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Congenital myopathy with ringlike distribution of myonuclei and mitochondria and accumulation of nemaline rods. A variant of centronuclear myopathy?
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ELSEVIER
Congenital Myopathy With Ringlike Distribution of Myonuclei and Mitochondria and Accumulation of Nemaline Rods. A Variant of Centronuclear Myopathy? Andrew J. Waclawik, MD, Terence S. Edgar, MD, Barend P. Lotz, MD, Paul Lewandoski, BS, and Robert S. Rust, MD Itistopathologic and ultrastructural findings in a muscle biopsy performed on an l 1-year old boy with congenital hypotonia, weakness, respiratory insufficiency requiring chronic ventilatory support, and a probable X.linked inheritance are presented. The muscle biopsy disclosed a peculiar, ringlike arrangement of mitochondria and myonuclei in most muscle fibers. Accumulations of nemaline rods were present in approxi. mately 10-15% of fibers. We believe that our patient represents a variant of myotubular/centronuciear myopathy. The histocbemicai findings suggest disturbance in developmental migration of nuclei and mito. chondria probably due to impaired function of the cytoskeleton.
From the Department of Neurology and Neuromuscular Service; University o f Wisconsin Medical School; Madison, Wisconsin.
370 PEDIATRIC NEUROLOGY
Vol. 12 No. 4
Waclawik AJ, Edgar TS, Lotz BP, Lewandoski P, Rust RS. Congenital myopathy with ringlike distribution of myonuclei and mitochondria and accumulation of nemaline rods. A variant of centronuclear myopathy? Pediatr Neurol 1995;12:370-373.
Introduction The clinical and morphologic findings in congenital myopathies are frequently nonspecific. It is the predominance of 1 characteristic light microscopic or ultrastructural finding, in combination with clinical features, that permits classification of a given case into one of the established nosologic entities. Myonuclear/centronuclear [ 1] and nemaline rod [2] myopathies have been recognized on both clinical and histochemical grounds as separate myopathies. We report peculiar histochemical and ultrastructural findings in a patient with a congenital myopathy, who exhibited clinicopathologic features consistent with the diagnosis of centronuclear myopathy. The muscle biopsy also disclosed accumulation of nemaline rods in 1015% of muscle fibers.
Case Report The patient, an 11-year-old boy referred for reevaluation of chronic hypotonia, was born at term weighing 2,968 gm. Fetal movements were observed from the 16th week of pregnancy but were never robust. No parental consanguinity was reported. Labor was uncomplicated, but at delivery he was weak, responded poorly, and had Apgar scores of 1 at 1 rain and 4 at 5 rain. Hypotonia and weakness with poor oropharyngeal function persisted throughout the neonatal period and he required tube feeding until 15 months of age. At age 3 months the child underwent initial muscle biopsy from the biceps muscle. Reviewed 11 years later, the histochemically stained tissue was technically suboptimal but displayed prominent type 1 fiber atrophy and preponderance. The oxidative enzyme stains disclosed strongest reactions in central regions in a majority of fibers with decrease of reaction intensity at the periphery. Approximately 30-50% of nuclei were positioned centrally. There was no muscle fiber necrosis or regeneration. The connective tissue elements were unremarkable. The patient's subsequent motor development was markedly delayed, although he achieved independent ambulation. At age 8 years he was hospitalized with respiratory failure probably caused by adenovirus infection. A tracheostomy was performed and he received ventilatory support. Subsequent to that hospitalization he was no longer able to walk independently. Examination at age 11 years disclosed a high arched palate, malocclusion of teeth, and large hands with small fingers. Mental status was normal. Cranial nerve examination disclosed diminished extraocular eye movements and prominent biracial weakness. Muscle bulk
Communications should be addressed to: Dr. Waclawik; Department of Neurology, Neuromuscular Service; University of Wisconsin Hospital and Clinics; Clinical Science Center H6/574; 600 Highland Avenue; Madison, WI 53792. Received November 18, 1994; accepted March 15, 1995.
© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 SSDI 0887-8994(95)00060-S
was diminished with profound hypotonia and severe generalized weakness. There was no myotonia. Upper extremity strength was in the range of 3/5 proximally (Medical Research Council scale) and 4/5 distally. Proximal strength in the legs was 1-2/5 and the distal muscles were graded 3-4/5. Sensation was normal. Tendon reflexes were depressed. Severe scoliosis required a spinal fusion at age 11 years during which the second muscle biopsy was performed. Family history (Fig 1) was positive for a maternal stepbrother who was hypotonic at birth and died of respiratory failure at age 2V2 months. Another male child on the mother's side was very weak and hypotonic at birth and died of respiratory failure in the early neonatal period.
Pathology A muscle biopsy specimen was obtained from the thoracic paraspinal muscle. The specimen was snap frozen in isopentane chilled to - 150"(2 and later in liquid nitrogen. Frozen sections, 6 gm thick, were processed for hematoxylin and eosin, modified Gomori trichrome, NADH and succinic dehydrogenases, cytochrome c oxidase, cytochrome c reductase, adenosinetriphosphatnse after preincubation at pH 4.3, 4.6, and 9.4, acid pliosphatase, periodic acid-Schiff, oil Red O, and nonspecific esterase. For immunocytochemistry the sections were stained with monoclonal antibodies against desmin (Dako, 1:50), et-actinin (Sigma, 1:25), and against the N terminal, C terminal, and rod portion of the dystrophin molecule (Novocastra 1:20, 1:8, 1:4, respectively). For electron microscopy the muscle was fixed in 5% glutaraldehyde in 0.1 moi/L sodium cacodylate (pH 7.4) and postfixed in 2% osmium tetroxide. Sections 1 Izm thick were stained with toluidine blue for survey by light microscopy, and thin sections from selected areas were examined with an electron microscope after staining with lead citrate and uranyl acetate. Light microscopic examination disclosed muscle fibers ranging from 25-50 pan in diameter with a few fibers as small as 8 Izm (average fiber diameter at age 11 years is - 3 5 p.m). There was a marked preponderance of histochemically type 1 fibers (>90%). The nuclei in most muscle fibers were positioned in a ringlike zone at a distance of about 3-7 ~,m from the sarcolemma (Fig 2A), and only very few nuclei were located in the very center of the muscle fibers. Fibers with aberrant myofibrils were not observed. No necrotic or regenerating fibers were found. Inflammatory changes were absent. There was a mild increase in endomysial fibrous and a marked increase in perimysial fibrous and fatty connective tissue. There was a peculiar and consistent distribution of oxidative enzymes in more than 90% of fibers: in the center, the enzyme activity was normal or mildly decreased, while at the periphery there was a ringlike zone of marked overreactivity followed by a halo of relatively
• []
Hypotoniaand death in early infancydue to respiratoryfailure Patient
Figure 1. Pedigree of the family.
decreased enzyme activity (Fig 2B). The same pattern was observed in NADH, succmic dehydrogenase, cytochrome c oxidnse, and cytochrome c reductase stains. The ring of increased oxidative enzyme activity corresponded to a circular zone of red-staining membranous material seen in the trichrome sections (Fig 2A). R appeared that both mitochondria and nuclei were "trapped" in the same zone. In about 10-15% of fibers, nemaline rods were observed in the central regions (Fig 2C,D). The muscle fiber lipid and glycogen contents were normal. Immunostalning against the N terminal, C terminal, and rod portion of the dystrophin molecule disclosed normal distribution of dystrophin in subsarcolemmal regions. The intensity of the immtmostain against desmin was not increased as compared to controls. Some rods stained positively for desmin and few rods reacted for a-actinin. The dominant ultrastructurai abnormality was the presence of multiple nemaline rods in the central regions in approximately 10% of fibers (Fig 3). In most fibers, even in those without nemaline rods, the mitochondria appeared morphologically normal, were diminished in number in the central regions, but appeared to accumulate in the same ringlike zone as was seen on light microscopic examination of frozen and 1-1zm-thick plastic embedded sections. The sarcolemma and sarcotubular elements were normal. There was focal loss or disorganization of contractile illaments where nemaline rods were abundant. The nuclei appeared structurally normal and were seen in the same ringlike zone as the mitochondria.
Discussion The clinical presentation, probable X-linked recessive inheritance, and pathologic f'mdings, especially the internalization of nuclei and preponderance of type 1 fibers in our patient, are consistent with the diagnosis of a myotubular myopathy. There are, however, several unusual morphologic features. The prominent accumulation of nemaline rods in a patient with myotubular/centronuclear myopathy has not previously been described. Nemaline rods, which represent one of the Z disk anomalies [3], have been reported as an associated finding in a variety of myopathies [4]. In children, the nemaline rods are frequently associated with type 1 preponderance and atrophy. Some authors have used this observation to hypothesize neurogenic etiology of at least some cases of nemaline rod myopathy [5]. The rod accumulation in our patient may represent a secondary change or a parallel process resulting from impairment of fetal muscle innervation. We emphasize that the nemaline rods were not the dominant morphologic abnormality in our patient. Mitochondria were seen in the same ringlike zone as the myonuclei, within a few microns from the sarcolemma, suggesting that the migration of cellular organelles from the center to the periphery, which normally occurs during development, had arrested. Some investigators repeated small core formations in association with centronuclear myopathy [6]; however, the very regular, consistent pattern of mitochondrial abnormalities observed in oxidative enzyme stains and electron microscopy, indicates clearly that in our patient this was due to the redistribution of mitochondria rather than focal myofibriUar or mitochondrial loss. Also, the adenosinetriphosphatase-stained sections displayed no focal loss of enzyme activity as is observed in typical target or core formations. Whether myotubular myopathy represents a global delay in the maturation of muscle fibers (as was postulated
Waclawik et al: Congenital Myopathy 371
i~iil
<;
7
Figure2. Light micr•sc•py findings fr•m the paraspinal muscle. (A) Ringlike accumulati•n •f membra••us material (arr•wheads) with myonuclei positioned in the same zone (arrows). Modified Gomori trichrome, original magnification: x900. (B) Circular distribution of oxidative enzymes representing accumulation of mitochondria (arrows). NADH dehydrogenase, original magnification: xgO0. (C) and (D) Accumulation of nemaline rods (arrows). Modified Gomori trichrome, original magnification: xgO0 (6"); 1 p,m plastic embedded, toluidine blue stained section, original magnification: xl,300 (D).
by Spiro et al. [1] in his original description), or whether there is a more selective dysfunction such as an impaired function of the cytoskeleton leading to abnormal migration of nuclei to subsarcolemmal regions [7], has long been debated. In our patient, the myofibers, except for the abnormal position of the myonuclei and mitochondria, appeared histologically mature, supporting the notion that the basic abnormality is an impairment of the normal developmental migration of some organelles rather than a global maturational arrest. The observed constellation of ringlike distribution of nuclei, mitochondria, and accumulation of nemaline rods in this patient suggests that there is a defect in the function of the cytoskeleton that might lead to impaired developmental trafficking of the organelles. Desmin, a major component of intermediate filaments in skeletal muscle, may play a role in such a pathophysiologic mechanism. Intermediate filaments are fundamental units of the cy-
372
PEDIATRIC NEUROL(~Y
Vol. 12 No. 4
toskeleton. In skeletal muscle the desmin filaments are most important in keeping the Z disks in register. Nemaline rods may then originate from disintegrating Z lines if they are not properly aligned by intermediate filaments. However, we did not find any significant abnormality of desmin expression in our patient. Sarnat [8] documented overexpression of desmin and vimentin in patients with myotubular myopathy as well as in other congenital myopathies. This suggests that the intermediate filaments may indeed "hold" and prevent the nuclei and mitochondria from normal, developmental migration. It is possible that we did not see overexpression of desmin in our patient because he was older than the patients studied by Sarnat. Our patient also underscores the clinical, histochemical, and ultrastructural overlap between many congenital muscle diseases. Many of these diseases may have similar etiologies and only the identification of specific genetic defects will resolve the issue and lead to a logical classi-
techniques will enable more satisfactory diagnosis, classification, and management o f these patients.
This work was supported in part by University of Wisconsin Medical School, Department of Neurology R & D fund.
References
Figure 3. Accumulation of nemaline rods (arrows) in the muscle fiber. Electron microscopy, original magnification: x16,500. fication. Linkage analysis o f congenital X-linked myotubular myopathy suggests that the Xq28 locus is the site of the genetic defect in that disorder [9-11]. However, the gene has not been cloned and therefore nothing further is known about the nature o f the genetic abnormality. It is our hope that advances in molecular diagnostic
[1] Spiro AJ, Shy GM, Gonatas NK. Myombular myopathy. Persistence of fetal muscle in an adolescent boy. Arch Neurol 1966;14:1-14. [2] Shy GM, Engel WK, Sommers JE, Wanko T. Nemaline myopathy. A new congenital myopathy. Brain 1963;86:793-810. [3] Gonatas NK, Shy GM, Godfrey EH. Nemaline myopathy. The origin of nemaline structures. N Engl J Med 1966,274:535-9. [4] Engel AG, Banker BQ. Ultrastructuralchanges in diseased muscle. In: Engel AG, Franzini-AmstrongC, eds. Myology. 2nd ed. Vol 1. New York: McGraw-Hill, 1994:924-5. [5] Engel WK. Selective and nonselective susceptibility of muscle fiber types: A new approach to human neuromuscular diseases. Arch Neurol 1970;22:97-117. [6] Aflfi AK, Smith JW, Zellweger H. Congenital nonprogressive myopathy: Central core disease and nemaline myopathy in one family. Neurology 1965;15:371-81. [7] Sarnat HB, New insight into the pathogenesis of congenital myopathies. J Child Neurol 1994;9:193-201. [8] Sarnat HB. Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 1992;42:1616-24. [9] Darnfors C, B6rje Larsson HE, Oldfors A, et al. X-linked myotubular myopathy: A linkage study. Clin Genet 1990;37:335-40. [10] Lehesjoki AE, Sankila EM, Miao J, et al. X linked neonatal myotubular myopathy: One recombination detected with four polymorphic DNA markers from Xq28. J Med Genet 1990;27:288-91. [11] Thomas NST, Williams H, Cole G, et al. X linked neonatal centronuclear/myotubularmyopathy: Evidence for linkage to Xq28 DNA marker loci. J Med Genet 1990;27:284-7.
Waclawik et al: Congenital Myopathy 373
ELSEVIER
Congenital Myopathy With Ringlike Distribution of Myonuclei and Mitochondria and Accumulation of Nemaline Rods. A Variant of Centronuclear Myopathy? Andrew J. Waclawik, MD, Terence S. Edgar, MD, Barend P. Lotz, MD, Paul Lewandoski, BS, and Robert S. Rust, MD Itistopathologic and ultrastructural findings in a muscle biopsy performed on an l 1-year old boy with congenital hypotonia, weakness, respiratory insufficiency requiring chronic ventilatory support, and a probable X.linked inheritance are presented. The muscle biopsy disclosed a peculiar, ringlike arrangement of mitochondria and myonuclei in most muscle fibers. Accumulations of nemaline rods were present in approxi. mately 10-15% of fibers. We believe that our patient represents a variant of myotubular/centronuciear myopathy. The histocbemicai findings suggest disturbance in developmental migration of nuclei and mito. chondria probably due to impaired function of the cytoskeleton.
From the Department of Neurology and Neuromuscular Service; University o f Wisconsin Medical School; Madison, Wisconsin.
370 PEDIATRIC NEUROLOGY
Vol. 12 No. 4
Waclawik AJ, Edgar TS, Lotz BP, Lewandoski P, Rust RS. Congenital myopathy with ringlike distribution of myonuclei and mitochondria and accumulation of nemaline rods. A variant of centronuclear myopathy? Pediatr Neurol 1995;12:370-373.
Introduction The clinical and morphologic findings in congenital myopathies are frequently nonspecific. It is the predominance of 1 characteristic light microscopic or ultrastructural finding, in combination with clinical features, that permits classification of a given case into one of the established nosologic entities. Myonuclear/centronuclear [ 1] and nemaline rod [2] myopathies have been recognized on both clinical and histochemical grounds as separate myopathies. We report peculiar histochemical and ultrastructural findings in a patient with a congenital myopathy, who exhibited clinicopathologic features consistent with the diagnosis of centronuclear myopathy. The muscle biopsy also disclosed accumulation of nemaline rods in 1015% of muscle fibers.
Case Report The patient, an 11-year-old boy referred for reevaluation of chronic hypotonia, was born at term weighing 2,968 gm. Fetal movements were observed from the 16th week of pregnancy but were never robust. No parental consanguinity was reported. Labor was uncomplicated, but at delivery he was weak, responded poorly, and had Apgar scores of 1 at 1 rain and 4 at 5 rain. Hypotonia and weakness with poor oropharyngeal function persisted throughout the neonatal period and he required tube feeding until 15 months of age. At age 3 months the child underwent initial muscle biopsy from the biceps muscle. Reviewed 11 years later, the histochemically stained tissue was technically suboptimal but displayed prominent type 1 fiber atrophy and preponderance. The oxidative enzyme stains disclosed strongest reactions in central regions in a majority of fibers with decrease of reaction intensity at the periphery. Approximately 30-50% of nuclei were positioned centrally. There was no muscle fiber necrosis or regeneration. The connective tissue elements were unremarkable. The patient's subsequent motor development was markedly delayed, although he achieved independent ambulation. At age 8 years he was hospitalized with respiratory failure probably caused by adenovirus infection. A tracheostomy was performed and he received ventilatory support. Subsequent to that hospitalization he was no longer able to walk independently. Examination at age 11 years disclosed a high arched palate, malocclusion of teeth, and large hands with small fingers. Mental status was normal. Cranial nerve examination disclosed diminished extraocular eye movements and prominent biracial weakness. Muscle bulk
Communications should be addressed to: Dr. Waclawik; Department of Neurology, Neuromuscular Service; University of Wisconsin Hospital and Clinics; Clinical Science Center H6/574; 600 Highland Avenue; Madison, WI 53792. Received November 18, 1994; accepted March 15, 1995.
© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 SSDI 0887-8994(95)00060-S
was diminished with profound hypotonia and severe generalized weakness. There was no myotonia. Upper extremity strength was in the range of 3/5 proximally (Medical Research Council scale) and 4/5 distally. Proximal strength in the legs was 1-2/5 and the distal muscles were graded 3-4/5. Sensation was normal. Tendon reflexes were depressed. Severe scoliosis required a spinal fusion at age 11 years during which the second muscle biopsy was performed. Family history (Fig 1) was positive for a maternal stepbrother who was hypotonic at birth and died of respiratory failure at age 2V2 months. Another male child on the mother's side was very weak and hypotonic at birth and died of respiratory failure in the early neonatal period.
Pathology A muscle biopsy specimen was obtained from the thoracic paraspinal muscle. The specimen was snap frozen in isopentane chilled to - 150"(2 and later in liquid nitrogen. Frozen sections, 6 gm thick, were processed for hematoxylin and eosin, modified Gomori trichrome, NADH and succinic dehydrogenases, cytochrome c oxidase, cytochrome c reductase, adenosinetriphosphatnse after preincubation at pH 4.3, 4.6, and 9.4, acid pliosphatase, periodic acid-Schiff, oil Red O, and nonspecific esterase. For immunocytochemistry the sections were stained with monoclonal antibodies against desmin (Dako, 1:50), et-actinin (Sigma, 1:25), and against the N terminal, C terminal, and rod portion of the dystrophin molecule (Novocastra 1:20, 1:8, 1:4, respectively). For electron microscopy the muscle was fixed in 5% glutaraldehyde in 0.1 moi/L sodium cacodylate (pH 7.4) and postfixed in 2% osmium tetroxide. Sections 1 Izm thick were stained with toluidine blue for survey by light microscopy, and thin sections from selected areas were examined with an electron microscope after staining with lead citrate and uranyl acetate. Light microscopic examination disclosed muscle fibers ranging from 25-50 pan in diameter with a few fibers as small as 8 Izm (average fiber diameter at age 11 years is - 3 5 p.m). There was a marked preponderance of histochemically type 1 fibers (>90%). The nuclei in most muscle fibers were positioned in a ringlike zone at a distance of about 3-7 ~,m from the sarcolemma (Fig 2A), and only very few nuclei were located in the very center of the muscle fibers. Fibers with aberrant myofibrils were not observed. No necrotic or regenerating fibers were found. Inflammatory changes were absent. There was a mild increase in endomysial fibrous and a marked increase in perimysial fibrous and fatty connective tissue. There was a peculiar and consistent distribution of oxidative enzymes in more than 90% of fibers: in the center, the enzyme activity was normal or mildly decreased, while at the periphery there was a ringlike zone of marked overreactivity followed by a halo of relatively
• []
Hypotoniaand death in early infancydue to respiratoryfailure Patient
Figure 1. Pedigree of the family.
decreased enzyme activity (Fig 2B). The same pattern was observed in NADH, succmic dehydrogenase, cytochrome c oxidnse, and cytochrome c reductase stains. The ring of increased oxidative enzyme activity corresponded to a circular zone of red-staining membranous material seen in the trichrome sections (Fig 2A). R appeared that both mitochondria and nuclei were "trapped" in the same zone. In about 10-15% of fibers, nemaline rods were observed in the central regions (Fig 2C,D). The muscle fiber lipid and glycogen contents were normal. Immunostalning against the N terminal, C terminal, and rod portion of the dystrophin molecule disclosed normal distribution of dystrophin in subsarcolemmal regions. The intensity of the immtmostain against desmin was not increased as compared to controls. Some rods stained positively for desmin and few rods reacted for a-actinin. The dominant ultrastructurai abnormality was the presence of multiple nemaline rods in the central regions in approximately 10% of fibers (Fig 3). In most fibers, even in those without nemaline rods, the mitochondria appeared morphologically normal, were diminished in number in the central regions, but appeared to accumulate in the same ringlike zone as was seen on light microscopic examination of frozen and 1-1zm-thick plastic embedded sections. The sarcolemma and sarcotubular elements were normal. There was focal loss or disorganization of contractile illaments where nemaline rods were abundant. The nuclei appeared structurally normal and were seen in the same ringlike zone as the mitochondria.
Discussion The clinical presentation, probable X-linked recessive inheritance, and pathologic f'mdings, especially the internalization of nuclei and preponderance of type 1 fibers in our patient, are consistent with the diagnosis of a myotubular myopathy. There are, however, several unusual morphologic features. The prominent accumulation of nemaline rods in a patient with myotubular/centronuclear myopathy has not previously been described. Nemaline rods, which represent one of the Z disk anomalies [3], have been reported as an associated finding in a variety of myopathies [4]. In children, the nemaline rods are frequently associated with type 1 preponderance and atrophy. Some authors have used this observation to hypothesize neurogenic etiology of at least some cases of nemaline rod myopathy [5]. The rod accumulation in our patient may represent a secondary change or a parallel process resulting from impairment of fetal muscle innervation. We emphasize that the nemaline rods were not the dominant morphologic abnormality in our patient. Mitochondria were seen in the same ringlike zone as the myonuclei, within a few microns from the sarcolemma, suggesting that the migration of cellular organelles from the center to the periphery, which normally occurs during development, had arrested. Some investigators repeated small core formations in association with centronuclear myopathy [6]; however, the very regular, consistent pattern of mitochondrial abnormalities observed in oxidative enzyme stains and electron microscopy, indicates clearly that in our patient this was due to the redistribution of mitochondria rather than focal myofibriUar or mitochondrial loss. Also, the adenosinetriphosphatase-stained sections displayed no focal loss of enzyme activity as is observed in typical target or core formations. Whether myotubular myopathy represents a global delay in the maturation of muscle fibers (as was postulated
Waclawik et al: Congenital Myopathy 371
i~iil
<;
7
Figure2. Light micr•sc•py findings fr•m the paraspinal muscle. (A) Ringlike accumulati•n •f membra••us material (arr•wheads) with myonuclei positioned in the same zone (arrows). Modified Gomori trichrome, original magnification: x900. (B) Circular distribution of oxidative enzymes representing accumulation of mitochondria (arrows). NADH dehydrogenase, original magnification: xgO0. (C) and (D) Accumulation of nemaline rods (arrows). Modified Gomori trichrome, original magnification: xgO0 (6"); 1 p,m plastic embedded, toluidine blue stained section, original magnification: xl,300 (D).
by Spiro et al. [1] in his original description), or whether there is a more selective dysfunction such as an impaired function of the cytoskeleton leading to abnormal migration of nuclei to subsarcolemmal regions [7], has long been debated. In our patient, the myofibers, except for the abnormal position of the myonuclei and mitochondria, appeared histologically mature, supporting the notion that the basic abnormality is an impairment of the normal developmental migration of some organelles rather than a global maturational arrest. The observed constellation of ringlike distribution of nuclei, mitochondria, and accumulation of nemaline rods in this patient suggests that there is a defect in the function of the cytoskeleton that might lead to impaired developmental trafficking of the organelles. Desmin, a major component of intermediate filaments in skeletal muscle, may play a role in such a pathophysiologic mechanism. Intermediate filaments are fundamental units of the cy-
372
PEDIATRIC NEUROL(~Y
Vol. 12 No. 4
toskeleton. In skeletal muscle the desmin filaments are most important in keeping the Z disks in register. Nemaline rods may then originate from disintegrating Z lines if they are not properly aligned by intermediate filaments. However, we did not find any significant abnormality of desmin expression in our patient. Sarnat [8] documented overexpression of desmin and vimentin in patients with myotubular myopathy as well as in other congenital myopathies. This suggests that the intermediate filaments may indeed "hold" and prevent the nuclei and mitochondria from normal, developmental migration. It is possible that we did not see overexpression of desmin in our patient because he was older than the patients studied by Sarnat. Our patient also underscores the clinical, histochemical, and ultrastructural overlap between many congenital muscle diseases. Many of these diseases may have similar etiologies and only the identification of specific genetic defects will resolve the issue and lead to a logical classi-
techniques will enable more satisfactory diagnosis, classification, and management o f these patients.
This work was supported in part by University of Wisconsin Medical School, Department of Neurology R & D fund.
References
Figure 3. Accumulation of nemaline rods (arrows) in the muscle fiber. Electron microscopy, original magnification: x16,500. fication. Linkage analysis o f congenital X-linked myotubular myopathy suggests that the Xq28 locus is the site of the genetic defect in that disorder [9-11]. However, the gene has not been cloned and therefore nothing further is known about the nature o f the genetic abnormality. It is our hope that advances in molecular diagnostic
[1] Spiro AJ, Shy GM, Gonatas NK. Myombular myopathy. Persistence of fetal muscle in an adolescent boy. Arch Neurol 1966;14:1-14. [2] Shy GM, Engel WK, Sommers JE, Wanko T. Nemaline myopathy. A new congenital myopathy. Brain 1963;86:793-810. [3] Gonatas NK, Shy GM, Godfrey EH. Nemaline myopathy. The origin of nemaline structures. N Engl J Med 1966,274:535-9. [4] Engel AG, Banker BQ. Ultrastructuralchanges in diseased muscle. In: Engel AG, Franzini-AmstrongC, eds. Myology. 2nd ed. Vol 1. New York: McGraw-Hill, 1994:924-5. [5] Engel WK. Selective and nonselective susceptibility of muscle fiber types: A new approach to human neuromuscular diseases. Arch Neurol 1970;22:97-117. [6] Aflfi AK, Smith JW, Zellweger H. Congenital nonprogressive myopathy: Central core disease and nemaline myopathy in one family. Neurology 1965;15:371-81. [7] Sarnat HB, New insight into the pathogenesis of congenital myopathies. J Child Neurol 1994;9:193-201. [8] Sarnat HB. Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 1992;42:1616-24. [9] Darnfors C, B6rje Larsson HE, Oldfors A, et al. X-linked myotubular myopathy: A linkage study. Clin Genet 1990;37:335-40. [10] Lehesjoki AE, Sankila EM, Miao J, et al. X linked neonatal myotubular myopathy: One recombination detected with four polymorphic DNA markers from Xq28. J Med Genet 1990;27:288-91. [11] Thomas NST, Williams H, Cole G, et al. X linked neonatal centronuclear/myotubularmyopathy: Evidence for linkage to Xq28 DNA marker loci. J Med Genet 1990;27:284-7.
Waclawik et al: Congenital Myopathy 373