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Pseudohypertrophic muscular dystrophy: Duchenne type
COMMENTS CURRENT
ON LITERATURE
Pseudohypertrophic muscular Duchen ne type
sons, or, in turn, carrier daughters, perpetuating the trait. While classification of the various types of muscular dystrophy has not been entirely satisfactory, the pseudohypertrophic type of Duchenne appears to be the most common form in childhood, with onset, as a general rule, before the fifth year of life. Certain groups of muscles become enlarged, showing the characteristic pseudohypertrophy. Atrophic changes occur in other muscles, and follow in those which initially appear to be enlarging. The disease is progressive, and is usually fatal before the second decade of life. The first clinical signs may be apparent when the child attempts to "pull up." He finds it difficult to stand, and since there is progressive weakness of the legs, he has difficulty in learning to walk. A waddling gait with feet set wide apart results from weakness of the gluteal muscles. Weakness of the shoulder girdle muscles usually follows. A well recognized feature in older children is the so-called "climbing the legs" or "building the body" maneuver which is necessary to rise to a standing position from a sitting position on the floor. No satisfactory therapy is available at present. Treatment with anabolic steroids alone or in combination with digitoxin gave qualified promise in some instances? More extensive trials, however, did not show these measures to be therapeutically effective, 2 and a recent evaluation of the anabolic steroids
I-[ A fi; L O N O b e e n recognized t h a t i n certain hereditary conditions the clinically normal carriers of an abnormal gene may show to a minor degree manifestations characteristic of the disease. The detection of such carriers in a kinship in which one or more members have the disease is of great value in genetic counseling and in providing information as to genetic prognosis. Parents of children with serious conditions inherited as autosomal or sex-linked recessive traits may desire family limitation thereafter, or at least should be made aware of the risk to the offspring. In the human population gene mutations appear to be relatively infrequent, so that in conditions inherited as autosomal recessives, the parents are nearly always carriers. In sex-linked recessive conditions, detection of the carrier state in the mother, in her daughters as they reach marriageable age, and knowledge concerning the mother's relatives are of importance to the physician whose advice is sought. Among the serious conditions following a sex-linked inheritance pattern, for which reliable tests for the identification of carriers would be very helpful, is severe muscular dystrophy, such as pseudohypertrophic muscular dystrophy of the Duchenne type. Families in which sons have died, or have been incapacitated by this form of dystrophy, are often eager for information concerning the mode of inheritance, and especially the risk that the daughters may have affected I T
503
504
Comment~ on current literature
and digitoxin in the therapy of progressive muscular dystrophy confirms these reports that this form of treatment is not effective, and indeed may accelerate the dystrophic process. :~ Other significant contributions in recent years have included knowledge of muscle pathology in the muscular dystrophies, partieularly the fact that structural alterations of the muscles occur even in the early preclinical phase, notably in the Duchenne type. ~ Likewise, information has been accumulating concerning enzyme abnormalities and disturbances in enzyme activity?, ,9 Abnormally high levels of certain enzymes have been found in the serum of patients with early clinical manifestations of the disease, and also in a significant number of persons who are carriers or potential carriers, as judged by family history. In some instances it has been possible to predict which child in the sibship containin~ dystrophic individuals will subsequently develop the condition. In the Duchenne type of muscular dystrophy the level of the serum enzyme, creatine phosphokinase, appears to be the most sensitive indicator of the disease. The average normal level for this enzyme is within the range of 2.0 units to 3.5 units per milliliter?' " In some early cases of muscular dystrophy vaIues up to several hundred units have been encountered. In a series studied by Walton,: the highest serum creatine kinase value recorded was 1,060 units per milliliter. Walton; considers it possible to identify shortly after birth those males who will later develop the clinical features of the disease. T h o u g h the source of the enzylne has not been fully established, it is thought to arise from the muscle tissue. There is preliminary evidence from a study of muscle preparations in vitro that a factor is present in the serum of patients with Dnchenne muscular dystrophy which accelerates the release of creatine phosphokinase from muscleY Little information has been available, however, to explain the wide variability in muscle change in relation to enzyme changes, and "it is not known in which portion of the nmscle fiber the initial dystrophic process is
September 1965
manifest."" In this connection, a recent publication by Emery ~ in the Journal of Medical Genetics is of interest. This author points out that though the studies of preclinical cases have demonstrated that definite histopathologic changes are present in the muscle before the onset of clinical weakness, "they have not been very helpful in determining the initial manifestation of the dystrophic process. ''~) The histopathologic changes are already well advanced even in young infants in the preelinical stage. With these facts in mind, Emery initiated a detailed study of the structural muscle changes to be seen in carriers of muscular dystrophy. Nine known carriers of Duchenne muscular dystrophy and 3 normal healthy control women were studied by muscle biopsy, and, at the same time, by enzyme estimation for ereatine kinase. A known carrier of sexlinked Duchenne muscular dystrophy is defined as a w o m a n who has at least 2 affected sons, or one affected son and a family history of other male relatives similarly affected, such as a brother or a maternal uncle. All individuals in the study were examined for evidence of muscle weakness. T w o of the 9 carriers showed definite evidence of weakness. Creatine kinase determinations were made on fresh serum samples. T h e microscopic structure of gastroenemius muscle was studied in 3 healthy women, who had no history of any neuromuscular disease, and in 9 carriers of muscular dystrophy. T h e carriers ranged in age from 29 to 55 years, and the 3 control women were 30, 40, and 48 years of age. All biopsy specimens were obtained from the belly of the muscle, and, in the controls, were taken during operations for ligation of varicose veins. In the carriers biopsy was obtained under local anesthesia. Special care was exercised in both the biopsy procedure and in subsequent fixation of the tissue in order to insure a good representative specimen and to avoid artifacts. Biopsy specimens were uniform in size, and were obtained with the muscle fibers running parallel to the long axis. During the course of the study, creatine kinase determinations were made several times on each subject.
Volume 67 Number 3
Methods of histologic study and the changes observed in the muscle are described by Emery 9 in detail: swollen fibers, hyaline change, fiber size variation, increase in nuclei, necrosis, etc. As might be anticipated, structural changes in the fibers were most marked in the 2 carriers who had shown muscle weakness. I n 2 of the 9 carriers there was minimal evidence of muscle abnormality. T h e earliest structural change appears to be swelling of the muscle fibers. However, all gradations were observed from apparently normal fibers in 2 carrier individuals to a markedly abnormal structural pattern in 2 of the carriers. These changes were correlated significantly with the serum levels of creatine kinase, the highest enzyme level occurring in a carrier w o m a n in whose muscle fibers every histologic change: considered as a criterion for analysis was observed. All of the findings in the control subjects were within normal limits. Emery concludes that histologic study of muscle biopsy specimens, together with the estimation of serum ereatine phosphokinase, can be of considerable value in carrier detection in Duchenne muscular dystrophy. As a possible explanation of the wide variability a m o n g carriers, Emery discusses the Lyon hypothesis concerning the action of the X-chromosome. This hypothesis, first formulated by Lyon ~~ in 1961, suggests that in a small proportion of the female cells, one X-chromosome m a y be partially inactivated. This inactivation occurs early in development, and possibly is associated with the formation of the chromatin body. Apparently either X-chromosome may be inactivated in different cells of the same individual, which gives rise to "patchiness" (groups of cells, some with one X-chromosome inactivated and some with the other X-chromosome inactivated). I n female mammals heterozygous for certain sex-linked coat color factors, a mottled spotty appearance can result. Likewise, in carriers heterozygous for the recessive sex-linked factor for D u c h e n n e muscular dystrophy, if the normal X-chromosome is partially inactivated in a few cells, the Xchromosome carrying the recessive gene for
C o m m e n t s on current literature
50 5
dystrophy would then have the opportunity for phenotypic expression, and such a situation could result in patchy muscle fiber degeneration. T h e proportion of these cells is thought to be small and variable, which could account for the fact that clinical evidence of muscle weakness is lacking in some carriers, but may be quite apparent in others. Detailed studies by various techniques of patients with pseudohypertrophic muscular dystrophy and their kinship are providing the physician and the scientist with a more rational approach to this well recognized, but poorly understood clinical syndrome. As more knowledge concerning the basic features of this disorder is accumulated, it seems reasonable to anticipate that effective preventive and therapeutic regimens will emerge. RUSSELL J. BLATTNER~ M.D.
REFERENCES
1. Dowben, R. M.: Treatment of muscular dystrophy with steroids: A preliminary report, New England J. Med. 268: 912, 1963. 2. Fowler, W. M., Jr., Pearson, C. M., Egstrom, G. H., and Gardner G. W.: Ineffective treatment of muscular dystrophy with an anabolic steroid and other measures, New England J. Med. 272: 875, 1965. 3. Heyck, H., Laudahn, G., Liiders, C. J., Mfiller-Stephann, H. and Schmidt-Peter, P.: Anabolie steroids and digitoxin in the treatment of progressive muscular dystrophy, Acta paediat, scandinav. 54: 205, 1965. 4. Pearson, C. M.: Histological features of the muscle in the preclinical stages of muscular dystrophy, Brain 85: 109, 1962; Muscular dystrophy: Review and recent developments, Am. J. Med. 35: 632, 1963. 5. Pennington, R. J. T.: Biochemical aspects of muscle disease, in Walton, John N., editor: Disorders of voluntary muscle, Boston, 1964, Little, Brown & Company, chap. 10, p. 255. 6. Pearce, J. M. S., Pennington, R. J. T., and Walton, J. N.: Serum enzyme studies in muscle disease. I I I : Serum creatine kinase activity in relatives of patients with Duchenne type of muscular dystrophy, J. Neurol., Neurosurg., & Psychiat. 27" 181, 1964. 7. Walton, John N.: Some diseases of muscle, Lancet 1: 447, 1964; Muscular dystrophy: Some recent advances in knowledge, Brit. M. J. 1: 1344, 1964; Disorders of voluntary muscle, Boston, 1964, Little, Brown & Company. 8. Sugita, Hideo, and Tyler, Frank M. : Pathogenesis of muscular dystrophy, Tr. A. Am. Physicians 76: 231, 1963. 9. Emery, A. E. H.: Clinical manifestations in
506
C o m m e n t s on current literature'
two carriers of Duchenne muscular dystrophy, Lancet 1: 1126, 1963; Muscle histology in carriers of Duchenne muscular dystrophy, J. Med. Genet. 2: 1, 1965. I0. Lyon, M. F.: Gene action in the X-chromo-
September 1965
some of the mouse (Mus musculus L.), Nature 190: 372, t961; Sex chromatin and gene action in the mammalian X-chromosome, Am. J. H u m a n Genet. 14: 135, 1962.
ON LITERATURE
Pseudohypertrophic muscular Duchen ne type
sons, or, in turn, carrier daughters, perpetuating the trait. While classification of the various types of muscular dystrophy has not been entirely satisfactory, the pseudohypertrophic type of Duchenne appears to be the most common form in childhood, with onset, as a general rule, before the fifth year of life. Certain groups of muscles become enlarged, showing the characteristic pseudohypertrophy. Atrophic changes occur in other muscles, and follow in those which initially appear to be enlarging. The disease is progressive, and is usually fatal before the second decade of life. The first clinical signs may be apparent when the child attempts to "pull up." He finds it difficult to stand, and since there is progressive weakness of the legs, he has difficulty in learning to walk. A waddling gait with feet set wide apart results from weakness of the gluteal muscles. Weakness of the shoulder girdle muscles usually follows. A well recognized feature in older children is the so-called "climbing the legs" or "building the body" maneuver which is necessary to rise to a standing position from a sitting position on the floor. No satisfactory therapy is available at present. Treatment with anabolic steroids alone or in combination with digitoxin gave qualified promise in some instances? More extensive trials, however, did not show these measures to be therapeutically effective, 2 and a recent evaluation of the anabolic steroids
I-[ A fi; L O N O b e e n recognized t h a t i n certain hereditary conditions the clinically normal carriers of an abnormal gene may show to a minor degree manifestations characteristic of the disease. The detection of such carriers in a kinship in which one or more members have the disease is of great value in genetic counseling and in providing information as to genetic prognosis. Parents of children with serious conditions inherited as autosomal or sex-linked recessive traits may desire family limitation thereafter, or at least should be made aware of the risk to the offspring. In the human population gene mutations appear to be relatively infrequent, so that in conditions inherited as autosomal recessives, the parents are nearly always carriers. In sex-linked recessive conditions, detection of the carrier state in the mother, in her daughters as they reach marriageable age, and knowledge concerning the mother's relatives are of importance to the physician whose advice is sought. Among the serious conditions following a sex-linked inheritance pattern, for which reliable tests for the identification of carriers would be very helpful, is severe muscular dystrophy, such as pseudohypertrophic muscular dystrophy of the Duchenne type. Families in which sons have died, or have been incapacitated by this form of dystrophy, are often eager for information concerning the mode of inheritance, and especially the risk that the daughters may have affected I T
503
504
Comment~ on current literature
and digitoxin in the therapy of progressive muscular dystrophy confirms these reports that this form of treatment is not effective, and indeed may accelerate the dystrophic process. :~ Other significant contributions in recent years have included knowledge of muscle pathology in the muscular dystrophies, partieularly the fact that structural alterations of the muscles occur even in the early preclinical phase, notably in the Duchenne type. ~ Likewise, information has been accumulating concerning enzyme abnormalities and disturbances in enzyme activity?, ,9 Abnormally high levels of certain enzymes have been found in the serum of patients with early clinical manifestations of the disease, and also in a significant number of persons who are carriers or potential carriers, as judged by family history. In some instances it has been possible to predict which child in the sibship containin~ dystrophic individuals will subsequently develop the condition. In the Duchenne type of muscular dystrophy the level of the serum enzyme, creatine phosphokinase, appears to be the most sensitive indicator of the disease. The average normal level for this enzyme is within the range of 2.0 units to 3.5 units per milliliter?' " In some early cases of muscular dystrophy vaIues up to several hundred units have been encountered. In a series studied by Walton,: the highest serum creatine kinase value recorded was 1,060 units per milliliter. Walton; considers it possible to identify shortly after birth those males who will later develop the clinical features of the disease. T h o u g h the source of the enzylne has not been fully established, it is thought to arise from the muscle tissue. There is preliminary evidence from a study of muscle preparations in vitro that a factor is present in the serum of patients with Dnchenne muscular dystrophy which accelerates the release of creatine phosphokinase from muscleY Little information has been available, however, to explain the wide variability in muscle change in relation to enzyme changes, and "it is not known in which portion of the nmscle fiber the initial dystrophic process is
September 1965
manifest."" In this connection, a recent publication by Emery ~ in the Journal of Medical Genetics is of interest. This author points out that though the studies of preclinical cases have demonstrated that definite histopathologic changes are present in the muscle before the onset of clinical weakness, "they have not been very helpful in determining the initial manifestation of the dystrophic process. ''~) The histopathologic changes are already well advanced even in young infants in the preelinical stage. With these facts in mind, Emery initiated a detailed study of the structural muscle changes to be seen in carriers of muscular dystrophy. Nine known carriers of Duchenne muscular dystrophy and 3 normal healthy control women were studied by muscle biopsy, and, at the same time, by enzyme estimation for ereatine kinase. A known carrier of sexlinked Duchenne muscular dystrophy is defined as a w o m a n who has at least 2 affected sons, or one affected son and a family history of other male relatives similarly affected, such as a brother or a maternal uncle. All individuals in the study were examined for evidence of muscle weakness. T w o of the 9 carriers showed definite evidence of weakness. Creatine kinase determinations were made on fresh serum samples. T h e microscopic structure of gastroenemius muscle was studied in 3 healthy women, who had no history of any neuromuscular disease, and in 9 carriers of muscular dystrophy. T h e carriers ranged in age from 29 to 55 years, and the 3 control women were 30, 40, and 48 years of age. All biopsy specimens were obtained from the belly of the muscle, and, in the controls, were taken during operations for ligation of varicose veins. In the carriers biopsy was obtained under local anesthesia. Special care was exercised in both the biopsy procedure and in subsequent fixation of the tissue in order to insure a good representative specimen and to avoid artifacts. Biopsy specimens were uniform in size, and were obtained with the muscle fibers running parallel to the long axis. During the course of the study, creatine kinase determinations were made several times on each subject.
Volume 67 Number 3
Methods of histologic study and the changes observed in the muscle are described by Emery 9 in detail: swollen fibers, hyaline change, fiber size variation, increase in nuclei, necrosis, etc. As might be anticipated, structural changes in the fibers were most marked in the 2 carriers who had shown muscle weakness. I n 2 of the 9 carriers there was minimal evidence of muscle abnormality. T h e earliest structural change appears to be swelling of the muscle fibers. However, all gradations were observed from apparently normal fibers in 2 carrier individuals to a markedly abnormal structural pattern in 2 of the carriers. These changes were correlated significantly with the serum levels of creatine kinase, the highest enzyme level occurring in a carrier w o m a n in whose muscle fibers every histologic change: considered as a criterion for analysis was observed. All of the findings in the control subjects were within normal limits. Emery concludes that histologic study of muscle biopsy specimens, together with the estimation of serum ereatine phosphokinase, can be of considerable value in carrier detection in Duchenne muscular dystrophy. As a possible explanation of the wide variability a m o n g carriers, Emery discusses the Lyon hypothesis concerning the action of the X-chromosome. This hypothesis, first formulated by Lyon ~~ in 1961, suggests that in a small proportion of the female cells, one X-chromosome m a y be partially inactivated. This inactivation occurs early in development, and possibly is associated with the formation of the chromatin body. Apparently either X-chromosome may be inactivated in different cells of the same individual, which gives rise to "patchiness" (groups of cells, some with one X-chromosome inactivated and some with the other X-chromosome inactivated). I n female mammals heterozygous for certain sex-linked coat color factors, a mottled spotty appearance can result. Likewise, in carriers heterozygous for the recessive sex-linked factor for D u c h e n n e muscular dystrophy, if the normal X-chromosome is partially inactivated in a few cells, the Xchromosome carrying the recessive gene for
C o m m e n t s on current literature
50 5
dystrophy would then have the opportunity for phenotypic expression, and such a situation could result in patchy muscle fiber degeneration. T h e proportion of these cells is thought to be small and variable, which could account for the fact that clinical evidence of muscle weakness is lacking in some carriers, but may be quite apparent in others. Detailed studies by various techniques of patients with pseudohypertrophic muscular dystrophy and their kinship are providing the physician and the scientist with a more rational approach to this well recognized, but poorly understood clinical syndrome. As more knowledge concerning the basic features of this disorder is accumulated, it seems reasonable to anticipate that effective preventive and therapeutic regimens will emerge. RUSSELL J. BLATTNER~ M.D.
REFERENCES
1. Dowben, R. M.: Treatment of muscular dystrophy with steroids: A preliminary report, New England J. Med. 268: 912, 1963. 2. Fowler, W. M., Jr., Pearson, C. M., Egstrom, G. H., and Gardner G. W.: Ineffective treatment of muscular dystrophy with an anabolic steroid and other measures, New England J. Med. 272: 875, 1965. 3. Heyck, H., Laudahn, G., Liiders, C. J., Mfiller-Stephann, H. and Schmidt-Peter, P.: Anabolie steroids and digitoxin in the treatment of progressive muscular dystrophy, Acta paediat, scandinav. 54: 205, 1965. 4. Pearson, C. M.: Histological features of the muscle in the preclinical stages of muscular dystrophy, Brain 85: 109, 1962; Muscular dystrophy: Review and recent developments, Am. J. Med. 35: 632, 1963. 5. Pennington, R. J. T.: Biochemical aspects of muscle disease, in Walton, John N., editor: Disorders of voluntary muscle, Boston, 1964, Little, Brown & Company, chap. 10, p. 255. 6. Pearce, J. M. S., Pennington, R. J. T., and Walton, J. N.: Serum enzyme studies in muscle disease. I I I : Serum creatine kinase activity in relatives of patients with Duchenne type of muscular dystrophy, J. Neurol., Neurosurg., & Psychiat. 27" 181, 1964. 7. Walton, John N.: Some diseases of muscle, Lancet 1: 447, 1964; Muscular dystrophy: Some recent advances in knowledge, Brit. M. J. 1: 1344, 1964; Disorders of voluntary muscle, Boston, 1964, Little, Brown & Company. 8. Sugita, Hideo, and Tyler, Frank M. : Pathogenesis of muscular dystrophy, Tr. A. Am. Physicians 76: 231, 1963. 9. Emery, A. E. H.: Clinical manifestations in
506
C o m m e n t s on current literature'
two carriers of Duchenne muscular dystrophy, Lancet 1: 1126, 1963; Muscle histology in carriers of Duchenne muscular dystrophy, J. Med. Genet. 2: 1, 1965. I0. Lyon, M. F.: Gene action in the X-chromo-
September 1965
some of the mouse (Mus musculus L.), Nature 190: 372, t961; Sex chromatin and gene action in the mammalian X-chromosome, Am. J. H u m a n Genet. 14: 135, 1962.