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Muscle Disorders
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Killer Activity of TG Cells from Children with Myasthenia Gravis
Comparative Muscle Histochemistry between Fukuyama Type Congenital Muscular Dystrophy (FCMD) and Duchenne Muscular Dystrophy (DMD)
Noriaki Shinomiya, MD, Kazue Honda, MD, Yoshiko Nomura, MD, and Masaya Segawa, MD Segawa Neurologic Clinic for Children, Tokyo (NS, KH, YN, MS); Department of Pediatrics, Tokyo Medical and Dental University, Tokyo (NS)
Autoantibody against choline receptors has no doubt important role in the pathogenesis of myasthenia gravis (MG). In order to disclose the mechanism of the receptor injury and the possible abnormalities of immunoregulatory system in MG, the killer activities of TG cells (T-cells bearing receptors for Fc portion of IgG) from childhood MG patients were examined. Methods The peripheral blood lymphocytes were isolated by density gradients. T-cells and non T-cells were separated from each other by rosette formation with sheep erythrocytes. TG cells were separated from T-cells by their loss of the ability to form rosettes with sheep erythrocytes after treatment with theophyllin. TG cells were tested for their ability to lyse the target cells. Three cytotoxicity tests were separated by several variables, including target cell, source of antibody and source of complement. Natural killer (NK) activity, antibody dependent T-cell mediated cytotoxicity (ADCC) activity and immune complexes dependent T-cell mediated cytostasis (IDTC) activity were examined. Results NK activity in the patients in early stage of the disease was not decreased whereas in some of advanced stage this activity was decreased. ADCC activity was as active in MG patients as in the normal individuals. IDTC activity was active in early stage and fluctuated in the course of the disease. This cytotoxicity seemed to be induced by immune complexes. Conclusion Activation by immune complexes of TG cells would be important in controlling the cytotoxicic activity of TG cells. TG cells in the presence of immune complexes showed the active IDTC activity whereas NK activity and ADCC activity were blocked with immune complexes. The cytotoxicity caused by immune complexes and TG cells observed in MG patients may play some roles in receptor injury especially in chronic changes of tissue. Key words: Childhood myasthenia gravis, natural killer activity, ADCC activity, IDTC activity, immune complex.
/kuya Nonaka, MD and Kuniyasu Takada, MD Division of Neuromuscular Research, National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo
The muscle histology in FCMD is closely mimicking to that of DMD including active muscle fiber degeneration and regeneration, variation in fiber size and interstitial fibrosis. However clinical symptoms differ in many aspects; patients with FCMD are always mentally retarded in association with occasional febrile or afebrile convulsions. Furthermore a hypothesis of intrauterine infection affecting both central nervous system (CNS) and muscles has been recently proposed. To examine how the CNS factor influences upon the muscles and whether the infectious evidence exists in the muscles, a histological and histochemical study on biopsied muscles was attempted in eight younger patients with FCMD. The histochemical results were also compared with those of 10 DMD patients. In both FCMD and DMD, there were a significant variation in fiber size, scattered necrotic fibers with acid phosphatase positive phagocytes, regenerating fibers with alkaline phosphatase activity and opaque fibers. On histochemical examination on FCMD muscles, both type 1 and 2 fibers were distributed in checkerboard pattern without fiber type grouping or group atrophy. Type 1 fiber predominance was recognized in three and 2B fiber deficiency in six of eight cases. There were numerous type 2C fibers in FCMD (average 25.75% of total fibers) and DMD (15.71%). With GBHA, alizarin red, and von Kossa methods, scattered throughout were fibers with calcium positive reaction in both dystrophies. The present study represented no apparent evidence of neural or infectious process involving the skeletal muscles. Fiber type distribution in FCMD did not significantly differ from that of DMD except for relatively large number of type 2C fibers in the former. A recently proposed hypothesis in muscle fiber necrosis of DMD is as follows; an excess calcium accumulation in the muscle fibers through the defect membranes may activate a certain proteases such as calcium-activated neutral protease which initiate alpha-actinin release from the Z-line and troponin digestion leading final muscle fiber degeneration. A similar pathogenetic mechanism might take place in FCMD because of quantitative similarity in histological and histochemical fmdings in both dystrophies. Key words: Fukuyama type congenital muscular dystrophy, muscle biopsy, muscle histochemistry, Duchenne muscular dystrophy.
238 Brain & Development, Vol 3, No 2,1981
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Clinical Study of Congenital Muscular Dystrophy (Fukuyama Type)
Comparative Pathological Studies on Muscles from Myotonic Dystrophy in Infancy, Childhood and Adulthood
Michiko Hayashi, MD, Yutaka A waya, MD, Hiroko Iwamoto, MD, Kazuhiko Komiya, MD, and Nobuko Misugi,MD Departments of Pediatric Neurology (MH, YA, HI, KK) and Orthopedics (NM), Kanagawa Children's Medical Center, Yokohama, Kanagawa
We studied 28 patients with congenital muscular dystrophy of Fukuyama type (FCMD), admitted to Kanagawa Children's Medical Center during 19661973. Clinical picture of FCMD: Characterized by 1) early onset, 2) generalized muscle weakness, 3) facial involvement, 4) mental retardation, 5) joint contructure, 6) elevated serum CPK, 7) EMG showing low amplitude and short duration, 8) muscle biopsy fmdings consisting from variation in fiber size, proliferated connective tissue and extensive fibrosis. We classified 28 patients into two groups: the group I consists of 6 cases who have been able to walk, and the group 2 consists of 22 cases who have never walked. The comparison between group I and group 2 was summarized as follows. Number of cases Sibling cases Prenatal abnormality Perinatal abnormality Minor and major anomalies Convulsion EEG abnormality Abnormal CT (PEG) Mental retardation Joint contructure Facial involvement Tubular structure in muscle biopsy
Group 1
Group 2
6 2
22 2 50% 40% 45% 36% 32% 9/10 (4/5) 100% 100% 100% 4 cases
17% 17% 1/3 100% 100% 100% 1 case
Conclusion
The grade of mental retardation and motor disability was more severe in the group 2 than in the group 1, and history of pre- or perinatal abnormalities was found only in the group 2.
Key words: Fukuyama type congenital muscular dystrophy, facial involvement, mental retardation, joint contructure.
Nobuko Misugi, MD and Kazuaki Misugi, MD Departments of Orthopedics (NM) and Pathology (KM), Yokohama City University, School of Medicine, Yokohama, Kanagawa; Department of Orthopedics, Kanagawa Children's Medical Center, Yokohama, Kanagawa (NM)
Many reports concerning histopathological studies of myotonic dystrophy of the neonate and the adult have been published. However, those in childhood are not available. In an attempt to study the morphological changes by ages, the muscle biopsies from an infant, 5 school children and 5 adults were examined by light microscopy (LM), histochemistry and electron microscopy (EM).
Findings
(a) In adult, all 5 cases demonstrated marked irregularity of the muscle fiber size, central nuclei, fiber splitting, ring fibers and type 1 atrophy with type 1 predominance without exception. Two cases demonstrated ragged red fibers by LM and accumulation of abnormal mitochondria. One case showed nemaline bodies. (b) In an infant case, LM showed no remarkable abnormality. Histochemical studies demonstrated type 1 atrophy with type 1 predominance in minimal degree. EM showed rim of homogeneous area beneath the sarcolemma due to disappearance of the Ipyofllaments and mitochondria. (c) In childhood cases, LM was unremarkable except for one case which showed irregularity of the fiber size. This case (Case 2) had been treated with leg brace for club foot. Histochemical study showed type 2 atrophy with type 2 predominance in 3 cases. TYpe 1 atrophy with type 2 predominance was observed in one case. The other (Case 2) showed type 1 atrophy with type 1 predominance as observed in the adult cases. EM showed accumulation of abnormal mitochondria beneath the sarcolemma and cytoplasmic bodies.
Consideration
Childhood cases demonstrated reverse or different histochemical fmdings as compared with the adult cases. But EM fmdings of childhood cases were similar to the adult cases. It is difficult to draw conclusion from the study on the limited number of cases. However it is speCUlated that the childhood cases showed changing pattern of histochemical characteristics and transitional ultrastructural forms from the neonate to the adult. The findings of a child (Case 2) which showed adult type fmdings may be due to immobilization secondary to application of leg brace for a long period. IDtrastructures of abnormal mitochondria show many similar features as reported in ocular myopathies. This observation in adult cases suggest that myotonic dystrophy is multisystemic metabolic disorder.
Key words: Myotonic dystrophy in infancy and childhood, type 1 fiber atrophy, muscle histochemistry, muscle electron microscopy. Brain & Development, Vol 3, No 2,1981 239
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Malocclusion in Duchenne Muscular Dystrophy and Its Pathology
Two Autopsied Cases of Fukuyama Type Congenital Muscular Dystrophy, with Particular Reference to Morphometric Analysis of the Anterior Spinal Roots
Sanji Miyoshino, MD, Hiroaki Kan, MD, and Koji Shigenaga, MD Department of Pediatrics, Nishibeppu Hospital, Beppu, Ohita (SM, HK); Shinbeppu Hospital (An Association of National Public Official), Beppu, Ohita (KS) Facial muscle involvement is well recognized in facioscapulo-humeral muscular dystrophy and in congenital muscular dystrophy of Fukuyama type, whereas this abnormality is less pronounced in Duchenne muscular dystrophy (DMD). In advanced stage of DMD, however, several facial muscles including masseter are involved and this abnormality results in clinical feature of open bite expression. The present studies were performed in DMD patients as follows: (1) epidemiologic survey of open bite expression in nationwide scale, (2) clinical characterization of bite expression and X-ray examination of mandible, (3) histological examination of masseter, digastrics and temporal muscles at autopsy. Results obtained: (1) open bite expression was found in 34% of the patients, (2) frontal angle of mandible was more wide in the patients, (3) dystrophic changes were severe in masseter but mild in digastrics in patients with open bite expression. In patients without this expression dystrophic changes were mild and similar both in masseter and digastrics.
Key words: Duchenne muscular dystrophy, malocclusion, open bite expression, masseter muscle pathology.
Kuniyasu Takada, MD, Ikuya Nonaka, MD, Kei Shioda, MD, Takako Hasebe, MD, and Chieko Takada, MD National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo (KT, IN); Department of Pathology, Saitama Medical School, Moroyama, Saitama (KS); Tokyo Infant Recuperation Hospital, Musashi-Murayama, Tokyo (TH, CT) Most of over a dozen autosied cases with Fukuyama type congenital muscular dystrophy (FCMD) revealed hypoplastic or heterotopic corticospinal tracts, and cerebral as well as cerebellar micropolygyria. In order to clarify whether the abnormal corticospinal tracts would be responsible in producing the muscular lesions either directly or indirectly, we examined the anterior and posterior spinal roots with morphometric analysis. Two autopsied cases with typical clinical features of FCMD, who died at the age of 2 years and 1 year 11 months respectively, were subjected for pathologic evaluation. Resin-embedded transverse sections of the anterior and posterior spinal roots at L3 were photographed at the final magnification of 1,000 times to count numbers and measure diameter of myelinated fibers and compared with controls (Chou and Nonaka, 1978). Nerve teasing method was also applied. Both cases demonstrated typical neuropathologic changes with FCMD, including cerebral and cerebellar micropolygyria, focal fusion of frontal lobes, diffuse pallor of centrum semiovale and marked diminution of the corticospinal tracts. Total numbers of myelinated fibers in the anterior spinal roots were 5,750 and 6,873 respectively, while those of controls were ranging from 4,194 to 5,848. The diameter histogram of the myelinated fibers represented bimodal distribution with peaks at 4}.Lm and 6-7 }.Lm, which were essentially similar to those of controls. Teased nerves were unremarkable with no evidence of demyelination. The myelinated fibers in the posterior spinal roots in FCMD and controls showed no significant difference both in numbers and in diameter profIle. In cases with FCMD, the anterior and posterior spinal roots were intact. The present findings were quite different from those of so-called neurogenic muscular atrophies, such as Werdnig-Hoffmann disease. Though there were notable hypoplastic corticospinal tracts in FCMD, muscle involvement might be resulted from degenerative process in muscle itself, but not from central as well as peripheral nervous system abnormality.
Reference Chou SM, Nonaka I. Werdnig-Hoffmann disease: proposal of a pathogenetic mechanism. Acta Neuropathol (Bert) 1978;41:45-54. Key words: Fukuyama type congenital muscular dystrophy, corticospinal tracts, anterior spinal roots, morphometric analysis. 240 Brain & Development, Vol 3, No 2,1981
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Three Cases of Congenital Muscular Dystrophy with Cardiac Malformations
An Autopsy Case of Duchenne Type Muscular Dystrophy with Congenital Adrenal Hypoplasia
Kenji Nihei, MD, Haruko Naitoh, MD, Nobuhiko Koizumi, MD, and Sadayuki Suzuki, MD Department of Neurology, National Children's Hos· pital, Tokyo
Congenital muscular dystrophy (Fukuyama type) (FCMD) are well known to be associated with abnormalities of the CNS such as micropolygyria or hydrocephaly. We reported 3 cases of FCMD with congenital heart disease. Case 1 (5-year-old boy): He was delivered normally with a birth weight of 3,750 g. Being floppy from birth with motor retardation he has been unable to stand by himself till now. There was no convulsion but mental retardation with impairment of facial muscles, contraction of the knee joint and muscular hypotonia. He had an elevated serum CPK level of 1,418 IV/ml. Marked dystrophic change of the biopsied muscle was observed. The cranial CT scan showed decreased resorption in the white matter of the brain with enlargement of the fourth ventricle. Systolic murmurs were audible in the chest. Cardiac catheterization, together with other findings, led to the diagnosis of VSD. Case 2 (22-month-old female): Her mother took a medicine for a common cold she had at 4 months of pregnancy. The patient was delivered at 39 weeks of gestation, with birth weight of 2,050 g. Being floppy from birth with motor retardation, she has been unable to control her head. Serum CPK level elevated to 2,440 IV/ml. There was generalized cyanosis. A diagnosis of tetralogy of Fallot was made by a cardiologist. Case 3 (5-year-old boy): He was delivered normally at 40 weeks with a birth weight of 3,945 g. Being floppy from birth, he had motor retardation but nontheless was able to walk at age 2. Serum CPK level slightly elevated. Cardiac catheterization and other procedures led to the diagnosis of double chamber of RVand VSD. Patients with congenital heart disease often present with muscular hypotonia similar to that seen in myopathy but never have an elevated serum CPK level or degenerative change in muscle tissue. However, the cases presented here were considered to be suffered from FCMD associated with congenital heart disease. This may be a significant fact in estimating the pathogenesis of CMD.
Teruko Toyofuku, MD, Sachio Takashima, MD, Hiroshi Nagafuji, MD, and Taketoshi Watanabe, MD Division of Child Neurology, Tottori University, School of Medicine, Yonago, Tottori (TT, ST); Tenri Hospital, Tenri, Nara (HN); Matsue Red Cross Hospital, Matsue, Shimane (TW) An autopsy case of Duchenne muscular dystrophy associated with uncommon congenital adrenal hypoplasia was reported. There was no consanguinity. He had a healthy elder sister, and affected elder brother with the similar symptoms and laboratory fmdings who died at 3 years 7 months. He was born at a full-term pregnancy and uneventful delivery. He had episodic vomitings shortly after birth and admitted to the Matsue Red Cross Hospital because of feeding difficulty, weight loss and decreased activity at 23 days. On admission, the physical examination revealed mild dehydration and brown pigmentation of the skin but no abnormalities of external genitalia. Laboratory examination showed serum potassium of 7.5, sodium 116 mEq/L and markedly elevated serum enzyme activities (GOT 205 U, CPK 2220 IV, LDH 3400 U). There were 0.2 mg of 17-KS, 0.8 mg of 17-0HCS and 0.25 IJ.g of aldosterone in a 24 hour-urine sample. Serum ACTH was 661 pg/dl, /3-MSH 1085 pg/dl, angiotensin 2000 U. Adrenocortical insufficiency was treated with glucocorticoid and mineral corticoid. Subsequently his general conditon and serum electrolytes were improved but CPK, LDH and GOT activities were not. At the age of 9 months adrenal scintigram revealed absence of bilateral adrenal glands. Muscle biopsy showed myopathic changes consistent with the fmdings of Duchenne muscular dystrophy. He walked at 14 months with waddling iait and was able to stand up by Gowers' maneuver. He showed prominence of calves. Since he was placed on insufficient medication for a week, he developed generalized convulsions, unconsciousness and apneic spells, died at the age of 3 years 5 months. The pathological examination showed adrenal hypoplasia, muscular dystrophy and ischemic-hypoxic brain damage. Key words: Duchenne muscular dystrophy, congenital adrenal hypoplasia.
Key words: Congenital muscular dystrophy, floppy infant, congenital heart disease.
Brain & Development, Vol 3, No 2,1981 241
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An Autopsy Case of Fatal Neonatal Nemaline Myopathy
A Case of Ullrich Syndrome with Congenital Fiber Type Disproportion
Chieko Shimomura, MD, Masaaki Yoshimoto, MD, Yoshio Nakashita, MD, Yoshinobu Watanabe, MD, Akiyuki Ogawa, MD, and Mitsuhiro Tsugihata, MD Departments of Pediatrics (CS, MY, YN, YW, AO) and Internal Medicine (MT), Nagasaki University, School of Medicine, Nagasaki In 1963, Shy et al. first described congenital nemaline myopathy. The most common manifestation of the disease is a non-progressive myopathy. We will report a patient with fatal neonatal nemaline myopathy who had more severe involvement than those previously described.
Case Report The patient, a girl, was born prematurely at 37 weeks of gestation. There was no family history of neuromuscular disease. She had high-arched palate, ear deformity, and arachnodactyly. There was no spontaneous motor activity. No Moro or sucking reflex was present, and deep tendon reflexes were absent. She could not be weaned from the ventilator. She died at five months of age. Rectus femoris muscle biopsy was performed at the third month of age. The routine ATPase reaction differentiated two major fiber types. The type I fiber was smaller than type 2 fiber. In the diaphragm many rods were identified. And these rods had a periodicity. Discussion Neuromuscular disease may be Ii cause of respiratory insufficiency in the neonatal period. Reports of severe cases of nemaline myopathy are rare and were described by McComb et a1. Presence of type I fiber atrophy may suggest that this case had other disease such as congenital fiber type disproportion. But, many rods were identified, and we diagnosed this case as a case of fatal neonatal nemaline myopathy. Key words: Nemaline myopathy, type 1 fiber atrophy, congenital fiber type disproportion.
Hideo Tamari, MD, Yoshinobu Otani, MD, Makoto Matsukura, MD, Yoshihiro Origuchi, MD, Ichiro Matsuda, MD, and Sanji Miyoshino, MD Department of Pediatrics, Kumamoto University, School of Medicine, Kumamoto (HT, YO, MM, YO, 1M); Nishibeppu National Hospital, Beppu, Ohita (SM)
A 2-year-6-month-old Japanese boy with Ullrich syndrome was described. His major clinical findings were distal dominant generalized muscle weakness and atrophy, acroatonia, contracture of hip joint, scoliosis, areflexia, high arched palate, prominent calcaneus, soft and elastic skin. These were comparable to Ullrich syndrome (Die Kongenitale atonisch-sklerotische Muskeldystrophie Typ Ullrich, 1930). Creatine phosphokinase was 184 IU/l (normal less than 200 IU/l). Motor nerve conduction velocity of the right peroneal nerve was normal (54 m/sec). Electromyographic examination of his left tibialis anterior muscle revealed neurogenic pattern of high amplitude potentials of 4 mY. Pathological finding of the muscle biopsy obtained from right quadriceps revealed: 1) an increase in endomysia! connective tissue, 2) variation in the size of muscle fiber diameter, 3) degenerative and regenerative fibers stained with hematoxylin-eosin and Gomori's trichrome. A histographic analysis was performed by measuring 400 fibers stained with myofibrillar ATPase reaction. They were categorized as type I, lIA, lIB and lIC according to Brooke's method. Proportion and diameter of each fiber were as follow; type I (63%, 24.1 /.I), type lIA (15%, 28.7/.1), type lIB (19%, 29.9/.1) and type lIC (3%, 23.0/.1). These results indicated type I fiber hypotrophy. Occasionally type grouping was seen. Observed results revealed that there were findings of congenital muscular dystrophy accompanying with fiber type disproportion and also neurogenic involvement in the present case. We presumed that these features were the results of fetal developmental disorder rather than of primary nerve or muscle origin.
Key words: Ullrich syndrome, congenital fiber type disproportion, acroatonia, hypotonia.
242 Brain & Development, Vol 3, No 2,1981
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An Unusual Mitochondrial Myopathy with Mental Retardation and Dwarfism
A Case of Congenital Myopathy with Moebius Syndrome and Pulmonaly Stenosis
Osamu Fujino, MD, Kiyoshi Hashimoto, MD, Miho Maeda,MD,IkuyaNonaka,MD Department of Pediatrics, Nippon Medical School Hospital, Tokyo (OF, KH, MM); National Center for Nervous, Mental, and Muscular Disorders, Kodaira, Tokyo (IN)
An 8-year-old girl was born with an uneventful delivery
after 32 weeks gestation and birth weight was 2,400 g. She was the third child to related parents in the nfth degree. The eldest sister was similarly affected and died of accident at 7 years. She was a floppy infant and slowly gained body weight because of poor sucking. Congenital hip dislocation was noted at 5 months. Her motor milestones were delayed and she learned to walk at 3 years though with unsteady gait. On examination at the age of 7 years 3 months, she was 103 cm in height (below -3 SD) and 17 kg in weight (-1.5 SD). She had mild lordosis and moderate proximal muscle weakness with Gowers' sign and waddling gait. Tendon jerks were decreased and there were no pathological reflexes. Cranial nerves and sensation were intact. She was mentally retarded with IQ score of below 39. The routine urinalysis, blood chemistry, hematological examinations and bone survey by X-ray were within normal limits. Serum CPK level was 62 mU/ml (5-60). EMG showed myopathic pattern and motor nerve conduction velocity was normal. The biopsied left biceps brachii muscle represented a moderate variation in fiber size with slight increase in perimysial and endomysial connective tissue. On ATPase stain, type 1 fibers were predominant in numbers (57.9%) whereas type 2B fibers were scant (9%). With modified Gomori trichrome stain, both type 1 and 2 fibers contained scattered red granular materials, predominantly in the peripheral regions of muscle fibers. Although the materials were stained in dark with NADH-TR and MAG, they differed from those in "ragged-red" fibers where mitochondria were usually aggregated in the subsarcolemmal zones. Electron microscopy also conllrmed abnormal mitochondria with complicated cristae measuring up to 3 microns in dimension, though there was little change in myofibrils. Since a sister of the patient had had the similar symptoms of muscle weakness, mental retardation and dwarf and parents were in blood relative, the disorder seems to be genetically determined. Scattered, but increased number of large mitochondria in the muscle fiber may responsible in producing muscle weakness. Further study must be necessary to clarify whether mitochondrial abnormality is multisystemic involving not only the skeletal muscle but the central nervous system.
Masutomo Miyao, MD, Kunio Kaneshi, MD, Yoshikuni Beppu, MD, and Kazuhiko Hirose, MD Departments of Pediatrics (MM, KK) and Neurology (YB, KH), Tokyo Metropolitan Hospital of Fuchu, Fuchu, Tokyo
The syndrome of congenital facial diplegia associated with extraocular muscle paralysis, described by Moebius in 1888, and recent evidence suggests that some cases of Moebius syndrome may be due to progressive diseases of muscle, anterior hom cell, or peripheral nerve. Recently the relation between the Moebius syndrome and muscle disease has attracted notice. Case Report A 7-year-old boy was admitted in March 1979 because of facial paralysis and weakness of muscle power. He has no family history. He was born at term, but mother felt decreased fetal movement in prenatal period. In neonatal period, he was unable to suck from a bottle and was nourished by tube. His right half chest was concaved and didn't move fully. Sometimes he had cyanosis which necessitated oxygen inhalation. Soon after birth, a high pitched cry, lack of facial expression, and hypotonic posture were noted. He sat alone at 1 year, walked at 3 years. Physical Examination He was unable to move the forehead muscles, nor able to close the eyes and mouth. The posture was lordotic, the gait moderately slow. There was marked weakness and wasting of all shoulder and pelvic muscles. Deep tendon reflexes were normal. On Wechsler scale, he attained a IQ of 80. Routine studies including serum GOT, GPT, LDH, CPK, creatine were normal. EMG revealed myogenic pattern in the right orbital orbicularis and biceps muscles. On ECG IRBBB pattern was noticed but no low voltage was found. Chest X-ray showed an elevation of diaphragma of the right side. Muscle biopsy: Myogenic pattern. Summary A patient with Moebius syndrome, pulmonaly stenosis and the paralysis of right diaphragma was described. Facial diplegia in this case was based on nonprogressive myopathy of an uncertain nature. Key words: Congenital myopathy, pulmonaly stenosis, Moebius syndrome.
Key words: Mitochondrial myopathy, dwarfism, mental retardation, muscle histochemistry.
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Muscle Pathology of Perifascicular Atrophy in Childhood Type Dermatomyositis
Clinical Study on Cases with Infantile Acute Myoglohinwia
Teruhisa Miike, MD and Samuel M, Chou, MD, PhD Department of Neuropathology, West Virginia University Medical Center, Morgantown, WV, USA
Childhood dermatomyositis is a distinctive clinicopathologic entity. Myofiber damage in childhood dermatomyositis has been considered secondary to ischemia due to a capillary lesion. While a high serum CPK level is one of the diagnostic feature in dermatomyositis. High serum levels of muscle enzymes have been explained on basis of the "leaky membrane" theory in DMD. This work advocates an alternative site of leakage for muscle enzymes, as demonstrated in six cases of childhood dermatomyositis, at the triads where the transverse or T-tubules and the terminal cisternae are closely opposed. In addition the number of capillaries around individual myofibers was counted in 3 cases of relatively normal cases. Materials and Methods Biopsied muscles were prefixed with glutaraldehyde. Postfixation with osmium tetraoxide was performed simultaneously with lanthanum staining. Ultrathin sections cut with an LKB ultratome, stained with uranyl acetate and lead citrate, as well as semiultrathin sections (0.25 It thick) without staining were studied with an AEI (Corinth 275) electron microscope. For study of capillary beds in perifascicular and centrofascicular myofibers a 3, 3', 4, 4', diaminobenzidine (DAB) method (Adams IC. Neuroscience 1977;2:141) was devised to visualize RBCs in capillaries and types of myofibers simultaneously. Results The consistent abnormalities are tubular system (TS) -sarcoplasmic reticulum (SR) anastomosis as visualized by lanthanum stainin.s. Conical dilatations at the junctional sites between the extracellular and intracellular spaces progress to become spheroidal before they presumably rupture and disappear in severely degenerated myofibers. T-tubules aggregates in honeycomb forms suggestive of a repair process are seen at the junctional sites. The number of capillaries surrounding an individual myofiber is significantly less in the perifascicular than in the centrofascicular zone. The mean numbers of capillaries shared by the perifascicular myofibers range from 2.4 to 2.6 and the number for centrofascicular myofibers is 3.4 to 3.6. Conclusion TS-SR anastomoses was proposed to be the anatomical correlate for leakage of muscle enzymes as well as degraded structural protein molecules. Relative paucity of the capillary bed in perifascicular zone is one of the causes of the perifascicular muscle atrophy in' childhood dermatomyositis. Key words: Muscle enzyme leakage, childhood dermatomyositis, tubular system-sarcoplasmic reticulum anastomosis, perifascicular myofiber atrophy.
244 Brain & Development, Vol 3, No 2, 1981
Tsunesaburo Ando, MD, Tomoyoshi Kato, MD, Tsutomu Ohtani, MD, Yutaka Nishimura, MD, Shigeru Nagaki, MD, Yoko Sugie, MD, Hideo Sugie, MD, Tomoko Goto, MD, Keiko Shishikura, MD, and Yukio Fukuyama, MD Department of Pediatrics, Nagoya Daini Red Cross Hospital, Nagoya, Aichi (TA, TK); Toyohashi Municipal Hospital, Toyohashi, Aichi (TO, YN); Department of Pediatrics, Tokyo Women's Medical College, Tokyo (SN, YS, HS, TG, KS, YF)
Twelve cases of infantile acute myoglobinuria (grossly brown urine) were studied as to underlying conditions, predisposing factors, complications and prognosis. Subjects and Methods The patients, 9 male and 3 female, ranged in age from 7 months to 14 years. There were 5 cases of so-called idiopathic paroxysmal myoglobinuria secondary to infections, 4 cases of myoglobinuria associated with acute encephalopathy including Reye syndrome, 2 cases of malignant hyperthermia and a case of myohemoglobinuria associated with burns. Myoglobin (Mb) determinations were carried out by counterimmunoelectrophoresis or radioimmunoassay. Results Of the 5 patients with idiopathic paroxysmal myoglobinuria, 3 patients had cerebral paralysis of the rigospastic type and 1 had congenital muscular dystrophy as underlying conditions. Lipid storage myopathy was suspected in 1 of the cases of malignant hyperthermia. As predisposing factors, upper respiratory tract infections were noted in 7 cases and measles in 2 cases, thus suggesting a possible relation of viral infections to the development of myoglobinuria. Seven of the 12 patients studied had renal disorders complicating the condition, of whom 3 have died. Marked elevation of serum enzyme activity, such as CPK and GOT, was observed during the acute phase. Conclusion Acute myoglobinuria of children is unexpectedly high in incidence and the review of the cases have revealed that it developed often secondarily to infections of the upper respiratory tract in children with neuromuscular disorders as underlying conditions. It has also been noted that, in acute myoglobinuria, there was a high incidence of complication by renal disorders, frequently with an unfavorable prognosis. All these findings stress importance of recognition, early detection and early treatment of the condition. Key words: Myoglobinuria, acute renal failure, idiopathic paroxysmal myoglobinuria, acute encephalopathy.
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Spinal Cord Lesions in Scapuloperoneal Muscular Atrophy with Cardiomyopathy
Serum CK Isoenzyme in Children with Nervous System Disorders
Hideaki Kudo, MD, Sadayuki Yano, MD, Masayoshi Yanagisawa, MD, and Shigehiko Kamoshita, MD Department ofPediatrics, lichi Medical School, School of Medicine, Tochigi Although the scapuloperoneal muscular atrophy is a group of heterogeneous diseases, one of them, which was originally described by Emery and Dreifuss in 1966, seems to be a definite disease entity. All the patients reported as this entity were male, and showed the joint contracture at elbow, ancle, and neck in early childhood. The weakness of scapuloperoneal muscles appeared in early childhood, and was slowly progressive. Cardiac conduction abnormalities appeared later. Muscle biopsy studies and EMG findings of this disease showed both neurogenic and myopathic characteristics. While the clinical case reports were not very rare, the pathological studies of the spinal cord were described only in two cases, and their observation were not conclusive. We have had an opportunity to study the spinal cord of another case of the disease. Clinical and pathological findings of the case were already reported last year. Specimens were taken from every segment from the first cervical to the fourth sacral cord, 8 micron paraffin sections were stained with H&E, Kluver-Barrera, Bodian, and Holzer methods. Neurons in the anterior and lateral horns of each segment were classified into 3 groups, normal, subnormal, and degenerated. Thus classified neurons were plotted diagrammatically on a sheet, and axonal degenerations on Bodian stains were added to it. Focal neuronal degenerations were obvious, and the most severely affected segments were C s ' C6 , C 7 , Ls and S,. In these segments, only a few normal neurons were remained. The sites of the lesion seemed to correspond well with the affected muscles. In addition, the neurons in the lateral horn of thoracic segments showed central chromatolysis. These observations indicate a definite involvement of spinal motor neurons in scapuloperoveal muscular atrophy with cardiomyopathy.
Shigeru Kimura, MD and Yukinao Takebe, MD Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori Serum creatine kinase (CK) and its isoenzyme activities were studied in 97 children with CNS and/or neuromuscular disorders. CK isoenzyme was studied by the fiuorometric-electrophoretic method. The following results were obtained. 1. Increased CK activity was observed in epilepsy with recent convulsion especially under 4 years of age, in Kugelberg-Welander disease, and in other chronic brain damage with convulsion. 2. CK-BB (brain type) was detected in 2 cases with epileptic encephalopathy (Le., West syndrome and focal seizure following West syndrome), 3 cases with severely multiple handicapped children (MHC) due to cerebral palsy, 2 cases with other chronic brain damage (Le., progressive encephalopathy and ceroid lipofuscinosis), and 2 cases with intracranial hemorrhage. Four of 9 CK-BB positive children with CNS disorders died within 4 months after this CK isoenzyme study was done. It was elucidate in the present study that positive serum CK-BB can be useful index of extensive severe brain damage with poor prognosis in children with CNS disorders. The number of cases with CNS and/or neuromuscular disorders were as follows: epilepsy 21, febrile convulsion 10, MHC 24, Duchenne muscular dystrophy 19, congenital muscular dystrophy 5, neurogenic muscular atrophy 6, other chronic brain damage 8 (TaySachs disease 1, hyperphenylalaninemia 1, progressive encephalopathy of unknown origin 1, infantile metachromatic leucodystrophy 1, SSPE 1, spinocerebellar degeneration 1, neuronal ceroid lipofuscinosis 1, Menkes kinky hair disease 1), and acute brain damage 4 (acute encephalopathy-Lyon 1, intracranial hemorrhage 2, uremic coma 1).
Key words: CK-BB, CK isoenzyme, children with neurological disorders.
Key words: Scapuloperoneal muscular atrophy, Emery-Dreifuss muscular dystrophy, cardiomyopathy, spinal cord.
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176 A Case of Periodic Paralysis with Persistent Elevation of CPK Values
Tomoaki Nagaura, MD, Kiyoomi Sumi, MD, liro Abe, MD, Hiroshi Shimizu, MD, Yukiko Onoue, MD, Hyakuji Yabuuchi, MD, Emiko Senba, MD, and Sigeo Hashimoto, MD Department of Pediatrics, Osaka Welfare Pension Hospital, Osaka (TN, KS); Department of Pediatrics, Osaka University Hospital, Osaka (lA, HS, YO, HY); The Second Department of Pathology, Kinki University Hospital, Osaka (ES, SH) There are few reports about the persistent elevation of CPK values and pathologic changes of peripheral nerve in periodic paralysis. The patient had been in good health until age 12, when he suddenly felt a severe weakness oflower limbs and found himself unable to stand up and walk for a few days, but this episode disappeared spontaneously. Since then, he experienced several episodes once a few months, but he could enjoy playing tennis every day. He was admitted to our hospital 7 months after the onset. The physical examination was not remarkable. Muscle wasting of the pelvic girdle and lower limbs was not present. The neurological examination revealed hypoactive patellar reflex. The values of the serum CPK and aldolase were markedly and persistently elevated. There were no abnormalities in the values of serum electrolytes, GOT, LDH, lactate, pyruvate, renin, aldosterone and blood gas. Thyroid function was normal. Provocation tests were unsuccessful with OGTT and glucose-insulin combined methods. The serum potassium levels were found to decrease to 3.4 mEq/1 at attack. The potassium in erythrocytes showed low level compared to normal values, but these values of the patient further fell down remarkably during an attack. We examined biopsy samples of peroneus brevis muscle and sural nerve histologically. The muscle demonstra ted slight hypo trophic type I fibers and angulated fibers. Fiber necrosis, vacuolation and cell infiltration did not exist. On electron microscopy, slight dilatation of t-tubules and some membranelimited vacuoles communicated with several t-tubules were the additional findings. The sural nerve showed slight decrease of large size myelinated fibers in semithin transverse section. Electron microscopic findings were the swelling of cytoplasma in some Schwann cells surrounding myelinated fibers and denuded axons. Frequency of attack decreased gradually with the oral administration of potassium chloride and acetazolamide, though this case was supposed to be an atypical type of hypokalemic periodic paralysis. Moreover, the values of serum CPK were normalized by steroid therapy (predonine 1 mg/kg) and then the attack disappeared.
Key words: Periodic paralysis, serum CPK, hypotrophic type I fiber, denuded axon.
246 Brain & Development, Vo13;No 2,1981
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Killer Activity of TG Cells from Children with Myasthenia Gravis
Comparative Muscle Histochemistry between Fukuyama Type Congenital Muscular Dystrophy (FCMD) and Duchenne Muscular Dystrophy (DMD)
Noriaki Shinomiya, MD, Kazue Honda, MD, Yoshiko Nomura, MD, and Masaya Segawa, MD Segawa Neurologic Clinic for Children, Tokyo (NS, KH, YN, MS); Department of Pediatrics, Tokyo Medical and Dental University, Tokyo (NS)
Autoantibody against choline receptors has no doubt important role in the pathogenesis of myasthenia gravis (MG). In order to disclose the mechanism of the receptor injury and the possible abnormalities of immunoregulatory system in MG, the killer activities of TG cells (T-cells bearing receptors for Fc portion of IgG) from childhood MG patients were examined. Methods The peripheral blood lymphocytes were isolated by density gradients. T-cells and non T-cells were separated from each other by rosette formation with sheep erythrocytes. TG cells were separated from T-cells by their loss of the ability to form rosettes with sheep erythrocytes after treatment with theophyllin. TG cells were tested for their ability to lyse the target cells. Three cytotoxicity tests were separated by several variables, including target cell, source of antibody and source of complement. Natural killer (NK) activity, antibody dependent T-cell mediated cytotoxicity (ADCC) activity and immune complexes dependent T-cell mediated cytostasis (IDTC) activity were examined. Results NK activity in the patients in early stage of the disease was not decreased whereas in some of advanced stage this activity was decreased. ADCC activity was as active in MG patients as in the normal individuals. IDTC activity was active in early stage and fluctuated in the course of the disease. This cytotoxicity seemed to be induced by immune complexes. Conclusion Activation by immune complexes of TG cells would be important in controlling the cytotoxicic activity of TG cells. TG cells in the presence of immune complexes showed the active IDTC activity whereas NK activity and ADCC activity were blocked with immune complexes. The cytotoxicity caused by immune complexes and TG cells observed in MG patients may play some roles in receptor injury especially in chronic changes of tissue. Key words: Childhood myasthenia gravis, natural killer activity, ADCC activity, IDTC activity, immune complex.
/kuya Nonaka, MD and Kuniyasu Takada, MD Division of Neuromuscular Research, National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo
The muscle histology in FCMD is closely mimicking to that of DMD including active muscle fiber degeneration and regeneration, variation in fiber size and interstitial fibrosis. However clinical symptoms differ in many aspects; patients with FCMD are always mentally retarded in association with occasional febrile or afebrile convulsions. Furthermore a hypothesis of intrauterine infection affecting both central nervous system (CNS) and muscles has been recently proposed. To examine how the CNS factor influences upon the muscles and whether the infectious evidence exists in the muscles, a histological and histochemical study on biopsied muscles was attempted in eight younger patients with FCMD. The histochemical results were also compared with those of 10 DMD patients. In both FCMD and DMD, there were a significant variation in fiber size, scattered necrotic fibers with acid phosphatase positive phagocytes, regenerating fibers with alkaline phosphatase activity and opaque fibers. On histochemical examination on FCMD muscles, both type 1 and 2 fibers were distributed in checkerboard pattern without fiber type grouping or group atrophy. Type 1 fiber predominance was recognized in three and 2B fiber deficiency in six of eight cases. There were numerous type 2C fibers in FCMD (average 25.75% of total fibers) and DMD (15.71%). With GBHA, alizarin red, and von Kossa methods, scattered throughout were fibers with calcium positive reaction in both dystrophies. The present study represented no apparent evidence of neural or infectious process involving the skeletal muscles. Fiber type distribution in FCMD did not significantly differ from that of DMD except for relatively large number of type 2C fibers in the former. A recently proposed hypothesis in muscle fiber necrosis of DMD is as follows; an excess calcium accumulation in the muscle fibers through the defect membranes may activate a certain proteases such as calcium-activated neutral protease which initiate alpha-actinin release from the Z-line and troponin digestion leading final muscle fiber degeneration. A similar pathogenetic mechanism might take place in FCMD because of quantitative similarity in histological and histochemical fmdings in both dystrophies. Key words: Fukuyama type congenital muscular dystrophy, muscle biopsy, muscle histochemistry, Duchenne muscular dystrophy.
238 Brain & Development, Vol 3, No 2,1981
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Clinical Study of Congenital Muscular Dystrophy (Fukuyama Type)
Comparative Pathological Studies on Muscles from Myotonic Dystrophy in Infancy, Childhood and Adulthood
Michiko Hayashi, MD, Yutaka A waya, MD, Hiroko Iwamoto, MD, Kazuhiko Komiya, MD, and Nobuko Misugi,MD Departments of Pediatric Neurology (MH, YA, HI, KK) and Orthopedics (NM), Kanagawa Children's Medical Center, Yokohama, Kanagawa
We studied 28 patients with congenital muscular dystrophy of Fukuyama type (FCMD), admitted to Kanagawa Children's Medical Center during 19661973. Clinical picture of FCMD: Characterized by 1) early onset, 2) generalized muscle weakness, 3) facial involvement, 4) mental retardation, 5) joint contructure, 6) elevated serum CPK, 7) EMG showing low amplitude and short duration, 8) muscle biopsy fmdings consisting from variation in fiber size, proliferated connective tissue and extensive fibrosis. We classified 28 patients into two groups: the group I consists of 6 cases who have been able to walk, and the group 2 consists of 22 cases who have never walked. The comparison between group I and group 2 was summarized as follows. Number of cases Sibling cases Prenatal abnormality Perinatal abnormality Minor and major anomalies Convulsion EEG abnormality Abnormal CT (PEG) Mental retardation Joint contructure Facial involvement Tubular structure in muscle biopsy
Group 1
Group 2
6 2
22 2 50% 40% 45% 36% 32% 9/10 (4/5) 100% 100% 100% 4 cases
17% 17% 1/3 100% 100% 100% 1 case
Conclusion
The grade of mental retardation and motor disability was more severe in the group 2 than in the group 1, and history of pre- or perinatal abnormalities was found only in the group 2.
Key words: Fukuyama type congenital muscular dystrophy, facial involvement, mental retardation, joint contructure.
Nobuko Misugi, MD and Kazuaki Misugi, MD Departments of Orthopedics (NM) and Pathology (KM), Yokohama City University, School of Medicine, Yokohama, Kanagawa; Department of Orthopedics, Kanagawa Children's Medical Center, Yokohama, Kanagawa (NM)
Many reports concerning histopathological studies of myotonic dystrophy of the neonate and the adult have been published. However, those in childhood are not available. In an attempt to study the morphological changes by ages, the muscle biopsies from an infant, 5 school children and 5 adults were examined by light microscopy (LM), histochemistry and electron microscopy (EM).
Findings
(a) In adult, all 5 cases demonstrated marked irregularity of the muscle fiber size, central nuclei, fiber splitting, ring fibers and type 1 atrophy with type 1 predominance without exception. Two cases demonstrated ragged red fibers by LM and accumulation of abnormal mitochondria. One case showed nemaline bodies. (b) In an infant case, LM showed no remarkable abnormality. Histochemical studies demonstrated type 1 atrophy with type 1 predominance in minimal degree. EM showed rim of homogeneous area beneath the sarcolemma due to disappearance of the Ipyofllaments and mitochondria. (c) In childhood cases, LM was unremarkable except for one case which showed irregularity of the fiber size. This case (Case 2) had been treated with leg brace for club foot. Histochemical study showed type 2 atrophy with type 2 predominance in 3 cases. TYpe 1 atrophy with type 2 predominance was observed in one case. The other (Case 2) showed type 1 atrophy with type 1 predominance as observed in the adult cases. EM showed accumulation of abnormal mitochondria beneath the sarcolemma and cytoplasmic bodies.
Consideration
Childhood cases demonstrated reverse or different histochemical fmdings as compared with the adult cases. But EM fmdings of childhood cases were similar to the adult cases. It is difficult to draw conclusion from the study on the limited number of cases. However it is speCUlated that the childhood cases showed changing pattern of histochemical characteristics and transitional ultrastructural forms from the neonate to the adult. The findings of a child (Case 2) which showed adult type fmdings may be due to immobilization secondary to application of leg brace for a long period. IDtrastructures of abnormal mitochondria show many similar features as reported in ocular myopathies. This observation in adult cases suggest that myotonic dystrophy is multisystemic metabolic disorder.
Key words: Myotonic dystrophy in infancy and childhood, type 1 fiber atrophy, muscle histochemistry, muscle electron microscopy. Brain & Development, Vol 3, No 2,1981 239
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Malocclusion in Duchenne Muscular Dystrophy and Its Pathology
Two Autopsied Cases of Fukuyama Type Congenital Muscular Dystrophy, with Particular Reference to Morphometric Analysis of the Anterior Spinal Roots
Sanji Miyoshino, MD, Hiroaki Kan, MD, and Koji Shigenaga, MD Department of Pediatrics, Nishibeppu Hospital, Beppu, Ohita (SM, HK); Shinbeppu Hospital (An Association of National Public Official), Beppu, Ohita (KS) Facial muscle involvement is well recognized in facioscapulo-humeral muscular dystrophy and in congenital muscular dystrophy of Fukuyama type, whereas this abnormality is less pronounced in Duchenne muscular dystrophy (DMD). In advanced stage of DMD, however, several facial muscles including masseter are involved and this abnormality results in clinical feature of open bite expression. The present studies were performed in DMD patients as follows: (1) epidemiologic survey of open bite expression in nationwide scale, (2) clinical characterization of bite expression and X-ray examination of mandible, (3) histological examination of masseter, digastrics and temporal muscles at autopsy. Results obtained: (1) open bite expression was found in 34% of the patients, (2) frontal angle of mandible was more wide in the patients, (3) dystrophic changes were severe in masseter but mild in digastrics in patients with open bite expression. In patients without this expression dystrophic changes were mild and similar both in masseter and digastrics.
Key words: Duchenne muscular dystrophy, malocclusion, open bite expression, masseter muscle pathology.
Kuniyasu Takada, MD, Ikuya Nonaka, MD, Kei Shioda, MD, Takako Hasebe, MD, and Chieko Takada, MD National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo (KT, IN); Department of Pathology, Saitama Medical School, Moroyama, Saitama (KS); Tokyo Infant Recuperation Hospital, Musashi-Murayama, Tokyo (TH, CT) Most of over a dozen autosied cases with Fukuyama type congenital muscular dystrophy (FCMD) revealed hypoplastic or heterotopic corticospinal tracts, and cerebral as well as cerebellar micropolygyria. In order to clarify whether the abnormal corticospinal tracts would be responsible in producing the muscular lesions either directly or indirectly, we examined the anterior and posterior spinal roots with morphometric analysis. Two autopsied cases with typical clinical features of FCMD, who died at the age of 2 years and 1 year 11 months respectively, were subjected for pathologic evaluation. Resin-embedded transverse sections of the anterior and posterior spinal roots at L3 were photographed at the final magnification of 1,000 times to count numbers and measure diameter of myelinated fibers and compared with controls (Chou and Nonaka, 1978). Nerve teasing method was also applied. Both cases demonstrated typical neuropathologic changes with FCMD, including cerebral and cerebellar micropolygyria, focal fusion of frontal lobes, diffuse pallor of centrum semiovale and marked diminution of the corticospinal tracts. Total numbers of myelinated fibers in the anterior spinal roots were 5,750 and 6,873 respectively, while those of controls were ranging from 4,194 to 5,848. The diameter histogram of the myelinated fibers represented bimodal distribution with peaks at 4}.Lm and 6-7 }.Lm, which were essentially similar to those of controls. Teased nerves were unremarkable with no evidence of demyelination. The myelinated fibers in the posterior spinal roots in FCMD and controls showed no significant difference both in numbers and in diameter profIle. In cases with FCMD, the anterior and posterior spinal roots were intact. The present findings were quite different from those of so-called neurogenic muscular atrophies, such as Werdnig-Hoffmann disease. Though there were notable hypoplastic corticospinal tracts in FCMD, muscle involvement might be resulted from degenerative process in muscle itself, but not from central as well as peripheral nervous system abnormality.
Reference Chou SM, Nonaka I. Werdnig-Hoffmann disease: proposal of a pathogenetic mechanism. Acta Neuropathol (Bert) 1978;41:45-54. Key words: Fukuyama type congenital muscular dystrophy, corticospinal tracts, anterior spinal roots, morphometric analysis. 240 Brain & Development, Vol 3, No 2,1981
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Three Cases of Congenital Muscular Dystrophy with Cardiac Malformations
An Autopsy Case of Duchenne Type Muscular Dystrophy with Congenital Adrenal Hypoplasia
Kenji Nihei, MD, Haruko Naitoh, MD, Nobuhiko Koizumi, MD, and Sadayuki Suzuki, MD Department of Neurology, National Children's Hos· pital, Tokyo
Congenital muscular dystrophy (Fukuyama type) (FCMD) are well known to be associated with abnormalities of the CNS such as micropolygyria or hydrocephaly. We reported 3 cases of FCMD with congenital heart disease. Case 1 (5-year-old boy): He was delivered normally with a birth weight of 3,750 g. Being floppy from birth with motor retardation he has been unable to stand by himself till now. There was no convulsion but mental retardation with impairment of facial muscles, contraction of the knee joint and muscular hypotonia. He had an elevated serum CPK level of 1,418 IV/ml. Marked dystrophic change of the biopsied muscle was observed. The cranial CT scan showed decreased resorption in the white matter of the brain with enlargement of the fourth ventricle. Systolic murmurs were audible in the chest. Cardiac catheterization, together with other findings, led to the diagnosis of VSD. Case 2 (22-month-old female): Her mother took a medicine for a common cold she had at 4 months of pregnancy. The patient was delivered at 39 weeks of gestation, with birth weight of 2,050 g. Being floppy from birth with motor retardation, she has been unable to control her head. Serum CPK level elevated to 2,440 IV/ml. There was generalized cyanosis. A diagnosis of tetralogy of Fallot was made by a cardiologist. Case 3 (5-year-old boy): He was delivered normally at 40 weeks with a birth weight of 3,945 g. Being floppy from birth, he had motor retardation but nontheless was able to walk at age 2. Serum CPK level slightly elevated. Cardiac catheterization and other procedures led to the diagnosis of double chamber of RVand VSD. Patients with congenital heart disease often present with muscular hypotonia similar to that seen in myopathy but never have an elevated serum CPK level or degenerative change in muscle tissue. However, the cases presented here were considered to be suffered from FCMD associated with congenital heart disease. This may be a significant fact in estimating the pathogenesis of CMD.
Teruko Toyofuku, MD, Sachio Takashima, MD, Hiroshi Nagafuji, MD, and Taketoshi Watanabe, MD Division of Child Neurology, Tottori University, School of Medicine, Yonago, Tottori (TT, ST); Tenri Hospital, Tenri, Nara (HN); Matsue Red Cross Hospital, Matsue, Shimane (TW) An autopsy case of Duchenne muscular dystrophy associated with uncommon congenital adrenal hypoplasia was reported. There was no consanguinity. He had a healthy elder sister, and affected elder brother with the similar symptoms and laboratory fmdings who died at 3 years 7 months. He was born at a full-term pregnancy and uneventful delivery. He had episodic vomitings shortly after birth and admitted to the Matsue Red Cross Hospital because of feeding difficulty, weight loss and decreased activity at 23 days. On admission, the physical examination revealed mild dehydration and brown pigmentation of the skin but no abnormalities of external genitalia. Laboratory examination showed serum potassium of 7.5, sodium 116 mEq/L and markedly elevated serum enzyme activities (GOT 205 U, CPK 2220 IV, LDH 3400 U). There were 0.2 mg of 17-KS, 0.8 mg of 17-0HCS and 0.25 IJ.g of aldosterone in a 24 hour-urine sample. Serum ACTH was 661 pg/dl, /3-MSH 1085 pg/dl, angiotensin 2000 U. Adrenocortical insufficiency was treated with glucocorticoid and mineral corticoid. Subsequently his general conditon and serum electrolytes were improved but CPK, LDH and GOT activities were not. At the age of 9 months adrenal scintigram revealed absence of bilateral adrenal glands. Muscle biopsy showed myopathic changes consistent with the fmdings of Duchenne muscular dystrophy. He walked at 14 months with waddling iait and was able to stand up by Gowers' maneuver. He showed prominence of calves. Since he was placed on insufficient medication for a week, he developed generalized convulsions, unconsciousness and apneic spells, died at the age of 3 years 5 months. The pathological examination showed adrenal hypoplasia, muscular dystrophy and ischemic-hypoxic brain damage. Key words: Duchenne muscular dystrophy, congenital adrenal hypoplasia.
Key words: Congenital muscular dystrophy, floppy infant, congenital heart disease.
Brain & Development, Vol 3, No 2,1981 241
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An Autopsy Case of Fatal Neonatal Nemaline Myopathy
A Case of Ullrich Syndrome with Congenital Fiber Type Disproportion
Chieko Shimomura, MD, Masaaki Yoshimoto, MD, Yoshio Nakashita, MD, Yoshinobu Watanabe, MD, Akiyuki Ogawa, MD, and Mitsuhiro Tsugihata, MD Departments of Pediatrics (CS, MY, YN, YW, AO) and Internal Medicine (MT), Nagasaki University, School of Medicine, Nagasaki In 1963, Shy et al. first described congenital nemaline myopathy. The most common manifestation of the disease is a non-progressive myopathy. We will report a patient with fatal neonatal nemaline myopathy who had more severe involvement than those previously described.
Case Report The patient, a girl, was born prematurely at 37 weeks of gestation. There was no family history of neuromuscular disease. She had high-arched palate, ear deformity, and arachnodactyly. There was no spontaneous motor activity. No Moro or sucking reflex was present, and deep tendon reflexes were absent. She could not be weaned from the ventilator. She died at five months of age. Rectus femoris muscle biopsy was performed at the third month of age. The routine ATPase reaction differentiated two major fiber types. The type I fiber was smaller than type 2 fiber. In the diaphragm many rods were identified. And these rods had a periodicity. Discussion Neuromuscular disease may be Ii cause of respiratory insufficiency in the neonatal period. Reports of severe cases of nemaline myopathy are rare and were described by McComb et a1. Presence of type I fiber atrophy may suggest that this case had other disease such as congenital fiber type disproportion. But, many rods were identified, and we diagnosed this case as a case of fatal neonatal nemaline myopathy. Key words: Nemaline myopathy, type 1 fiber atrophy, congenital fiber type disproportion.
Hideo Tamari, MD, Yoshinobu Otani, MD, Makoto Matsukura, MD, Yoshihiro Origuchi, MD, Ichiro Matsuda, MD, and Sanji Miyoshino, MD Department of Pediatrics, Kumamoto University, School of Medicine, Kumamoto (HT, YO, MM, YO, 1M); Nishibeppu National Hospital, Beppu, Ohita (SM)
A 2-year-6-month-old Japanese boy with Ullrich syndrome was described. His major clinical findings were distal dominant generalized muscle weakness and atrophy, acroatonia, contracture of hip joint, scoliosis, areflexia, high arched palate, prominent calcaneus, soft and elastic skin. These were comparable to Ullrich syndrome (Die Kongenitale atonisch-sklerotische Muskeldystrophie Typ Ullrich, 1930). Creatine phosphokinase was 184 IU/l (normal less than 200 IU/l). Motor nerve conduction velocity of the right peroneal nerve was normal (54 m/sec). Electromyographic examination of his left tibialis anterior muscle revealed neurogenic pattern of high amplitude potentials of 4 mY. Pathological finding of the muscle biopsy obtained from right quadriceps revealed: 1) an increase in endomysia! connective tissue, 2) variation in the size of muscle fiber diameter, 3) degenerative and regenerative fibers stained with hematoxylin-eosin and Gomori's trichrome. A histographic analysis was performed by measuring 400 fibers stained with myofibrillar ATPase reaction. They were categorized as type I, lIA, lIB and lIC according to Brooke's method. Proportion and diameter of each fiber were as follow; type I (63%, 24.1 /.I), type lIA (15%, 28.7/.1), type lIB (19%, 29.9/.1) and type lIC (3%, 23.0/.1). These results indicated type I fiber hypotrophy. Occasionally type grouping was seen. Observed results revealed that there were findings of congenital muscular dystrophy accompanying with fiber type disproportion and also neurogenic involvement in the present case. We presumed that these features were the results of fetal developmental disorder rather than of primary nerve or muscle origin.
Key words: Ullrich syndrome, congenital fiber type disproportion, acroatonia, hypotonia.
242 Brain & Development, Vol 3, No 2,1981
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An Unusual Mitochondrial Myopathy with Mental Retardation and Dwarfism
A Case of Congenital Myopathy with Moebius Syndrome and Pulmonaly Stenosis
Osamu Fujino, MD, Kiyoshi Hashimoto, MD, Miho Maeda,MD,IkuyaNonaka,MD Department of Pediatrics, Nippon Medical School Hospital, Tokyo (OF, KH, MM); National Center for Nervous, Mental, and Muscular Disorders, Kodaira, Tokyo (IN)
An 8-year-old girl was born with an uneventful delivery
after 32 weeks gestation and birth weight was 2,400 g. She was the third child to related parents in the nfth degree. The eldest sister was similarly affected and died of accident at 7 years. She was a floppy infant and slowly gained body weight because of poor sucking. Congenital hip dislocation was noted at 5 months. Her motor milestones were delayed and she learned to walk at 3 years though with unsteady gait. On examination at the age of 7 years 3 months, she was 103 cm in height (below -3 SD) and 17 kg in weight (-1.5 SD). She had mild lordosis and moderate proximal muscle weakness with Gowers' sign and waddling gait. Tendon jerks were decreased and there were no pathological reflexes. Cranial nerves and sensation were intact. She was mentally retarded with IQ score of below 39. The routine urinalysis, blood chemistry, hematological examinations and bone survey by X-ray were within normal limits. Serum CPK level was 62 mU/ml (5-60). EMG showed myopathic pattern and motor nerve conduction velocity was normal. The biopsied left biceps brachii muscle represented a moderate variation in fiber size with slight increase in perimysial and endomysial connective tissue. On ATPase stain, type 1 fibers were predominant in numbers (57.9%) whereas type 2B fibers were scant (9%). With modified Gomori trichrome stain, both type 1 and 2 fibers contained scattered red granular materials, predominantly in the peripheral regions of muscle fibers. Although the materials were stained in dark with NADH-TR and MAG, they differed from those in "ragged-red" fibers where mitochondria were usually aggregated in the subsarcolemmal zones. Electron microscopy also conllrmed abnormal mitochondria with complicated cristae measuring up to 3 microns in dimension, though there was little change in myofibrils. Since a sister of the patient had had the similar symptoms of muscle weakness, mental retardation and dwarf and parents were in blood relative, the disorder seems to be genetically determined. Scattered, but increased number of large mitochondria in the muscle fiber may responsible in producing muscle weakness. Further study must be necessary to clarify whether mitochondrial abnormality is multisystemic involving not only the skeletal muscle but the central nervous system.
Masutomo Miyao, MD, Kunio Kaneshi, MD, Yoshikuni Beppu, MD, and Kazuhiko Hirose, MD Departments of Pediatrics (MM, KK) and Neurology (YB, KH), Tokyo Metropolitan Hospital of Fuchu, Fuchu, Tokyo
The syndrome of congenital facial diplegia associated with extraocular muscle paralysis, described by Moebius in 1888, and recent evidence suggests that some cases of Moebius syndrome may be due to progressive diseases of muscle, anterior hom cell, or peripheral nerve. Recently the relation between the Moebius syndrome and muscle disease has attracted notice. Case Report A 7-year-old boy was admitted in March 1979 because of facial paralysis and weakness of muscle power. He has no family history. He was born at term, but mother felt decreased fetal movement in prenatal period. In neonatal period, he was unable to suck from a bottle and was nourished by tube. His right half chest was concaved and didn't move fully. Sometimes he had cyanosis which necessitated oxygen inhalation. Soon after birth, a high pitched cry, lack of facial expression, and hypotonic posture were noted. He sat alone at 1 year, walked at 3 years. Physical Examination He was unable to move the forehead muscles, nor able to close the eyes and mouth. The posture was lordotic, the gait moderately slow. There was marked weakness and wasting of all shoulder and pelvic muscles. Deep tendon reflexes were normal. On Wechsler scale, he attained a IQ of 80. Routine studies including serum GOT, GPT, LDH, CPK, creatine were normal. EMG revealed myogenic pattern in the right orbital orbicularis and biceps muscles. On ECG IRBBB pattern was noticed but no low voltage was found. Chest X-ray showed an elevation of diaphragma of the right side. Muscle biopsy: Myogenic pattern. Summary A patient with Moebius syndrome, pulmonaly stenosis and the paralysis of right diaphragma was described. Facial diplegia in this case was based on nonprogressive myopathy of an uncertain nature. Key words: Congenital myopathy, pulmonaly stenosis, Moebius syndrome.
Key words: Mitochondrial myopathy, dwarfism, mental retardation, muscle histochemistry.
Brain & Development, Vol 3, No 2, 1981 243
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Muscle Pathology of Perifascicular Atrophy in Childhood Type Dermatomyositis
Clinical Study on Cases with Infantile Acute Myoglohinwia
Teruhisa Miike, MD and Samuel M, Chou, MD, PhD Department of Neuropathology, West Virginia University Medical Center, Morgantown, WV, USA
Childhood dermatomyositis is a distinctive clinicopathologic entity. Myofiber damage in childhood dermatomyositis has been considered secondary to ischemia due to a capillary lesion. While a high serum CPK level is one of the diagnostic feature in dermatomyositis. High serum levels of muscle enzymes have been explained on basis of the "leaky membrane" theory in DMD. This work advocates an alternative site of leakage for muscle enzymes, as demonstrated in six cases of childhood dermatomyositis, at the triads where the transverse or T-tubules and the terminal cisternae are closely opposed. In addition the number of capillaries around individual myofibers was counted in 3 cases of relatively normal cases. Materials and Methods Biopsied muscles were prefixed with glutaraldehyde. Postfixation with osmium tetraoxide was performed simultaneously with lanthanum staining. Ultrathin sections cut with an LKB ultratome, stained with uranyl acetate and lead citrate, as well as semiultrathin sections (0.25 It thick) without staining were studied with an AEI (Corinth 275) electron microscope. For study of capillary beds in perifascicular and centrofascicular myofibers a 3, 3', 4, 4', diaminobenzidine (DAB) method (Adams IC. Neuroscience 1977;2:141) was devised to visualize RBCs in capillaries and types of myofibers simultaneously. Results The consistent abnormalities are tubular system (TS) -sarcoplasmic reticulum (SR) anastomosis as visualized by lanthanum stainin.s. Conical dilatations at the junctional sites between the extracellular and intracellular spaces progress to become spheroidal before they presumably rupture and disappear in severely degenerated myofibers. T-tubules aggregates in honeycomb forms suggestive of a repair process are seen at the junctional sites. The number of capillaries surrounding an individual myofiber is significantly less in the perifascicular than in the centrofascicular zone. The mean numbers of capillaries shared by the perifascicular myofibers range from 2.4 to 2.6 and the number for centrofascicular myofibers is 3.4 to 3.6. Conclusion TS-SR anastomoses was proposed to be the anatomical correlate for leakage of muscle enzymes as well as degraded structural protein molecules. Relative paucity of the capillary bed in perifascicular zone is one of the causes of the perifascicular muscle atrophy in' childhood dermatomyositis. Key words: Muscle enzyme leakage, childhood dermatomyositis, tubular system-sarcoplasmic reticulum anastomosis, perifascicular myofiber atrophy.
244 Brain & Development, Vol 3, No 2, 1981
Tsunesaburo Ando, MD, Tomoyoshi Kato, MD, Tsutomu Ohtani, MD, Yutaka Nishimura, MD, Shigeru Nagaki, MD, Yoko Sugie, MD, Hideo Sugie, MD, Tomoko Goto, MD, Keiko Shishikura, MD, and Yukio Fukuyama, MD Department of Pediatrics, Nagoya Daini Red Cross Hospital, Nagoya, Aichi (TA, TK); Toyohashi Municipal Hospital, Toyohashi, Aichi (TO, YN); Department of Pediatrics, Tokyo Women's Medical College, Tokyo (SN, YS, HS, TG, KS, YF)
Twelve cases of infantile acute myoglobinuria (grossly brown urine) were studied as to underlying conditions, predisposing factors, complications and prognosis. Subjects and Methods The patients, 9 male and 3 female, ranged in age from 7 months to 14 years. There were 5 cases of so-called idiopathic paroxysmal myoglobinuria secondary to infections, 4 cases of myoglobinuria associated with acute encephalopathy including Reye syndrome, 2 cases of malignant hyperthermia and a case of myohemoglobinuria associated with burns. Myoglobin (Mb) determinations were carried out by counterimmunoelectrophoresis or radioimmunoassay. Results Of the 5 patients with idiopathic paroxysmal myoglobinuria, 3 patients had cerebral paralysis of the rigospastic type and 1 had congenital muscular dystrophy as underlying conditions. Lipid storage myopathy was suspected in 1 of the cases of malignant hyperthermia. As predisposing factors, upper respiratory tract infections were noted in 7 cases and measles in 2 cases, thus suggesting a possible relation of viral infections to the development of myoglobinuria. Seven of the 12 patients studied had renal disorders complicating the condition, of whom 3 have died. Marked elevation of serum enzyme activity, such as CPK and GOT, was observed during the acute phase. Conclusion Acute myoglobinuria of children is unexpectedly high in incidence and the review of the cases have revealed that it developed often secondarily to infections of the upper respiratory tract in children with neuromuscular disorders as underlying conditions. It has also been noted that, in acute myoglobinuria, there was a high incidence of complication by renal disorders, frequently with an unfavorable prognosis. All these findings stress importance of recognition, early detection and early treatment of the condition. Key words: Myoglobinuria, acute renal failure, idiopathic paroxysmal myoglobinuria, acute encephalopathy.
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175
Spinal Cord Lesions in Scapuloperoneal Muscular Atrophy with Cardiomyopathy
Serum CK Isoenzyme in Children with Nervous System Disorders
Hideaki Kudo, MD, Sadayuki Yano, MD, Masayoshi Yanagisawa, MD, and Shigehiko Kamoshita, MD Department ofPediatrics, lichi Medical School, School of Medicine, Tochigi Although the scapuloperoneal muscular atrophy is a group of heterogeneous diseases, one of them, which was originally described by Emery and Dreifuss in 1966, seems to be a definite disease entity. All the patients reported as this entity were male, and showed the joint contracture at elbow, ancle, and neck in early childhood. The weakness of scapuloperoneal muscles appeared in early childhood, and was slowly progressive. Cardiac conduction abnormalities appeared later. Muscle biopsy studies and EMG findings of this disease showed both neurogenic and myopathic characteristics. While the clinical case reports were not very rare, the pathological studies of the spinal cord were described only in two cases, and their observation were not conclusive. We have had an opportunity to study the spinal cord of another case of the disease. Clinical and pathological findings of the case were already reported last year. Specimens were taken from every segment from the first cervical to the fourth sacral cord, 8 micron paraffin sections were stained with H&E, Kluver-Barrera, Bodian, and Holzer methods. Neurons in the anterior and lateral horns of each segment were classified into 3 groups, normal, subnormal, and degenerated. Thus classified neurons were plotted diagrammatically on a sheet, and axonal degenerations on Bodian stains were added to it. Focal neuronal degenerations were obvious, and the most severely affected segments were C s ' C6 , C 7 , Ls and S,. In these segments, only a few normal neurons were remained. The sites of the lesion seemed to correspond well with the affected muscles. In addition, the neurons in the lateral horn of thoracic segments showed central chromatolysis. These observations indicate a definite involvement of spinal motor neurons in scapuloperoveal muscular atrophy with cardiomyopathy.
Shigeru Kimura, MD and Yukinao Takebe, MD Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori Serum creatine kinase (CK) and its isoenzyme activities were studied in 97 children with CNS and/or neuromuscular disorders. CK isoenzyme was studied by the fiuorometric-electrophoretic method. The following results were obtained. 1. Increased CK activity was observed in epilepsy with recent convulsion especially under 4 years of age, in Kugelberg-Welander disease, and in other chronic brain damage with convulsion. 2. CK-BB (brain type) was detected in 2 cases with epileptic encephalopathy (Le., West syndrome and focal seizure following West syndrome), 3 cases with severely multiple handicapped children (MHC) due to cerebral palsy, 2 cases with other chronic brain damage (Le., progressive encephalopathy and ceroid lipofuscinosis), and 2 cases with intracranial hemorrhage. Four of 9 CK-BB positive children with CNS disorders died within 4 months after this CK isoenzyme study was done. It was elucidate in the present study that positive serum CK-BB can be useful index of extensive severe brain damage with poor prognosis in children with CNS disorders. The number of cases with CNS and/or neuromuscular disorders were as follows: epilepsy 21, febrile convulsion 10, MHC 24, Duchenne muscular dystrophy 19, congenital muscular dystrophy 5, neurogenic muscular atrophy 6, other chronic brain damage 8 (TaySachs disease 1, hyperphenylalaninemia 1, progressive encephalopathy of unknown origin 1, infantile metachromatic leucodystrophy 1, SSPE 1, spinocerebellar degeneration 1, neuronal ceroid lipofuscinosis 1, Menkes kinky hair disease 1), and acute brain damage 4 (acute encephalopathy-Lyon 1, intracranial hemorrhage 2, uremic coma 1).
Key words: CK-BB, CK isoenzyme, children with neurological disorders.
Key words: Scapuloperoneal muscular atrophy, Emery-Dreifuss muscular dystrophy, cardiomyopathy, spinal cord.
Brain & Development, Vol 3, No 2,1981
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176 A Case of Periodic Paralysis with Persistent Elevation of CPK Values
Tomoaki Nagaura, MD, Kiyoomi Sumi, MD, liro Abe, MD, Hiroshi Shimizu, MD, Yukiko Onoue, MD, Hyakuji Yabuuchi, MD, Emiko Senba, MD, and Sigeo Hashimoto, MD Department of Pediatrics, Osaka Welfare Pension Hospital, Osaka (TN, KS); Department of Pediatrics, Osaka University Hospital, Osaka (lA, HS, YO, HY); The Second Department of Pathology, Kinki University Hospital, Osaka (ES, SH) There are few reports about the persistent elevation of CPK values and pathologic changes of peripheral nerve in periodic paralysis. The patient had been in good health until age 12, when he suddenly felt a severe weakness oflower limbs and found himself unable to stand up and walk for a few days, but this episode disappeared spontaneously. Since then, he experienced several episodes once a few months, but he could enjoy playing tennis every day. He was admitted to our hospital 7 months after the onset. The physical examination was not remarkable. Muscle wasting of the pelvic girdle and lower limbs was not present. The neurological examination revealed hypoactive patellar reflex. The values of the serum CPK and aldolase were markedly and persistently elevated. There were no abnormalities in the values of serum electrolytes, GOT, LDH, lactate, pyruvate, renin, aldosterone and blood gas. Thyroid function was normal. Provocation tests were unsuccessful with OGTT and glucose-insulin combined methods. The serum potassium levels were found to decrease to 3.4 mEq/1 at attack. The potassium in erythrocytes showed low level compared to normal values, but these values of the patient further fell down remarkably during an attack. We examined biopsy samples of peroneus brevis muscle and sural nerve histologically. The muscle demonstra ted slight hypo trophic type I fibers and angulated fibers. Fiber necrosis, vacuolation and cell infiltration did not exist. On electron microscopy, slight dilatation of t-tubules and some membranelimited vacuoles communicated with several t-tubules were the additional findings. The sural nerve showed slight decrease of large size myelinated fibers in semithin transverse section. Electron microscopic findings were the swelling of cytoplasma in some Schwann cells surrounding myelinated fibers and denuded axons. Frequency of attack decreased gradually with the oral administration of potassium chloride and acetazolamide, though this case was supposed to be an atypical type of hypokalemic periodic paralysis. Moreover, the values of serum CPK were normalized by steroid therapy (predonine 1 mg/kg) and then the attack disappeared.
Key words: Periodic paralysis, serum CPK, hypotrophic type I fiber, denuded axon.
246 Brain & Development, Vo13;No 2,1981