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Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case report
Brain & Development 20 (1998) 112–115
Case report
Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case report Yukino Itakura a ,*, Yunosuke Ogawa a, Nobuyuki Murakami b, Ikuya Nonaka b a
b
Department of Pediatrics, Saitama Medical Center, Saitama Medical School, 1981 Tsujido, Kamoda, Kawagoe, Saitama 350, Japan Departments of Laboratory Medicine and Ultrastructural Research, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi-cho, Kodaira, Tokyo 187, Japan Received 5 March 1997; revised version received 21 September 1997; accepted 25 October 1997
Abstract A Japanese boy had marked generalized hypotonia and weakness and progressive respiratory failure since birth. Left biceps brachii muscle biopsy at 47 days of age showed marked variation in muscle fiber size, and nemaline and/or cytoplasmic bodies in approximately 10% of the muscle fibers. To our knowledge, the presence of nemaline and cytoplasmic bodies in the same muscle has not been previously reported. The severity of his respiratory failure and muscle weakness were thought to be related to muscle immaturity since there were many undifferentiated type 2C fibers. 1998 Elsevier Science B.V. Keywords: Nemaline body; Cytoplasmic body; Congenital myopathy; Severe infantile form
1. Introduction
2. Case report
Nemaline myopathy was first described by Shy et al. in 1963 [1] as a congenital non-progressive muscle disease characterized by the presence of rod-like structures in skeletal muscle fibers. However, in 1967 Shafiq et al. [2], and subsequently others, described patients with severe muscle weakness from birth and poor prognosis [3–5]. Cytoplasmic body myopathy is also one of the congenital myopathies in which there are cytoplasmic bodies in muscle fibers. Cytoplasmic body formation itself is not a specific abnormality and is seen in muscles from patients with a variety of neuromuscular diseases, such as chronic muscular dystrophies, myotonic dystrophy and inflammatory myopathies [6]. However, the coexistence of cytoplasmic and nemaline bodies in the same patient have not been reported in any of the congenital myopathies. We report a patient with severe congenital myopathy with both nemaline and cytoplasmic bodies.
The patient was the first male of twins. His parents, two elder brothers and a younger sister had no muscle symptom. His fetal movements were weaker than that of his twin sister. He was born at 38 weeks’ gestation by normal vaginal delivery and weighed 3022 g. Apgar scores were 8 and 9 at 1 and 5 min after birth. He developed inspiratory wheezes and had poor muscle activity so that he was transferred to our NICU 8 h after birth. On admission, he was hypotonic and could not lift his arms and legs against gravity. Deep tendon reflexes were absent but there were no pathological reflexes. He could not close his mouth and he had a high arched palate. Because of his poor suck, he had to be fed through a nasogastric tube. Chest X-ray revealed pneumonia, and oxygen and intravenous antibiotics were begun. Though serum acute phase reactants were not elevated, mild wheezing and increased secretions in the respiratory tracts persisted. Supplemental oxygen was discontinued on day 10. Over the next month he exhibited intermittent cyanosis and continuous oxygen supplementation was reinstituted. Serum creatine kinase, aldolase and amino acids were nor-
* Corresponding author. Fax +81 492 26 1424.
0387-7604/98/$19.00 1998 Elsevier Science B.V. All rights reserved PII S0387-7604 (97 )0 0100-9
Y. Itakura et al. / Brain & Developlment 20 (1998) 112–115
mal. Electromyogram (EMG) revealed low amplitude motor units with some fibrillation potential at rest. Electrocardiogram (ECG) was normal. He was placed on mechanical ventilation on day 53 because his PaCO2 exceeded 50 Torr. Respiratory insufficiency persisted and he required a tracheotomy at age 5 months. He smiled at age 2 months despite facial muscle weakness. He was able to move his limbs slightly against gravity and began to pick up small toys to play. He was still respirator-dependent at age 14 months when he was still unable to swallow and had not acquired head control.
3. Muscle biopsies Biopsy of the left biceps brachii muscle taken at 47 days showed marked variation in muscle fiber size which ranged from 2 to 30 mm in diameter. Although there were no necrotic muscle fibers, some basophilic fibers were scattered. Fibers with central nuclei were not increased in number. Modified Gomori trichrome stain revealed cytoplasmic bodies and nemaline bodies in approximately 10% of the fibers, and a few fibers had both (Fig. 1). The proportion of type 1, 2A, 2B and 2C fibers was 30%, 8%, 0% and 62%, respectively (Fig. 2). At the time of tracheostomy, a second biopsy was taken from the anterior cervical muscle. This showed marked variation in muscle fiber size, ranging from 10 to 80 mm in diameter. In sections with the modified Gomori trichrome stain almost all the fibers had nemaline bodies but there were no cytoplasmic bodies (Fig. 3). The proportion of type 1, 2A, 2B, and 2C fibers was 56%, 41%, 0% and 3%, respectively.
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Electron microscopy of the first biopsy showed nemaline bodies in approximately 10% of the fibers and these fibers showed severe myofibrillar disorganization. Fibers with both nemaline and cytoplasmic bodies were only rarely found (Fig. 4). Cytoplasmic bodies were round and had a thin pale halo and they were slightly less electron dense than the nemaline bodies. Neuromuscular junctions were not included in this biopsy.
4. Discussion Nemaline myopathy was originally described as a benign congenital non-progressive myopathy with muscle weakness and hypotonia from early infancy. However, some infants with nemaline bodies may have severe symptoms at birth leading to death in infancy [2–5]. Occasionally, symptoms may not appear until adult life. Nemaline myopathy, therefore, is classified into three types: (1) severe infantile, (2) benign congenital and (3) adult onset forms [7]. Our patient belongs to the severe infantile form because he had severe muscle weakness and hypotonia requiring tube feedings at birth with progressive respiratory failure. Except for a Japanese girl with the severe infantile form who survived beyond 5 years of age [8], most patients with this form of nemaline myopathy succumb to respiratory insufficiency by 2 years of age. The unusual findings in the muscle biopsy from our patient was the presence of both cytoplasmic and nemaline bodies in the same muscle fibers. We did not find cytoplasmic bodies in the second biopsy from the anterior cervical muscle. It is said that the proportion of muscle fibers with cytoplasmic or nemaline bodies is highly variable among different muscle groups [2].
Fig. 1. In some fascicles, almost all of the fibers have either cytoplasmic (arrow) or nemaline (arrowhead) bodies. Only a few fibers have both inclusion bodies (asterisk). There is marked variation in fiber size. Modified Gomori trichrome. ×900.
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Y. Itakura et al. / Brain & Development 20 (1998) 112–115
Fig. 2. Undifferentiated type 2C fibers (C) stained dark on routine ATPase (A) and ATPase with preincubation at pH 4.3 (B) are increased in number. Type 1 (1) fiber. (A,B) (serial sections), ×650.
Since the first patient with cytoplasmic bodies was reported by Nakashima et al. [9], there have been further reports of approximately 40 patients. Among them only two patients with what may be classified as the severe infantile form have been documented: a boy reported by Bertini et al. [10] died of respiratory failure at age 14 months, and a 6 year old girl reported by Mizuno et al. [11] who required respirator support from age 6 months.
The pathogenetic significance of nemaline or cytoplasmic body formation in the various diseases is unknown. There is no correlation between the proportion of muscle fibers with nemaline bodies and the clinical severity of nemaline myopathy [3]. In the severe infantile form the most likely explanation for the severe muscle weakness is the presence of many immature muscle fibers with fetal characteristics [3]. Since, normally, undifferentiated type 2C fibers constitute
Fig. 3. In the second biopsy, almost all of fibers have nemaline bodies but with no cytoplasmic body. Modified Gomori trichrome, ×900.
Y. Itakura et al. / Brain & Developlment 20 (1998) 112–115
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Fig. 4. A muscle fiber contains a cytoplasmic body (CB) and numerous nemaline bodies (arrow). The core region of the cytoplasmic body has high but less intense electron density than the nemaline bodies. Myofibrils are markedly disorganized. Bar, 1 mm.
less than 5% of muscle fibers in newborn infants, the increased numbers of type 2C fibers in our patient to 60% appear to indicate muscle fiber immaturity. Both nemaline and cytoplasmic bodies are thought to originate from Z-line protein since they are both electron dense by electron microscopy and are anti-alpha-actininpositive [12], but they have never been found together in patients with congenital myopathy. Further studies are necessary to determine whether our patient had nemaline myopathy with the coincidental association of cytoplasmic bodies or he had two different hereditary disorders.
References [1] Shy GM, Engel WK, Somers JE, Wanko T. Nemaline myopathy: a new congenital myopathy. Brain 1963;86:793–810. [2] Shafiq SA, Dubowitz V, Peterson HC, Milhorat AT. Nemaline myopathy: report of a fetal case, with histochemical and electron microscopic studies. Brain 1967;90:817–828. [3] Nonaka I, Tojo M, Sugita H. Fetal muscle characteristics in nemaline myopathy. Neuropediatrics 1983;14:47–52.
[4] Norton P, Ellison P, Sulaiman AR, Harb J. Nemaline myopathy in the neonate. Neurology 1983;33:351–356. [5] Rifai Z, Kazee AM, Kamp C, Griggs RC. Intranuclear rods in severe congenital nemaline myopathy. Neurology 1993;43:2372–2377. [6] Akiyama C, Sakuta R, Matsuoka T, Nonaka I. The significance of cytoplasmic body in neuromuscular diseases (in Japanese). Clin Neurol (Tokyo) 1993;33:278–281. [7] Martinez BA, Lake BD. Childhood nemaline myopathy: a review of clinical presentation in relation to prognosis. Dev Med Child Neurol 1987;29:815–820. [8] Tojo M, Sakuragawa N, Sugai K, Maeda K, Nonaka I. A survival child of severe nemaline myopathy (in Japanese). Neurol Med (Tokyo) 1989;30:53–60. [9] Nakashima N, Tamura Z, Okamoto S, Goto H. Inclusion bodies in human neuromuscular disorder. Arch Neurol 1970;22:270–278. [10] Bertini E, Ricci E, Boldrini R, et al. Involvement of respiratory muscles in cytoplasmic body myopathy – a pathological study. Brain Dev 1990;12:798–806. [11] Mizuno Y, Nakamura Y, Komiya K. The spectrum of cytoplasmic body myopathy: report of a congenital severe case. Brain Dev 1989;11:20–25. [12] Fukuhara N, Inoue Y, Yoshimura N, Sugita H, Ii K. Histochemical, immunohistochemical and electron microscopic study on cytoplasmic body (in Japanese). Clin Neurol (Tokyo) 1987;27:1713.
Case report
Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case report Yukino Itakura a ,*, Yunosuke Ogawa a, Nobuyuki Murakami b, Ikuya Nonaka b a
b
Department of Pediatrics, Saitama Medical Center, Saitama Medical School, 1981 Tsujido, Kamoda, Kawagoe, Saitama 350, Japan Departments of Laboratory Medicine and Ultrastructural Research, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi-cho, Kodaira, Tokyo 187, Japan Received 5 March 1997; revised version received 21 September 1997; accepted 25 October 1997
Abstract A Japanese boy had marked generalized hypotonia and weakness and progressive respiratory failure since birth. Left biceps brachii muscle biopsy at 47 days of age showed marked variation in muscle fiber size, and nemaline and/or cytoplasmic bodies in approximately 10% of the muscle fibers. To our knowledge, the presence of nemaline and cytoplasmic bodies in the same muscle has not been previously reported. The severity of his respiratory failure and muscle weakness were thought to be related to muscle immaturity since there were many undifferentiated type 2C fibers. 1998 Elsevier Science B.V. Keywords: Nemaline body; Cytoplasmic body; Congenital myopathy; Severe infantile form
1. Introduction
2. Case report
Nemaline myopathy was first described by Shy et al. in 1963 [1] as a congenital non-progressive muscle disease characterized by the presence of rod-like structures in skeletal muscle fibers. However, in 1967 Shafiq et al. [2], and subsequently others, described patients with severe muscle weakness from birth and poor prognosis [3–5]. Cytoplasmic body myopathy is also one of the congenital myopathies in which there are cytoplasmic bodies in muscle fibers. Cytoplasmic body formation itself is not a specific abnormality and is seen in muscles from patients with a variety of neuromuscular diseases, such as chronic muscular dystrophies, myotonic dystrophy and inflammatory myopathies [6]. However, the coexistence of cytoplasmic and nemaline bodies in the same patient have not been reported in any of the congenital myopathies. We report a patient with severe congenital myopathy with both nemaline and cytoplasmic bodies.
The patient was the first male of twins. His parents, two elder brothers and a younger sister had no muscle symptom. His fetal movements were weaker than that of his twin sister. He was born at 38 weeks’ gestation by normal vaginal delivery and weighed 3022 g. Apgar scores were 8 and 9 at 1 and 5 min after birth. He developed inspiratory wheezes and had poor muscle activity so that he was transferred to our NICU 8 h after birth. On admission, he was hypotonic and could not lift his arms and legs against gravity. Deep tendon reflexes were absent but there were no pathological reflexes. He could not close his mouth and he had a high arched palate. Because of his poor suck, he had to be fed through a nasogastric tube. Chest X-ray revealed pneumonia, and oxygen and intravenous antibiotics were begun. Though serum acute phase reactants were not elevated, mild wheezing and increased secretions in the respiratory tracts persisted. Supplemental oxygen was discontinued on day 10. Over the next month he exhibited intermittent cyanosis and continuous oxygen supplementation was reinstituted. Serum creatine kinase, aldolase and amino acids were nor-
* Corresponding author. Fax +81 492 26 1424.
0387-7604/98/$19.00 1998 Elsevier Science B.V. All rights reserved PII S0387-7604 (97 )0 0100-9
Y. Itakura et al. / Brain & Developlment 20 (1998) 112–115
mal. Electromyogram (EMG) revealed low amplitude motor units with some fibrillation potential at rest. Electrocardiogram (ECG) was normal. He was placed on mechanical ventilation on day 53 because his PaCO2 exceeded 50 Torr. Respiratory insufficiency persisted and he required a tracheotomy at age 5 months. He smiled at age 2 months despite facial muscle weakness. He was able to move his limbs slightly against gravity and began to pick up small toys to play. He was still respirator-dependent at age 14 months when he was still unable to swallow and had not acquired head control.
3. Muscle biopsies Biopsy of the left biceps brachii muscle taken at 47 days showed marked variation in muscle fiber size which ranged from 2 to 30 mm in diameter. Although there were no necrotic muscle fibers, some basophilic fibers were scattered. Fibers with central nuclei were not increased in number. Modified Gomori trichrome stain revealed cytoplasmic bodies and nemaline bodies in approximately 10% of the fibers, and a few fibers had both (Fig. 1). The proportion of type 1, 2A, 2B and 2C fibers was 30%, 8%, 0% and 62%, respectively (Fig. 2). At the time of tracheostomy, a second biopsy was taken from the anterior cervical muscle. This showed marked variation in muscle fiber size, ranging from 10 to 80 mm in diameter. In sections with the modified Gomori trichrome stain almost all the fibers had nemaline bodies but there were no cytoplasmic bodies (Fig. 3). The proportion of type 1, 2A, 2B, and 2C fibers was 56%, 41%, 0% and 3%, respectively.
113
Electron microscopy of the first biopsy showed nemaline bodies in approximately 10% of the fibers and these fibers showed severe myofibrillar disorganization. Fibers with both nemaline and cytoplasmic bodies were only rarely found (Fig. 4). Cytoplasmic bodies were round and had a thin pale halo and they were slightly less electron dense than the nemaline bodies. Neuromuscular junctions were not included in this biopsy.
4. Discussion Nemaline myopathy was originally described as a benign congenital non-progressive myopathy with muscle weakness and hypotonia from early infancy. However, some infants with nemaline bodies may have severe symptoms at birth leading to death in infancy [2–5]. Occasionally, symptoms may not appear until adult life. Nemaline myopathy, therefore, is classified into three types: (1) severe infantile, (2) benign congenital and (3) adult onset forms [7]. Our patient belongs to the severe infantile form because he had severe muscle weakness and hypotonia requiring tube feedings at birth with progressive respiratory failure. Except for a Japanese girl with the severe infantile form who survived beyond 5 years of age [8], most patients with this form of nemaline myopathy succumb to respiratory insufficiency by 2 years of age. The unusual findings in the muscle biopsy from our patient was the presence of both cytoplasmic and nemaline bodies in the same muscle fibers. We did not find cytoplasmic bodies in the second biopsy from the anterior cervical muscle. It is said that the proportion of muscle fibers with cytoplasmic or nemaline bodies is highly variable among different muscle groups [2].
Fig. 1. In some fascicles, almost all of the fibers have either cytoplasmic (arrow) or nemaline (arrowhead) bodies. Only a few fibers have both inclusion bodies (asterisk). There is marked variation in fiber size. Modified Gomori trichrome. ×900.
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Y. Itakura et al. / Brain & Development 20 (1998) 112–115
Fig. 2. Undifferentiated type 2C fibers (C) stained dark on routine ATPase (A) and ATPase with preincubation at pH 4.3 (B) are increased in number. Type 1 (1) fiber. (A,B) (serial sections), ×650.
Since the first patient with cytoplasmic bodies was reported by Nakashima et al. [9], there have been further reports of approximately 40 patients. Among them only two patients with what may be classified as the severe infantile form have been documented: a boy reported by Bertini et al. [10] died of respiratory failure at age 14 months, and a 6 year old girl reported by Mizuno et al. [11] who required respirator support from age 6 months.
The pathogenetic significance of nemaline or cytoplasmic body formation in the various diseases is unknown. There is no correlation between the proportion of muscle fibers with nemaline bodies and the clinical severity of nemaline myopathy [3]. In the severe infantile form the most likely explanation for the severe muscle weakness is the presence of many immature muscle fibers with fetal characteristics [3]. Since, normally, undifferentiated type 2C fibers constitute
Fig. 3. In the second biopsy, almost all of fibers have nemaline bodies but with no cytoplasmic body. Modified Gomori trichrome, ×900.
Y. Itakura et al. / Brain & Developlment 20 (1998) 112–115
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Fig. 4. A muscle fiber contains a cytoplasmic body (CB) and numerous nemaline bodies (arrow). The core region of the cytoplasmic body has high but less intense electron density than the nemaline bodies. Myofibrils are markedly disorganized. Bar, 1 mm.
less than 5% of muscle fibers in newborn infants, the increased numbers of type 2C fibers in our patient to 60% appear to indicate muscle fiber immaturity. Both nemaline and cytoplasmic bodies are thought to originate from Z-line protein since they are both electron dense by electron microscopy and are anti-alpha-actininpositive [12], but they have never been found together in patients with congenital myopathy. Further studies are necessary to determine whether our patient had nemaline myopathy with the coincidental association of cytoplasmic bodies or he had two different hereditary disorders.
References [1] Shy GM, Engel WK, Somers JE, Wanko T. Nemaline myopathy: a new congenital myopathy. Brain 1963;86:793–810. [2] Shafiq SA, Dubowitz V, Peterson HC, Milhorat AT. Nemaline myopathy: report of a fetal case, with histochemical and electron microscopic studies. Brain 1967;90:817–828. [3] Nonaka I, Tojo M, Sugita H. Fetal muscle characteristics in nemaline myopathy. Neuropediatrics 1983;14:47–52.
[4] Norton P, Ellison P, Sulaiman AR, Harb J. Nemaline myopathy in the neonate. Neurology 1983;33:351–356. [5] Rifai Z, Kazee AM, Kamp C, Griggs RC. Intranuclear rods in severe congenital nemaline myopathy. Neurology 1993;43:2372–2377. [6] Akiyama C, Sakuta R, Matsuoka T, Nonaka I. The significance of cytoplasmic body in neuromuscular diseases (in Japanese). Clin Neurol (Tokyo) 1993;33:278–281. [7] Martinez BA, Lake BD. Childhood nemaline myopathy: a review of clinical presentation in relation to prognosis. Dev Med Child Neurol 1987;29:815–820. [8] Tojo M, Sakuragawa N, Sugai K, Maeda K, Nonaka I. A survival child of severe nemaline myopathy (in Japanese). Neurol Med (Tokyo) 1989;30:53–60. [9] Nakashima N, Tamura Z, Okamoto S, Goto H. Inclusion bodies in human neuromuscular disorder. Arch Neurol 1970;22:270–278. [10] Bertini E, Ricci E, Boldrini R, et al. Involvement of respiratory muscles in cytoplasmic body myopathy – a pathological study. Brain Dev 1990;12:798–806. [11] Mizuno Y, Nakamura Y, Komiya K. The spectrum of cytoplasmic body myopathy: report of a congenital severe case. Brain Dev 1989;11:20–25. [12] Fukuhara N, Inoue Y, Yoshimura N, Sugita H, Ii K. Histochemical, immunohistochemical and electron microscopic study on cytoplasmic body (in Japanese). Clin Neurol (Tokyo) 1987;27:1713.