SECTION I CELLUILAR PHYSIOLOGY Duchenne Muscular Dystrophy Duchenne mscular dystrophy is a devastating.proressive disease that occurs in hoys;it is characterized by the progressive necrosis of skeletal musele fibers and death at an average age of 16,usully fromrespiratory failure.It is the seond wost comon genetic disorder in humans,and there iso specifi treatment.The frequent contractures.The discase is usually recognized at ages 2to5,and the child is usually confined byage 12 Laboratoryservations so highly elevated serun concentrations of creatine kinase and other soluble Both areaffected by fibers and phagocytosis,balanced by marked regeneration of cells in the early stages of the disease.The ithrked dedifferentiation.Fiber death and replacement by fat and coetive .DNA ysis reveals that the disease is csed by the deficienofagene on the chrom The productof the gene isacytoskeleta protein called dystrophin that forms network adjacent to the sarcole Dystrophin is a very large protein (426 kDa).It is a minor constituent of muscle into the nembrane. 1.Diseases affecting striated muscle cells are uncommon but are devastating and characteristically lethal.Why? 2.What is the significance of the elevated serum creatine kinase level? 3.Is elevated serm creatine kinase diagnostic for mscular dystrophy? 4.Some nuscles are nore affected than others.In fact,the muscles of the calves exhibit a characteristic hypertrophy.whereas the muscles of the upper legs are
SECTION I CELLULAR PHYSIOLOGY Duchenne Muscular Dystrophy Duchenne muscular dystrophy is a devastating, progressive disease that occurs in boys; it is characterized by the progressive necrosis of skeletal muscle fibers and death at an average age of 16, usually from respiratory failure. It is the second most common genetic disorder in humans, and there is no specific treatment. The course of the disease includes slow muscular development, progressive weakness, and frequent contractures. The disease is usually recognized at ages 2 to 5, and the child is usually confined to a wheelchair by age 12. Laboratory observations show highly elevated serum concentrations of creatine kinase and other soluble sarcoplasmic enzymes. Both fast and slow muscle fibers are affected by fiber necrosis and phagocytosis, balanced by marked regeneration of cells in the early stages of the disease. The fibers resemble fetal muscles, in terms of their isoenzyme patterns, with marked dedifferentiation. Fiber death and replacement by fat and connective tissue gradually predominate. DNA analysis reveals that the disease is caused by the deficiency of a gene on the X chromosome. The product of the gene is a cytoskeletal protein called dystrophin that forms a network adjacent to the sarcolemma. Dystrophin is a very large protein (426 kDa). It is a minor constituent of muscle and links sarcomeres to the sarcolemma via association with a glycoprotein inserted into the membrane. 1. Diseases affecting striated muscle cells are uncommon but are devastating and characteristically lethal. Why? 2. What is the significance of the elevated serum creatine kinase level? 3. Is elevated serum creatine kinase diagnostic for muscular dystrophy? 4. Some muscles are more affected than others. In fact, the muscles of the calves exhibit a characteristic hypertrophy, whereas the muscles of the upper legs are
weakened.What factors may influence differential responses in a patient whosc skeletal mscle cells lack a functional dystrophin gene? 5.Why is Duchenne muscular dystrophy progressive even though the genetic defect is present from conception? 7.Exercise is a major conponent of the clinical management of Duchenne nuscular dystrooby.What is the rationale? 8Would the introduction of a functionle of the dystrophin gene in the affected cellsbeapotential treatment that could cure the disease? ANSVER of mscle cells.Locomtion,commnication,respiration,eating.and many other activities thatare ded tomintain life and thatare essential tothe of life depend on normal muscle function. cells.Injury or cell death and necrosis allow this enzyme and other proteins to escape and to be detected in the serun. 3.No,it only indicates that the normal sarcolenmal perneability barrier that retains enzymes in cells has been breached in many mscle cells.However,in ae haby born in a fanily with a history of Duchenne muscular dystrophy,grossly elevated varindic thatthedysisdefetiv he essential to determine the cause of the increased serum creatine kinase levels to avoid missing treatahle diseases,such as polymyositis. 4.The reeurrent necrosis ins fibers balances the events. Weakness in some muscle groups for any cause leads to adaptive hypertrophic responses in synergistic muscles.The signals are unknomn.although mscular activity is implicated.Clearly the regenerative processes are limited and do not balance necrosis overall.Nevertheless,variations in the stimli for regeneration or
weakened. What factors may influence differential responses in a patient whose skeletal muscle cells lack a functional dystrophin gene? 5. Why is Duchenne muscular dystrophy progressive even though the genetic defect is present from conception? 6. Why don't girls develop Duchenne muscular dystrophy? 7. Exercise is a major component of the clinical management of Duchenne muscular dystrophy. What is the rationale? 8. Would the introduction of a functional allele of the dystrophin gene in the affected cells be a potential treatment that could cure the disease? ANSWER 1. Life without motion is impossible, and movement is generated by contraction of muscle cells. Locomotion, communication, respiration, eating, and many other activities that are needed to maintain life and that are essential to the quality of life depend on normal muscle function. 2. Creatine kinase is a soluble protein present in high concentrations in muscle cells. Injury or cell death and necrosis allow this enzyme and other proteins to escape and to be detected in the serum. 3. No, it only indicates that the normal sarcolemmal permeability barrier that retains enzymes in cells has been breached in many muscle cells. However, in a male baby born in a family with a history of Duchenne muscular dystrophy, grossly elevated levels would be a strong indication that the dystrophin gene is defective. It would be essential to determine the cause of the increased serum creatine kinase levels to avoid missing treatable diseases, such as polymyositis. 4. The recurrent necrosis in muscle fibers balances the regenerative events. Weakness in some muscle groups for any cause leads to adaptive hypertrophic responses in synergistic muscles. The signals are unknown, although muscular activity is implicated. Clearly the regenerative processes are limited and do not balance necrosis overall. Nevertheless, variations in the stimuli for regeneration or
perhaps the capacity to regenerate contribute to differential progression of the disease. 5.This is puzzling.but two factors are implicated.One is the offsetting regenerative capacity of muscle (see answer to question 4).The other is the fact that mascle cells go through a nurber of developeental stages.The observation that the muscle cells of affected individuals display fetal characteristics suggests that the adult fiber phenotypes are nore susceptible to the disease process or that there are developeental disturbances. 6.The defective gene aust be recessive and sex linked.Fenales have two X chronosores,one fron their father and one froa their nother.The X chromosone from the father must contain a normal dystrophin gene (because chrooosones coetaining the mutation are lethal in males by adolescence). 7.Unused motor units exhibit disuse atrophy and would exacerbate the weakness characteristic of the disease.Exercise will help preserve muscle function. 8.Yes,in theory.In this recessive disease the mutation deprives the cells of the essential protein dystrophin.Restoration of the normal gene,if expressed, could be expected to correct or mitigate the disease.In practice,the technology to introduce a functional gene to all muscle cells does not exist
perhaps the capacity to regenerate contribute to differential progression of the disease. 5. This is puzzling, but two factors are implicated. One is the offsetting regenerative capacity of muscle (see answer to question 4). The other is the fact that muscle cells go through a number of developmental stages. The observation that the muscle cells of affected individuals display fetal characteristics suggests that the adult fiber phenotypes are more susceptible to the disease process or that there are developmental disturbances. 6. The defective gene must be recessive and sex linked. Females have two X chromosomes, one from their father and one from their mother. The X chromosome from the father must contain a normal dystrophin gene (because chromosomes containing the mutation are lethal in males by adolescence). 7. Unused motor units exhibit disuse atrophy and would exacerbate the weakness characteristic of the disease. Exercise will help preserve muscle function. 8. Yes, in theory. In this recessive disease the mutation deprives the cells of the essential protein dystrophin. Restoration of the normal gene, if expressed, could be expected to correct or mitigate the disease. In practice, the technology to introduce a functional gene to all muscle cells does not exist