL MUSCLE FIBER? ILLUSTRATE. Skeletal Muscle fiber is a striated muscle. It contains small T tubules. Sarcoplasmic reticulum is well developed and Calcium pump acts rapidly. No syncytium. Plasmalemma lacks many hormone receptors. Its nerve impulse inititates contractions. Extracellular fluid Calciums is not important for contraction. Troponin system is present with very rapid cycling of the cross-bridges.

4. WHAT ARE THE CONTRACTILE PROTEINS PRESENT IN SKELETAL MUSCLE FIBERS. DESCRIBE AND ILLUSTRATE EACH. Actin and Myosin are the major proteins of muscle. Myosin, contributes 55% of muscle protein by weight and forms the thick filaments. It is an asymmetric hexamer with a molecular mass of approximately 460 kDa. Myosin has a fibrous tail consisting of two intertwined helices. Each helix has a globular head portion attached at one end. The hexamer consists of one pair of heavy (H) chains each of approximately 200 kDA molecular mass, and two pairs of light (L) chains each with a molecular mass of approximately 20 kDa. The L chains differ, one being called the essential light chain and the other the regulatory light chain. Skeletal muscle myosin binds actin to form actomyosin (actin-myosin), and its intrinsic ATPase activity is markedly enhanced in this complex. Isoforms of myosin exist whose amounts can vary in different anatomic, physiologic, and pathologic situations. Actin, Thin filaments are composed of many subunits of the globular protein Gactin (42 kD) and several accessory proteins. In thin filaments, G-Actin is polymerized into long fibrous arrays known as F-actin. A pair of linear F-actin arrays is helically wound to form the backbone structure of 1 complete thin filament. The main thin filament accessory proteins are tropomyosin and troponin. Tropomyosin is a long, rodlike, helically-interwound heterodimer that spans a length of 7 G-actin residues. A pair of tropomyosin molecules is associated with every 7 pairs of G-actin residues along a thin filament, 1 tropomyosin molecule in each of the grooves of the F-actin helix. In relaxed muscle, each tropomyosin molecule covers the myosin binding sites of 7 G-actin

residues, preventing interaction between actin and myosin and thus maintaining the relaxed state. The onset of contractile activity involves activating troponin, the second accessory protein of thin filaments. Troponin is a heterotrimer attached to one end of each tropomyosin molecule and to actin, physically linking tropomyosin to actin.

5. DESCRIBE THE MAJOR BIOCHEMICAL EVENTS OCCURING DURING ONE CYCLE OF MUSCLE CONTRACTION. The major biochemical events occurring during one cycle of muscle contraction and relaxation can be represented in the five steps: - In the relaxation phase of muscle contraction, the S-1 head of myosin hydrolyzes ATP to ADP and Pi, but these products remain bound. The resultant ADPPi-myosin complex has been energized and is in a socalled highenergy conformation. - When contraction of muscle is stimulated (via events involving Ca2+, troponin, tropomyosin, and actin, which are described below), actin becomes accessible and the S-1 head of myosin finds it, binds it, and forms the actinmyosin-ADP-Pi complex indicated. - Formation of this complex promotes the release of Pi , which initiates the power stroke. This is followed by release of ADP and is accompanied by a large conformational change in the head of myosin in relation to its tail (Figure 497), pulling actin about 10 nm toward the center of the sarcomere. This is the power stroke. The myosin is now in a so-called low-energy state, indicated as actin-myosin. - Another molecule of ATP binds to the S-1 head, forming an actin-myosinATP complex. - Myosin-ATP has a low affinity for actin, and actin is thus released. This last step is a key component of relaxation and is dependent upon the binding of ATP to the actin-myosin complex. 6. DISCUSS THE ROLE OF ATP AND THE MECHANISMS/REACTIONS USED TO REPLENISH STORES ATP IN MUSCLES. The ATP required as the constant energy source for the contraction-relaxation cycle of muscle can be generated (1) by glycolysis, using blood glucose or muscle

glycogen, (2) by oxidative phosphorylation, (3) from creatine phosphate, and (4) from two molecules of ADP in a reaction catalyzed by adenylyl kinase. The amount of ATP in skeletal muscle is only sufficient to provide energy for contraction for a few seconds, so that ATP must be constantly renewed from one or more of the above sources, depending upon metabolic conditions. 7. WHAT IS THE BIOCHEMICAL DEFECT IN MYASTHENIA GRAVIS. DESCRIBE THE ANTIBODY AGAINST ACETYLCHOLINE RECEPTOR. WHAT IS THEIR MECHANISM OF ACTION. Myasthenia gravis is the principal disease affecting the neuromuscular junction. The fundamental defect is not a deciency of ACh or its release, but rather its failure to attach to the postsynaptic receptor, which is blocked by an antibody at the receptor site. It features antibodies directed against the body's own proteins These antibodies block acetylcholine-binding sites, damage the postsynaptic membrane, and accelerate receptor degradation. Synaptic transmission fails when the autoantibodies cause a critical loss of the cation channel protein, which is required to activate the muscle action potential. 8. HOW IS MG CLASSIFIED BASED ON MG FOUNDATION OF AMERICA CLINICAL CLASSIFICATION? WHAT IS MYASTHENIA CRISES? The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America Clinical Classification: Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere Class II: Eye muscle weakness of any severity, mild weakness of other muscles Class IIa: Predominantly limb or axial muscles Class IIb: Predominantly bulbar and/or respiratory muscles Class III: Eye muscle weakness of any severity, moderate weakness of other muscles Class IIIa: Predominantly limb or axial muscles Class IIIb: Predominantly bulbar and/or respiratory muscles Class IV: Eye muscle weakness of any severity, severe weakness of other muscles Class IVa: Predominantly limb or axial muscles Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation) Class V: Intubation needed to maintain airway Myasthenic crisis is an exacerbation of the disease process characterized by severe generalized weakness and respiratory and bulbar weakness that may result in respiratory failure.

9. WHAT IS THE PREVALENCE OF MG? IS THERE GENETIC BASIS FOR MG? IS THERE ANY FAMILY AND SEX PREDESPOSITION? Approximately 60,000 people have myasthenia gravis in the United States (Phillips, 2004). Women are affected more frequently than men and they tend to develop the disease at an earlier age (20 to 40 years of age, compared to 60 to 70 years for men) (Scherer, Bedlack & Simel, 2005) 10. DISCUSS THE PATHOPHYSIOLOGY OF MYASTHENIA GRAVIS AND EXPLAIN THE PATHOPHYSIOLOGIC BASIS OF EACH SYMPTOMS. The normal neuromuscular junction releases acetylcholine (ACh) from the motor nerve terminal in discrete packages (quanta). The ACh quanta diffuse across the synaptic cleft and bind to receptors on the folded muscle end-plate membrane. Stimulation of the motor nerve releases many ACh quanta that depolarize the muscle end-plate region and then the muscle membrane causing muscle contraction. In acquired myasthenia gravis, the post-synaptic muscle membrane is distorted and simplified, having lost its normal folded shape. The concentration of ACh receptors on the muscle end-plate membrane is reduced, and antibodies are attached to the membrane. ACh is released normally, but its effect on the post-synaptic membrane is reduced. The post-junctional membrane is less sensitive to applied ACh, and the probability that any nerve impulse will cause a muscle action potential is reduced. Eye muscles - weakness of the eye muscles can lead to ptosis, the degree of which can be variable, switching from one eye to the other on separate examinations and occasionally increasing with sudden exposure to bright light. The extraocular eye muscles are often involved. The clinical manifestations of these vary from subtle blurring of vision to severe diplopia. Bulbar muscles a myasthenic snarl may be seen when the bulbar muscles are affected. This problem of facial muscle weakness occurs when smiling and can cause embarrassment. Other bulbar manifestations include nasal speech devoid of consonant sounds due to weakness of the palate and tongue, difficulty chewing and less often difficulty of swallowing and choking on liquids. The problem with chewing may be so severe that the patient must support his or her chin with a hand to finish chewing something tough. Supporting the chin may also be necessary if there is neck extensor weakness which can cause the head to fall forward out of the patients control. Limb and trunk involvement of the limbs and trunk in myasthenia produce symptoms similar to other muscle diseases. The proximal limbs are most commonly

affected. However, predominantly distal presentations of otherwise typical myasthenia occurs in 6 to 84 patients in one prospective series. Myasthenic symptoms tend to fluctuate over the course of the hour and throughout the day. They are often worst at night. Many physical and environmental conditions can either exacerbate or diminish the symptoms of myasthenia gravis. The muscle fatigue associated with myasthenia gravis is made worse by repetitive activity, excessive heat, overexertion, and emotional stress. Physical conditions can also irritate the condition, including any kind of physical stress: such as surgery, radiation therapy, infection, or fever. Also known to make symptoms worse are abnormal thyroid activity and low potassium levels. Drugs that interfere with muscle activity, such as muscle relaxants, anesthetics, anticonvulsants, antiarrhythmics, some antibiotics, curariform agents and other drugs that interfere with neuromuscular transmission will also greatly increase the severity of the symptoms. Myasthenic symptoms are improved most obviously by rest. It has also been found that they are improved with cold packs and in cooler environmental temperatures.