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Cytoplasmic body myopathy
Journal of the Neurological Sciences, 1983, 60:281-292
281
Elsevier
CYTOPLASMIC BODY MYOPATHY Report on a Family and Review of the Literature H. PATEL I, K. BERRY 2, P. MAcLEOD 3 and H.G. DUNN 1
Departments of Ipaediatrics, 2Pathology and 3Genetics, Faculty of Medicine, University of British Columbia, and Vancouver General Hospital, B.C. (Canada) (Received 1 December, 1982) (Revised, received 7 February, 1983) (Accepted 9 February, 1983)
SUMMARY
A 15-year-old girl who was seen for scoliosis presented with cardiorespiratory failure associated with a respiratory infection. She was found to have weakness predominant in the face, sternomastoid, proximal limb, respiratory, spinal and cardiac muscles. The serum creatine kinase level was slightly elevated and the electrocardiogram was abnormal. The electromyograph was consistent with a myopathy. The course was malignant. Her 14-year-old brother had similar findings and succumbed at the age of 14 and one-half years from cardiorespiratory failure. The mother had minimal weakness of proximal limb muscles since early life. The tendon reflexes were normal as was the serum creatine kinase level. The course was benign. On light microscopy the muscle biopsy in the girl showed fibre diameter variation, centrally placed nuclei, necrosis, fibrosis and cytoplasmic bodies. The muscle biopsy in the brother and mother had similar findings except that the inclusion bodies were not seen in the mother. On electron microscopy, the girl showed typical cytoplasmic bodies, involving predominantly type 1 fibres. The mother also had these structures. The literature is reviewed and the origin, pathogenesis and aetiology of the cytoplasmic body are discussed.
INTRODUCTION
Histochemistry and electron microscopy have permitted the recognition of several new muscle disease entities, based on morphological rather than clinical Correspondence to: Dr. H. Patel, Department of Paediatrics, B.C.'s Children's Hospital, 4480 Oak Street, Vancouver, B.C. V6H 3V4, Canada.
0022-510X/83/$03.00 © 1983 Elsevier Science Publishers B.V.
282 data. In some of these, abundant abnormal structures accumulate within the muscle fibres. For example, rod-shaped bodies in nemaline myopathy (Conen et al. 1963: Shy et al. 1963). Recently, we examined 2 siblings in whom muscle biopsies demonstrated abundant cytoplasmic bodies detected by electron and/or light microscopy. The mother's tissue contained similar structures which were seen only on eletron microscopy. We wish to report (1) the family history, (2) clinical and laboratory findings and (3) morphological data observed in these patients and their mother. MATERIALAND METHOD
(1) Family history (Fig. 1 shows the details) The parents were first cousins. The father had an unexplained transient paraparesis at the age of 35 years and died of a myocardial infarction 20 years later. The 55-year-old mother had mild limb-girdle weakness for as long as she could remember. She also had recurring joint discomfort attributed to "arthritis". A son with seizures and mental retardation secondary to meningitis died at the age of 17 years while the 19-year-old son was healthy. Six children from her previous nonconsanguineous marriage were healthy while 2 had died with respiratory infections in infancy. Her 1 sister with a deformed back died in childhood. A second cousin of our young patients required assisted ventilation for respiratory infection and failure when she was aged 20 years. She had residual generalized muscle weakness. Her electromyogram (EMG) was considered to indicate a myopathy but the muscle biopsy on routine H&E stain was reported as normal. A year later following another episode of respiratory infection and failure she received steroid
(
0
It RNeuromuscular lesion +Deceased
Fig. 1. Pedigreeof family.*Secondcousin of our youngpatients.
283 treatment which resulted in clinical recovery. However, the EMG remained abnormal with short duration, low amplitude motor units, excessive polyphasic units and full recruitment with maximum contraction. Similar EMG findings were present in her asymptomatic mother and her 18-month-old hypotonic nephew. The latter had a slightly elevated serum creatine kinase (CK) level and a normal muscle biopsy examined by H&E, histochemical stains and electron microscopy.
(2) Clinical and laboratory data (Tables 1 and 2 summarize the findings) Case 1 A native North
American
I n d i a n g i r l a g e d 15 y e a r s a n d
10 m o n t h s
w a s seen i n t h e S c o l i o s i s
Clinic a n d a d m i t t e d s o o n a f t e r w a r d s w i t h r e s p i r a t o r y failure. She was delivered by C a e s a r e a n section a t 37 w e e k s b e c a u s e o f a n t e p a r t u m 2.75 k g a n d i n t h e f i r s t m o n t h
haemorrhage.
Foetal movements
had been adequate. She weighed
had feeding difficulty and poor weight gain. Her early development
w a s n o r m a l b u t s h e w a l k e d f r e e l y o n l y a t t h e a g e o f 15 m o n t h s .
TABLE
1
CLINICAL
AND
LABORATORY
DATA
IN CYTOPLASMIC
BODY
MYOPATHY
Authors
Nakashima et al. (1970)
Kinoshita Clark Jerusalem Edstr6m et al. et al. et al. et al. (1975) (1978) (1979) (1980)
Goebel et al. (1981)
Wolburg et al. (1982)
Wolburg et al. (1982)
Present study
Family history
neg
neg
neg
neg
pos
pos
pos
pos
Sex Age (years) (1) at onset
M
F
F
M
F
F
M
F
53
16
infant
infant
13
5
53
22
early life 15
32
32
15
14
early life 55
Muscle weakness face sternomastoid proximal limb distal limb respiratory cardiac spinal other
+ + + NR NR NR
+ + + + + +
+ + + NR +
+ -
Tendon reflexes Serum CK
dec inc
dec inc
N N
ECG EMG Cardiorespiratory failure Course
(2) at examination
Case 1 Case 2 Case 3
pos AD M F
neg F
pos AD M F
late life late life
child
midlife
22
54-58
+ + + + + + +
+ -
+ + + NR +
+ + + + + + hand
+ NR + + -
+ NR + + neck
dec inc
dec N
N N
NR inc
dec inc
NR inc
N neur -
N myo +
dec N or inc NR myo -
NR + + + pupil general NR N
N neur +
NR myo -
N "myo" -
abn mixed -
NR myo +
abn myo +
NR myo +
N myo -
ben
mal
ben
mal
semimal
ben
NR
NR
real
mal
ben
pos = positive; neg = negative; neur = neurogenic; myo = myopathic; ben = benign; mal = malignant; NR = no record; A D = a u t o s o m a l d o m i n a n t ; N = n o r m a l ; a b n = a b n o r m a l ; inc = increased ; dec = decreased; + = p r e s e n t ; -
= absent.
284 TABLE 2 M O R P H O L O G I C A L DATA R E P O R T E D IN CYTOPLASMIC BODY M Y O P A T H Y Authors
Fibre diameter variation Internal nuclei Degeneration Fibrosis Atrophic fibres (1) group atrophy (2) fibre type Z-line change Filamentous body Cytoplasmic inclusion bodies and fibre type
Nakashima et al. (1970)
Kinoshita Clark Jerusalem Edstrtm Goebel Wolburg et al. et al. et al. et al. et al. et al. (1975) (1978)(1979) ( 1 9 8 0 ) (1981) ( 1 9 8 2 )
Wolburg et al. (1982)
Presenl stud.', ..... Case I Case 2 Case3
+
+
+
+
+
+
+
+
+
+
inc
inc
inc + +
inc
inc +
inc
inc
inc + +
inc + +
+ +
+
+ 1 + + 1& 2
+ *
1
1
+ + I&2
+ I
+ 1 + I
it~c +
+ + I
]
*
+ *
+ = present; - = absent; inc = increased; * = fibre type not possible to determine. She had frequent upper respiratory and ear infections and at 18 months recovered satisfactorily from pneumonia. A single brief non-febrile, generalized seizure occurred at the age of 1 year. When she was 13 years old she developed easy fatiguability, effort and nocturnal dyspnoea. difficulty with swallowing, chewing, articulation, expectoration, combing hair and climbing stairs. She had precordial pain with effort, also abdominal pain and constipation. Scoliosis was noted. Recently she had developed headaches. Four weeks before admission she had a febrile respiratory illness with partial recovery and 2 weeks later she developed rapid respiratory failure and required ventillator assistance. Examination revealed an intelligent, very thin girl with normal height and head circumference measurement. She had a long face, long thin hands and feet, a high-arched palate, prognathlsm. prominent eyes, patulous lips, lagophthalmos, scoliosis and small muscle mass. The sternomastoid muscles were very thin and weak. The masseter, facial and intercostal muscles had moderate impairment of strength while slight weakness was noted in the proximal limb-girdle muscles. The tendon reflexes were depressed. The remainder of the neuromuscular system was normal. The pulse was irregular at 120/min and the B.P. was 100/70 mm Hg. She had a grade 2 of 6 systolic murmur. Crepitations were heard at the lung bases. Her cardiac status improved with the rate, rhythm and size of heart returning to normal but the electrocardiograph (ECG) remained abnormal. The strength improved in the shoulder girdle. cranial and respiratory muscles but she continued to require intermittent ventilator assistance. The F.V.C. improved from 380 ml to 600-700 ml. She had 2 self-limited, brief episodes of profound weakness during which she was immobile, atonic and areflexic but fully conscious. These attacks could not be correlated with any specific change in blood gases, serum electrolyte levels or electroencephalogram. A course of steroid therapy was ineffective. Normal laboratory data included peripheral blood picture, serum electrolytes, erythrocyte sedimentation rate, routine analysis and amino acid chromatography of urine, antinuclear factor. serum protein electrophoresis and immunoglobulin IgG and IgA; The IgM was slightly elevated. The serum enzyme levels were elevated with LDH 466 IU/I (normal up to 350 IU/I), CK 220 IU/I (normal up to 120 IU/I). The electrodiagnostic studies were suggestive of a myopathy with normal motor nerve conduction velocity, short duration low amplitude motor unit potentials, excessive amount of polyphasic units and full interference patter.n Some long duration units were present. An occasional satellite unit was seen.
285 The electrocardiogram demonstrated left ventricular hypertrophy, depressed S-T segments in the left chest leads and conduction disturbance. The echoeardiogram revealed thickening of the posterior leaflet of the mitral valve with paradoxical movement. The electroencephalogram was reported as being slightly diffusely slow for age.
Case 2 This 14-year-old boy was the eldest of the 4 children in the sibship. He was admitted for evaluation of scoliosis. The mother's pregnancy was normal with adequate foetal movements. He was born at term after a 24-hour labour and weighed 2.9 kg. He behaved normally in the newborn period. He then developed appropriately but did not walk freely until the age of 18 months. At school he required a special class for slow learners. He had several upper respiratory infections and 2 attacks of pneumonia with satisfactory recovery. Frequent falls were noted at the age of 5 years and easy fatiguability when he was 9 years old. A stiff gait, leg pains, partial eye closure during sleep and scoliosis were observed at the age of 13 years. Examination showed that the height, weight and head circumference measurements were normal. Muscle mass was generally decreased. The sternomastoid muscles were thin and weak. The strength was impaired in the abdominal, spinal and limb-girdle muscles. The tendon reflexes were depressed. Severe dorsolumbar scoliosis was present. The remainder of the neuromuscular system was normal. The pulse was regular at 114/min and the B.P. was 125/80 mm Hg. No cardiac murmur was heard. The lung fields were clear. Normal laboratory tests included electroencephalogram and chest X-ray. The serum CK level was elevated at 295 IU/1 (normal up to 120 IU/1). The electrodiagnostic studies demonstrated normal motor and sensory nerve conduction velocity, short duration low amplitude motor unit potentials, excessive polyphasic units and full interference pattern, features which suggested a myopathy. Fibrillation and positive sharp waves were present. At the age of 14 and one-half years he developed progressive effort and nocturnal dyspnoea. He then had respiratory arrest and died before reaching the local hospital.
Case 3 The mother aged 55 years was generally healthy except for slight limb-girdle muscle weakness which she had all her life. Examination confirmed that she had mild proximal limb-girdle muscle weakness. Her muscle mass was generally small. The remainder of the examination was normal. The serum CK level was normal. The electrodiagnostic studies showed similar but less pronounced abnormalities than in her children. The amplitude reached with maximum volition was however only 1 mV in some muscles.
(3) Muscle biopsy data ( T h e s e a r e s u m m a r i z e d in T a b l e 2) Case 1. B i o p s i e s f r o m t h e left v a s t u s l a t e r a l i s a n d d e l t o i d m u s c l e s s h o w e d similar features but were more pronounced
in t h e f o r m e r . T h e f i n d i n g s o n l i g h t
m i c r o s c o p y w e r e c o n s i s t e n t w i t h a s e v e r e m y o p a t h y . A s t r i k i n g f e a t u r e in m a n y fibres w a s t h e a c c u m u l a t i o n o f c y t o p l a s m i c b o d i e s w h i c h a p p e a r e d as b r i g h t r e d s t r u c t u r e s w i t h t h e m o d i f i e d G o m o r i t r i c h r o m e stain. T h e y s t a i n e d n e g a t i v e l y w i t h v a r i o u s stains t h a t is N A D H ,
ATPase, PAS and phosphylorase
T h e u p t a k e o f d y e w a s v a r i a b l e in t h e m e n a d i o n e - l i n k e d preparation.
These bodies were present predominantly
(Figs. 2 a n d 3).
nitroblue-datrazolium
in t y p e 1 a n d o n l y v e r y
o c c a s i o n a l l y in t y p e 2 fibres. E l e c t r o n m i c r o s c o p y r e v e a l e d t h e s t r u c t u r e s
had
f e a t u r e s o f c y t o p l a s m i c b o d i e s w i t h a d e n s e c e n t r a l z o n e s u r r o u n d e d by a l i g h t e r h a l o a n d a n o u t e r shell (Figs. 4 a n d 5). S t r e a m i n g o f t h e Z b a n d w a s a l s o o b s e r v e d .
Case 2. L e f t d e l t o i d m u s c l e b i o p s y w i t h p a r a f f i n - e m b e d d e d s e c t i o n s s t a i n e d w i t h H & E d e m o n s t r a t e d f e a t u r e s c o n s i s t e n t w i t h a s e v e r e m y o p a t h y . In a d d i t i o n t h e r e was a n a c c u m u l a t i o n
o f r o u n d s t r u c t u r e s in t h e s a r c o l e m m a l a r e a s s i m i l a r
to t h o s e f o u n d in c a s e 1. T h e c a r d i a c m u s c l e w h e n r e v i e w e d f a i l e d to d e m o n s t r a t e i n c l u s i o n b o d i e s o n light m i c r o s c o p y .
286
Fig. 2. Case 1. Cross section of a specimen from left vastus lateralis muscle. Treatment with modified Gomori trichrome stain, shows multiple dark red, mostly subsarcolemmal cytoplasmic bodies in 4 fibres. Also variable fibre diameter change present, x 200.
Fig. 3. Case 1. Biopsy from left vastus lateralis muscle reacted for N A D H dehydrogenase shows absence of staining of cytoplasmic bodies in type 1 fibres. × 200.
287
Fig. 4. Case 1. Biopsy from left vastus lateralis muscle. Electron micrograph shows cytoplasmic body in 1 of 3 atrophic fibres, x 7280.
Case 3. The biopsy from the left vastus lateralis muscle showed on light microscopy only slight changes and these included mild variation of fibre diameter size, the smaller fibres being mostly type 2 fibres. Electron microscopy did show rare cytoplasmic bodies and also occasional filamentous masses (Fig. 6). DISCUSSION
(1) Family history In m y o p a t h y with abundant cytoplasmic bodies an autosomal dominant inheritance was observed by Clark et al. (1978) and by Edstr6m et al. (1980). One investigator reported it in 2 sisters (Wolburg et al. 1982). In 5 instances it occurred as a sporadic event (Nakashima et al. 1970; Kinoshita et al. 1975; Jerusalem et al. 1979; Goebel et al. 1981; Wolburg et al. 1982). There were however no extensive family data available. There appears to be no sex preponderance.
288
Fig. 5. Case 1. Biopsy from left vastus lateralis muscle. Electron micrograph shows cytoplasmic body with dense centre and radiating peripheral filaments. × 20~000.
In the present study we noted that 2 of 4 children t¥om the first cousin marriage had severe myopathy but none of the 6 offspring from her non-consanguineous marriage had symptoms of myopathy. The mother had minimal findings. This might suggest an autosomal recessive pattern of inheritance with the mother being a carrier. However, a dominant gene with much reduced penetrance is not excluded and further evaluation of asymptomatic family members may be helpful.
(2) Clinical findings A review of available data which are summarized in Table 1 indicates that the clinical picture is not uniform. Symptoms appear from early to late life, the sternomastoid and face muscles are frequently affected and the respiratory and cardiac muscles may be involved in some instances. The tendon reflexes are generally depressed. The serum C K level is normal or mildly elevated. The distribution and the severity of the muscle weakness varies as does the course. The patients described by Kinoshita et al, (1975) and Jerusalem et al.
289
Fig. 6. Case 3. Biopsy from left vastus lateralis muscle. Electron micrograph shows subsarcolemmal filamentous mass. x 12,200.
(1979) had symptoms in childhood with weakness of the sternomastoid and thoracic muscles and lesser involvement of the limb musculature. They succumbed in early adult life as a result of cardiorespiratory insufficiency with which they presented and which dominated the clinical picture. It also resulted in diagnostic difficulties (Jerusalem 1979). This contrasts with the findings in the cases reported by Nakashima et al. (1970)and Clark et al. (1978)where the symptoms appeared in late middle life, the limb-girdle muscles were predominantly involved and the course was benign. The family described by Edstr6m et al. (1980) fit in between these 2 extremes. The disability started in early m~ddle life; distal limb weakness was an early prominent feature while slight involvement of the sternomastoid and cardiorespiratory muscles was present. The course was not quite benign; the patients became confined to the wheelchair. Our 2 younger patients had a malignant course. They resembled the case described by Kinoshita et al. (1975) but they had additional features including
290 weakness of other cranial muscles, severe scoliosis and an elevated serum CK level. On the other hand the mother had a benign course resembling the patients described by Clark et al. (1978). Thus within the family the severity of the disease varied. Other authors did not report this (Clark et al. 1978; Edstr6m et al. 1980). The relationship of our younger patients' illness to that of their second cousin and her relatives or to that of the father, who had a transient paresis, is not clear.
(3) Morphology The striking finding in the muscle biopsy on light microscopy was the presence of abundant cytoplasmic bodies in our 2 cases and in those of other authors (Nakashima et al. 1970; Kinoshita et al. 1975; Clark et al. 1978; Edstr6m et al. 1980; Goebel et al. 1981; Wolburg et al. 1982). Other consistent features as seen in Table 2, were fibre diameter variation and many internally placed nuclei. In most instances the cytoplasmic bodies were confined to or predominently involved type 1 fibres; Nakashima et al. (1970) and Edstr6m et al. (1980) observed them in both fibre types. They were most easily demonstrated in the trichrome-stained material where their red colour contrasted with the green myofibrillar network. Edstr6m et al. (1980) claimed that the structures they observed were pathognomonic for the entity they described. On electron microscopy the cytoplasmic body typically appears to consist of 3 zones with a central dense "core", an intermediate less dense "halo" and an outer "shell" together with focal decrease of mitochondria (Engel 1962; MacDonald and Engel 1969). In some instances 2 zones were present and filaments may be seen in the centre of the electron-dense granular core (Goebel et al. 1981; Wolburg et al. 1982). Cytoplasmic bodies occur in pathological human skeletal muscle fibres (Engel 1962; Engel and MacDonald 1969). Rare cytoplasmic bodies restricted to type 2 fibres are generally a nonspecific finding observed in denervated muscle and myotonic dystrophy (Engel 1962), periodic paresis and muscular dystrophy (MacDonald et al. 1969), collagen vascular disease (Shafiq et al. 1967), mitochondrial myopathy (d'Agostino et al. 1968), psoriatic arthropathic myopathy (Serratrice et at. 1970) and trichopoliodystrophy (Ghatak et al. 1972). The presence of abundant cytoplasmic bodies and predominant involvement of type 1 fibres together with the absence of strong indicators of the known conditions associated with these structures as a secondary phenomenon, indicates that our patients have a distinct clinico-pathological entity. It may be argued that since the fibre type involved was unknown in our third patient, the rare cytoplasmic bodies may be a nonspecific finding as also may be the small type 2 fibres (Engel 1970). That this is probably not so is supported by the absence of known conditions associated with these nonspecific findings coupled with the life long mild limb-girdle weakness, general small muscle mass and an EMG pattern consistent with a myopathy. Edstr6m et al. (1980) reported additional morphological features in their 3 patients including leptomeric fibres, microtubules while some cytoplasmic bodies
291 were surrounded by a membrane. They found the cytoplasmic bodies were sulpharich structures. Whether the condition they reported is a distinct and separate entity from the cytoplasmic body myopathies described by other authors is at present not clear. Opinions vary about the origin o f cytoplasmic bodies. These include (a) Zband (MacDonald et al. 1969), (b) Z-band as well as myofibrils (Shafiq et al. 1967), (c) filaments of disorganized myofibrils (Nakashima et al. 1970; Kinoshita 1975; Wolburg 1982), (d) possible origin or relationship to intermediate-sized filaments (Edstr6m et al. 1978) and (e) relationship to filamentous bodies (Goebel 1981). The aetiology of neuromuscular disease with abundant cytoplasmic bodies is unknown. In at least some cases a neurogenic influence may be present. This is supported by the E M G findings viz. denervation units, high-amplitude longduration potentials and reduced interference pattern (Nakashima et al. 1970; Jerusalem et al. 1978; Wolburg et al. 1982) together with the morphological finding of angular fibres, group and type atrophy (Jerusalem et al. 1978 ; Wolburg et al. 1982). It is then of great interest that Fukuhara et al. (1977) found cytoplasmic bodies restricted to type 1 fibres in organophosphate neuropathy. A genetic factor may also be important in some cases. Edstr6m et al. (1980) suggested a possible developmental and metabolic basis for the condition in their patients. Wolburg et al. (1982) postulated a basic defect of myofilament biosynthesis, presumably evoked by a neurogenic factor affecting the trophic influence of the neurone on the muscle cell. ADDENDUM The second cousin of our young patients developed a third episode of severe muscle weakness, aggravated by emotional stress and partially improved by rest. The limbs, face and bulbar muscles were affected; the tendon reflexes were intact. The C K was normal. The E M G showed a combination of active denervation and an increase in small amplitude, short duration, polyphasic potentials. Some instability of neuromuscular transmission was also demonstrated. The biopsy from the deltoid muscle was normal on light microscopy, including histochemical studies and also on electron microscopy. The ECG and echocardiogram were normal. There was no response to steroid treatment. Five months after the onset o f weakness, muscle strength gradually returned a n d w h e n examined 2 months later she had only minimal weakness of the shoulder girdle muscles. REFERENCES Clark, J. R., A.N. d'Agostino, J. Wilson, R.R. Brooks and G.C. Cole (1978) Autosomal dominant myofibrillar inclusion body myopathy -- Clinical, histologic, histochemical and ultrastructural characteristics, Neurology (Minneap.), 28:399 (Abstr.). Conch, P.E., E.G. Murphy and W.L. Donohue (1963) Light and electron microscopic studies of "myogranules" in a child with hypotonia and muscle weakness, Canad. Med. Ass. J., 89: 983-986. d'Agostino, A. N., F.A. Ziter, M.L. Rallison and P. F. Bray (1968) Familial myopathy with abnormal muscle mitochondria, Arch. Neurol. (Chic.), 18: 388~,01.
292 Edstr6m, L., L. E. Thronell and A. Eriksson (1980) A new type of distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments, J. Neurol. Sci., 47:171. 190. Engel, W.K. (1962) The essentiality of histo- and cytochemical studies of skeletal muscles m the investigation of neuromuscular disease, Neurology (Minneap.), 12 : 778-794. Engel, W. K. (1970) Selective and non-selective susceptibility of muscle fibre types, Arch. Neurol. (Cht~'.., 22: 97-117. Fukuhara, N., M. Hoshi and S. Mori (1977) Core/targetoid fibres and multiple cytoplasmic bodies in organophosphate neuropathy, Acta Neuropath. (Berl.), 40:137 144. Ghatak, N.R., A. Hirano, T.P. Poon and J.H. French (1972) Trichopoliodystrophy, Arch. Neuroi. (Chic.), 26:60 72. Goebel, H.H., H. Schloon and H.G. Lenard (1981) Congenital myopathy with cytoplasmic bodies, Neuropediatrics, 12: 166-180. Jerusalem, F., H. Ludin, A. Bischoff and G. Hartmann (1979) Cytoplasmic body neuromyopathy presenting as respiratory failure and weight loss, J. Neurol. Sei., 41 : 1-9. Kinoshita, M., E. Satoyoshi and Y. Suzuki (1975) Atypical myopathy with myofibrillar aggregates. Arch. Neurol. (Chic.), 32:417-419. MacDonald, R.D. and A.G. Engel (1969) The cytoplasmic body -- Another structural anomaly of the Z disc, Acta Neuropath. (Berl.). 14: 99-107. Nakashima, N., Z. Tamura, S. Okamoto and H. Goto (1970) Inclusion bodies in human neuromuscular disorder, Arch. Neurol. (Chic.), 22: 270-278. Serratrice, G., H. Roux, R. Aquaron, D. Gambarelli, R. Baret and A. M. Recordier (1970) Myopathy associated with arthropathic psoriasis. In: J.N. Walton, N. Caval and G. Scarlato (Eds.) Muscle Disease (Intern. Congr. Series, No. 199), Excerpta Medica, Amsterdam, p. 642. Shafiq, S.A., A.T. Milhorat and M.A. Gorycki (1967) An electron microscope study of muscle degeneration and vascular changes in polymyositis, J. Path. Baet., 94: 139-147. Shy, G. M., W.K. Engel, J. E. Somers and T. Wanko (1963) Nemaline myopathy - - A new congenital myopathy, Brain, 86: 793-810. Wolburg, H., W. Schlote, H.D+ Langohr, J. Peiffer, K.H. Reiher and R.W. Heckt (1982) Slowly progressive congenital myopathy with cytoplasmic bodies - - Report of 2 cases and a review of the literature, Clin. Neuropath., 1 : 55-66.
281
Elsevier
CYTOPLASMIC BODY MYOPATHY Report on a Family and Review of the Literature H. PATEL I, K. BERRY 2, P. MAcLEOD 3 and H.G. DUNN 1
Departments of Ipaediatrics, 2Pathology and 3Genetics, Faculty of Medicine, University of British Columbia, and Vancouver General Hospital, B.C. (Canada) (Received 1 December, 1982) (Revised, received 7 February, 1983) (Accepted 9 February, 1983)
SUMMARY
A 15-year-old girl who was seen for scoliosis presented with cardiorespiratory failure associated with a respiratory infection. She was found to have weakness predominant in the face, sternomastoid, proximal limb, respiratory, spinal and cardiac muscles. The serum creatine kinase level was slightly elevated and the electrocardiogram was abnormal. The electromyograph was consistent with a myopathy. The course was malignant. Her 14-year-old brother had similar findings and succumbed at the age of 14 and one-half years from cardiorespiratory failure. The mother had minimal weakness of proximal limb muscles since early life. The tendon reflexes were normal as was the serum creatine kinase level. The course was benign. On light microscopy the muscle biopsy in the girl showed fibre diameter variation, centrally placed nuclei, necrosis, fibrosis and cytoplasmic bodies. The muscle biopsy in the brother and mother had similar findings except that the inclusion bodies were not seen in the mother. On electron microscopy, the girl showed typical cytoplasmic bodies, involving predominantly type 1 fibres. The mother also had these structures. The literature is reviewed and the origin, pathogenesis and aetiology of the cytoplasmic body are discussed.
INTRODUCTION
Histochemistry and electron microscopy have permitted the recognition of several new muscle disease entities, based on morphological rather than clinical Correspondence to: Dr. H. Patel, Department of Paediatrics, B.C.'s Children's Hospital, 4480 Oak Street, Vancouver, B.C. V6H 3V4, Canada.
0022-510X/83/$03.00 © 1983 Elsevier Science Publishers B.V.
282 data. In some of these, abundant abnormal structures accumulate within the muscle fibres. For example, rod-shaped bodies in nemaline myopathy (Conen et al. 1963: Shy et al. 1963). Recently, we examined 2 siblings in whom muscle biopsies demonstrated abundant cytoplasmic bodies detected by electron and/or light microscopy. The mother's tissue contained similar structures which were seen only on eletron microscopy. We wish to report (1) the family history, (2) clinical and laboratory findings and (3) morphological data observed in these patients and their mother. MATERIALAND METHOD
(1) Family history (Fig. 1 shows the details) The parents were first cousins. The father had an unexplained transient paraparesis at the age of 35 years and died of a myocardial infarction 20 years later. The 55-year-old mother had mild limb-girdle weakness for as long as she could remember. She also had recurring joint discomfort attributed to "arthritis". A son with seizures and mental retardation secondary to meningitis died at the age of 17 years while the 19-year-old son was healthy. Six children from her previous nonconsanguineous marriage were healthy while 2 had died with respiratory infections in infancy. Her 1 sister with a deformed back died in childhood. A second cousin of our young patients required assisted ventilation for respiratory infection and failure when she was aged 20 years. She had residual generalized muscle weakness. Her electromyogram (EMG) was considered to indicate a myopathy but the muscle biopsy on routine H&E stain was reported as normal. A year later following another episode of respiratory infection and failure she received steroid
(
0
It RNeuromuscular lesion +Deceased
Fig. 1. Pedigreeof family.*Secondcousin of our youngpatients.
283 treatment which resulted in clinical recovery. However, the EMG remained abnormal with short duration, low amplitude motor units, excessive polyphasic units and full recruitment with maximum contraction. Similar EMG findings were present in her asymptomatic mother and her 18-month-old hypotonic nephew. The latter had a slightly elevated serum creatine kinase (CK) level and a normal muscle biopsy examined by H&E, histochemical stains and electron microscopy.
(2) Clinical and laboratory data (Tables 1 and 2 summarize the findings) Case 1 A native North
American
I n d i a n g i r l a g e d 15 y e a r s a n d
10 m o n t h s
w a s seen i n t h e S c o l i o s i s
Clinic a n d a d m i t t e d s o o n a f t e r w a r d s w i t h r e s p i r a t o r y failure. She was delivered by C a e s a r e a n section a t 37 w e e k s b e c a u s e o f a n t e p a r t u m 2.75 k g a n d i n t h e f i r s t m o n t h
haemorrhage.
Foetal movements
had been adequate. She weighed
had feeding difficulty and poor weight gain. Her early development
w a s n o r m a l b u t s h e w a l k e d f r e e l y o n l y a t t h e a g e o f 15 m o n t h s .
TABLE
1
CLINICAL
AND
LABORATORY
DATA
IN CYTOPLASMIC
BODY
MYOPATHY
Authors
Nakashima et al. (1970)
Kinoshita Clark Jerusalem Edstr6m et al. et al. et al. et al. (1975) (1978) (1979) (1980)
Goebel et al. (1981)
Wolburg et al. (1982)
Wolburg et al. (1982)
Present study
Family history
neg
neg
neg
neg
pos
pos
pos
pos
Sex Age (years) (1) at onset
M
F
F
M
F
F
M
F
53
16
infant
infant
13
5
53
22
early life 15
32
32
15
14
early life 55
Muscle weakness face sternomastoid proximal limb distal limb respiratory cardiac spinal other
+ + + NR NR NR
+ + + + + +
+ + + NR +
+ -
Tendon reflexes Serum CK
dec inc
dec inc
N N
ECG EMG Cardiorespiratory failure Course
(2) at examination
Case 1 Case 2 Case 3
pos AD M F
neg F
pos AD M F
late life late life
child
midlife
22
54-58
+ + + + + + +
+ -
+ + + NR +
+ + + + + + hand
+ NR + + -
+ NR + + neck
dec inc
dec N
N N
NR inc
dec inc
NR inc
N neur -
N myo +
dec N or inc NR myo -
NR + + + pupil general NR N
N neur +
NR myo -
N "myo" -
abn mixed -
NR myo +
abn myo +
NR myo +
N myo -
ben
mal
ben
mal
semimal
ben
NR
NR
real
mal
ben
pos = positive; neg = negative; neur = neurogenic; myo = myopathic; ben = benign; mal = malignant; NR = no record; A D = a u t o s o m a l d o m i n a n t ; N = n o r m a l ; a b n = a b n o r m a l ; inc = increased ; dec = decreased; + = p r e s e n t ; -
= absent.
284 TABLE 2 M O R P H O L O G I C A L DATA R E P O R T E D IN CYTOPLASMIC BODY M Y O P A T H Y Authors
Fibre diameter variation Internal nuclei Degeneration Fibrosis Atrophic fibres (1) group atrophy (2) fibre type Z-line change Filamentous body Cytoplasmic inclusion bodies and fibre type
Nakashima et al. (1970)
Kinoshita Clark Jerusalem Edstrtm Goebel Wolburg et al. et al. et al. et al. et al. et al. (1975) (1978)(1979) ( 1 9 8 0 ) (1981) ( 1 9 8 2 )
Wolburg et al. (1982)
Presenl stud.', ..... Case I Case 2 Case3
+
+
+
+
+
+
+
+
+
+
inc
inc
inc + +
inc
inc +
inc
inc
inc + +
inc + +
+ +
+
+ 1 + + 1& 2
+ *
1
1
+ + I&2
+ I
+ 1 + I
it~c +
+ + I
]
*
+ *
+ = present; - = absent; inc = increased; * = fibre type not possible to determine. She had frequent upper respiratory and ear infections and at 18 months recovered satisfactorily from pneumonia. A single brief non-febrile, generalized seizure occurred at the age of 1 year. When she was 13 years old she developed easy fatiguability, effort and nocturnal dyspnoea. difficulty with swallowing, chewing, articulation, expectoration, combing hair and climbing stairs. She had precordial pain with effort, also abdominal pain and constipation. Scoliosis was noted. Recently she had developed headaches. Four weeks before admission she had a febrile respiratory illness with partial recovery and 2 weeks later she developed rapid respiratory failure and required ventillator assistance. Examination revealed an intelligent, very thin girl with normal height and head circumference measurement. She had a long face, long thin hands and feet, a high-arched palate, prognathlsm. prominent eyes, patulous lips, lagophthalmos, scoliosis and small muscle mass. The sternomastoid muscles were very thin and weak. The masseter, facial and intercostal muscles had moderate impairment of strength while slight weakness was noted in the proximal limb-girdle muscles. The tendon reflexes were depressed. The remainder of the neuromuscular system was normal. The pulse was irregular at 120/min and the B.P. was 100/70 mm Hg. She had a grade 2 of 6 systolic murmur. Crepitations were heard at the lung bases. Her cardiac status improved with the rate, rhythm and size of heart returning to normal but the electrocardiograph (ECG) remained abnormal. The strength improved in the shoulder girdle. cranial and respiratory muscles but she continued to require intermittent ventilator assistance. The F.V.C. improved from 380 ml to 600-700 ml. She had 2 self-limited, brief episodes of profound weakness during which she was immobile, atonic and areflexic but fully conscious. These attacks could not be correlated with any specific change in blood gases, serum electrolyte levels or electroencephalogram. A course of steroid therapy was ineffective. Normal laboratory data included peripheral blood picture, serum electrolytes, erythrocyte sedimentation rate, routine analysis and amino acid chromatography of urine, antinuclear factor. serum protein electrophoresis and immunoglobulin IgG and IgA; The IgM was slightly elevated. The serum enzyme levels were elevated with LDH 466 IU/I (normal up to 350 IU/I), CK 220 IU/I (normal up to 120 IU/I). The electrodiagnostic studies were suggestive of a myopathy with normal motor nerve conduction velocity, short duration low amplitude motor unit potentials, excessive amount of polyphasic units and full interference patter.n Some long duration units were present. An occasional satellite unit was seen.
285 The electrocardiogram demonstrated left ventricular hypertrophy, depressed S-T segments in the left chest leads and conduction disturbance. The echoeardiogram revealed thickening of the posterior leaflet of the mitral valve with paradoxical movement. The electroencephalogram was reported as being slightly diffusely slow for age.
Case 2 This 14-year-old boy was the eldest of the 4 children in the sibship. He was admitted for evaluation of scoliosis. The mother's pregnancy was normal with adequate foetal movements. He was born at term after a 24-hour labour and weighed 2.9 kg. He behaved normally in the newborn period. He then developed appropriately but did not walk freely until the age of 18 months. At school he required a special class for slow learners. He had several upper respiratory infections and 2 attacks of pneumonia with satisfactory recovery. Frequent falls were noted at the age of 5 years and easy fatiguability when he was 9 years old. A stiff gait, leg pains, partial eye closure during sleep and scoliosis were observed at the age of 13 years. Examination showed that the height, weight and head circumference measurements were normal. Muscle mass was generally decreased. The sternomastoid muscles were thin and weak. The strength was impaired in the abdominal, spinal and limb-girdle muscles. The tendon reflexes were depressed. Severe dorsolumbar scoliosis was present. The remainder of the neuromuscular system was normal. The pulse was regular at 114/min and the B.P. was 125/80 mm Hg. No cardiac murmur was heard. The lung fields were clear. Normal laboratory tests included electroencephalogram and chest X-ray. The serum CK level was elevated at 295 IU/1 (normal up to 120 IU/1). The electrodiagnostic studies demonstrated normal motor and sensory nerve conduction velocity, short duration low amplitude motor unit potentials, excessive polyphasic units and full interference pattern, features which suggested a myopathy. Fibrillation and positive sharp waves were present. At the age of 14 and one-half years he developed progressive effort and nocturnal dyspnoea. He then had respiratory arrest and died before reaching the local hospital.
Case 3 The mother aged 55 years was generally healthy except for slight limb-girdle muscle weakness which she had all her life. Examination confirmed that she had mild proximal limb-girdle muscle weakness. Her muscle mass was generally small. The remainder of the examination was normal. The serum CK level was normal. The electrodiagnostic studies showed similar but less pronounced abnormalities than in her children. The amplitude reached with maximum volition was however only 1 mV in some muscles.
(3) Muscle biopsy data ( T h e s e a r e s u m m a r i z e d in T a b l e 2) Case 1. B i o p s i e s f r o m t h e left v a s t u s l a t e r a l i s a n d d e l t o i d m u s c l e s s h o w e d similar features but were more pronounced
in t h e f o r m e r . T h e f i n d i n g s o n l i g h t
m i c r o s c o p y w e r e c o n s i s t e n t w i t h a s e v e r e m y o p a t h y . A s t r i k i n g f e a t u r e in m a n y fibres w a s t h e a c c u m u l a t i o n o f c y t o p l a s m i c b o d i e s w h i c h a p p e a r e d as b r i g h t r e d s t r u c t u r e s w i t h t h e m o d i f i e d G o m o r i t r i c h r o m e stain. T h e y s t a i n e d n e g a t i v e l y w i t h v a r i o u s stains t h a t is N A D H ,
ATPase, PAS and phosphylorase
T h e u p t a k e o f d y e w a s v a r i a b l e in t h e m e n a d i o n e - l i n k e d preparation.
These bodies were present predominantly
(Figs. 2 a n d 3).
nitroblue-datrazolium
in t y p e 1 a n d o n l y v e r y
o c c a s i o n a l l y in t y p e 2 fibres. E l e c t r o n m i c r o s c o p y r e v e a l e d t h e s t r u c t u r e s
had
f e a t u r e s o f c y t o p l a s m i c b o d i e s w i t h a d e n s e c e n t r a l z o n e s u r r o u n d e d by a l i g h t e r h a l o a n d a n o u t e r shell (Figs. 4 a n d 5). S t r e a m i n g o f t h e Z b a n d w a s a l s o o b s e r v e d .
Case 2. L e f t d e l t o i d m u s c l e b i o p s y w i t h p a r a f f i n - e m b e d d e d s e c t i o n s s t a i n e d w i t h H & E d e m o n s t r a t e d f e a t u r e s c o n s i s t e n t w i t h a s e v e r e m y o p a t h y . In a d d i t i o n t h e r e was a n a c c u m u l a t i o n
o f r o u n d s t r u c t u r e s in t h e s a r c o l e m m a l a r e a s s i m i l a r
to t h o s e f o u n d in c a s e 1. T h e c a r d i a c m u s c l e w h e n r e v i e w e d f a i l e d to d e m o n s t r a t e i n c l u s i o n b o d i e s o n light m i c r o s c o p y .
286
Fig. 2. Case 1. Cross section of a specimen from left vastus lateralis muscle. Treatment with modified Gomori trichrome stain, shows multiple dark red, mostly subsarcolemmal cytoplasmic bodies in 4 fibres. Also variable fibre diameter change present, x 200.
Fig. 3. Case 1. Biopsy from left vastus lateralis muscle reacted for N A D H dehydrogenase shows absence of staining of cytoplasmic bodies in type 1 fibres. × 200.
287
Fig. 4. Case 1. Biopsy from left vastus lateralis muscle. Electron micrograph shows cytoplasmic body in 1 of 3 atrophic fibres, x 7280.
Case 3. The biopsy from the left vastus lateralis muscle showed on light microscopy only slight changes and these included mild variation of fibre diameter size, the smaller fibres being mostly type 2 fibres. Electron microscopy did show rare cytoplasmic bodies and also occasional filamentous masses (Fig. 6). DISCUSSION
(1) Family history In m y o p a t h y with abundant cytoplasmic bodies an autosomal dominant inheritance was observed by Clark et al. (1978) and by Edstr6m et al. (1980). One investigator reported it in 2 sisters (Wolburg et al. 1982). In 5 instances it occurred as a sporadic event (Nakashima et al. 1970; Kinoshita et al. 1975; Jerusalem et al. 1979; Goebel et al. 1981; Wolburg et al. 1982). There were however no extensive family data available. There appears to be no sex preponderance.
288
Fig. 5. Case 1. Biopsy from left vastus lateralis muscle. Electron micrograph shows cytoplasmic body with dense centre and radiating peripheral filaments. × 20~000.
In the present study we noted that 2 of 4 children t¥om the first cousin marriage had severe myopathy but none of the 6 offspring from her non-consanguineous marriage had symptoms of myopathy. The mother had minimal findings. This might suggest an autosomal recessive pattern of inheritance with the mother being a carrier. However, a dominant gene with much reduced penetrance is not excluded and further evaluation of asymptomatic family members may be helpful.
(2) Clinical findings A review of available data which are summarized in Table 1 indicates that the clinical picture is not uniform. Symptoms appear from early to late life, the sternomastoid and face muscles are frequently affected and the respiratory and cardiac muscles may be involved in some instances. The tendon reflexes are generally depressed. The serum C K level is normal or mildly elevated. The distribution and the severity of the muscle weakness varies as does the course. The patients described by Kinoshita et al, (1975) and Jerusalem et al.
289
Fig. 6. Case 3. Biopsy from left vastus lateralis muscle. Electron micrograph shows subsarcolemmal filamentous mass. x 12,200.
(1979) had symptoms in childhood with weakness of the sternomastoid and thoracic muscles and lesser involvement of the limb musculature. They succumbed in early adult life as a result of cardiorespiratory insufficiency with which they presented and which dominated the clinical picture. It also resulted in diagnostic difficulties (Jerusalem 1979). This contrasts with the findings in the cases reported by Nakashima et al. (1970)and Clark et al. (1978)where the symptoms appeared in late middle life, the limb-girdle muscles were predominantly involved and the course was benign. The family described by Edstr6m et al. (1980) fit in between these 2 extremes. The disability started in early m~ddle life; distal limb weakness was an early prominent feature while slight involvement of the sternomastoid and cardiorespiratory muscles was present. The course was not quite benign; the patients became confined to the wheelchair. Our 2 younger patients had a malignant course. They resembled the case described by Kinoshita et al. (1975) but they had additional features including
290 weakness of other cranial muscles, severe scoliosis and an elevated serum CK level. On the other hand the mother had a benign course resembling the patients described by Clark et al. (1978). Thus within the family the severity of the disease varied. Other authors did not report this (Clark et al. 1978; Edstr6m et al. 1980). The relationship of our younger patients' illness to that of their second cousin and her relatives or to that of the father, who had a transient paresis, is not clear.
(3) Morphology The striking finding in the muscle biopsy on light microscopy was the presence of abundant cytoplasmic bodies in our 2 cases and in those of other authors (Nakashima et al. 1970; Kinoshita et al. 1975; Clark et al. 1978; Edstr6m et al. 1980; Goebel et al. 1981; Wolburg et al. 1982). Other consistent features as seen in Table 2, were fibre diameter variation and many internally placed nuclei. In most instances the cytoplasmic bodies were confined to or predominently involved type 1 fibres; Nakashima et al. (1970) and Edstr6m et al. (1980) observed them in both fibre types. They were most easily demonstrated in the trichrome-stained material where their red colour contrasted with the green myofibrillar network. Edstr6m et al. (1980) claimed that the structures they observed were pathognomonic for the entity they described. On electron microscopy the cytoplasmic body typically appears to consist of 3 zones with a central dense "core", an intermediate less dense "halo" and an outer "shell" together with focal decrease of mitochondria (Engel 1962; MacDonald and Engel 1969). In some instances 2 zones were present and filaments may be seen in the centre of the electron-dense granular core (Goebel et al. 1981; Wolburg et al. 1982). Cytoplasmic bodies occur in pathological human skeletal muscle fibres (Engel 1962; Engel and MacDonald 1969). Rare cytoplasmic bodies restricted to type 2 fibres are generally a nonspecific finding observed in denervated muscle and myotonic dystrophy (Engel 1962), periodic paresis and muscular dystrophy (MacDonald et al. 1969), collagen vascular disease (Shafiq et al. 1967), mitochondrial myopathy (d'Agostino et al. 1968), psoriatic arthropathic myopathy (Serratrice et at. 1970) and trichopoliodystrophy (Ghatak et al. 1972). The presence of abundant cytoplasmic bodies and predominant involvement of type 1 fibres together with the absence of strong indicators of the known conditions associated with these structures as a secondary phenomenon, indicates that our patients have a distinct clinico-pathological entity. It may be argued that since the fibre type involved was unknown in our third patient, the rare cytoplasmic bodies may be a nonspecific finding as also may be the small type 2 fibres (Engel 1970). That this is probably not so is supported by the absence of known conditions associated with these nonspecific findings coupled with the life long mild limb-girdle weakness, general small muscle mass and an EMG pattern consistent with a myopathy. Edstr6m et al. (1980) reported additional morphological features in their 3 patients including leptomeric fibres, microtubules while some cytoplasmic bodies
291 were surrounded by a membrane. They found the cytoplasmic bodies were sulpharich structures. Whether the condition they reported is a distinct and separate entity from the cytoplasmic body myopathies described by other authors is at present not clear. Opinions vary about the origin o f cytoplasmic bodies. These include (a) Zband (MacDonald et al. 1969), (b) Z-band as well as myofibrils (Shafiq et al. 1967), (c) filaments of disorganized myofibrils (Nakashima et al. 1970; Kinoshita 1975; Wolburg 1982), (d) possible origin or relationship to intermediate-sized filaments (Edstr6m et al. 1978) and (e) relationship to filamentous bodies (Goebel 1981). The aetiology of neuromuscular disease with abundant cytoplasmic bodies is unknown. In at least some cases a neurogenic influence may be present. This is supported by the E M G findings viz. denervation units, high-amplitude longduration potentials and reduced interference pattern (Nakashima et al. 1970; Jerusalem et al. 1978; Wolburg et al. 1982) together with the morphological finding of angular fibres, group and type atrophy (Jerusalem et al. 1978 ; Wolburg et al. 1982). It is then of great interest that Fukuhara et al. (1977) found cytoplasmic bodies restricted to type 1 fibres in organophosphate neuropathy. A genetic factor may also be important in some cases. Edstr6m et al. (1980) suggested a possible developmental and metabolic basis for the condition in their patients. Wolburg et al. (1982) postulated a basic defect of myofilament biosynthesis, presumably evoked by a neurogenic factor affecting the trophic influence of the neurone on the muscle cell. ADDENDUM The second cousin of our young patients developed a third episode of severe muscle weakness, aggravated by emotional stress and partially improved by rest. The limbs, face and bulbar muscles were affected; the tendon reflexes were intact. The C K was normal. The E M G showed a combination of active denervation and an increase in small amplitude, short duration, polyphasic potentials. Some instability of neuromuscular transmission was also demonstrated. The biopsy from the deltoid muscle was normal on light microscopy, including histochemical studies and also on electron microscopy. The ECG and echocardiogram were normal. There was no response to steroid treatment. Five months after the onset o f weakness, muscle strength gradually returned a n d w h e n examined 2 months later she had only minimal weakness of the shoulder girdle muscles. REFERENCES Clark, J. R., A.N. d'Agostino, J. Wilson, R.R. Brooks and G.C. Cole (1978) Autosomal dominant myofibrillar inclusion body myopathy -- Clinical, histologic, histochemical and ultrastructural characteristics, Neurology (Minneap.), 28:399 (Abstr.). Conch, P.E., E.G. Murphy and W.L. Donohue (1963) Light and electron microscopic studies of "myogranules" in a child with hypotonia and muscle weakness, Canad. Med. Ass. J., 89: 983-986. d'Agostino, A. N., F.A. Ziter, M.L. Rallison and P. F. Bray (1968) Familial myopathy with abnormal muscle mitochondria, Arch. Neurol. (Chic.), 18: 388~,01.
292 Edstr6m, L., L. E. Thronell and A. Eriksson (1980) A new type of distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments, J. Neurol. Sci., 47:171. 190. Engel, W.K. (1962) The essentiality of histo- and cytochemical studies of skeletal muscles m the investigation of neuromuscular disease, Neurology (Minneap.), 12 : 778-794. Engel, W. K. (1970) Selective and non-selective susceptibility of muscle fibre types, Arch. Neurol. (Cht~'.., 22: 97-117. Fukuhara, N., M. Hoshi and S. Mori (1977) Core/targetoid fibres and multiple cytoplasmic bodies in organophosphate neuropathy, Acta Neuropath. (Berl.), 40:137 144. Ghatak, N.R., A. Hirano, T.P. Poon and J.H. French (1972) Trichopoliodystrophy, Arch. Neuroi. (Chic.), 26:60 72. Goebel, H.H., H. Schloon and H.G. Lenard (1981) Congenital myopathy with cytoplasmic bodies, Neuropediatrics, 12: 166-180. Jerusalem, F., H. Ludin, A. Bischoff and G. Hartmann (1979) Cytoplasmic body neuromyopathy presenting as respiratory failure and weight loss, J. Neurol. Sei., 41 : 1-9. Kinoshita, M., E. Satoyoshi and Y. Suzuki (1975) Atypical myopathy with myofibrillar aggregates. Arch. Neurol. (Chic.), 32:417-419. MacDonald, R.D. and A.G. Engel (1969) The cytoplasmic body -- Another structural anomaly of the Z disc, Acta Neuropath. (Berl.). 14: 99-107. Nakashima, N., Z. Tamura, S. Okamoto and H. Goto (1970) Inclusion bodies in human neuromuscular disorder, Arch. Neurol. (Chic.), 22: 270-278. Serratrice, G., H. Roux, R. Aquaron, D. Gambarelli, R. Baret and A. M. Recordier (1970) Myopathy associated with arthropathic psoriasis. In: J.N. Walton, N. Caval and G. Scarlato (Eds.) Muscle Disease (Intern. Congr. Series, No. 199), Excerpta Medica, Amsterdam, p. 642. Shafiq, S.A., A.T. Milhorat and M.A. Gorycki (1967) An electron microscope study of muscle degeneration and vascular changes in polymyositis, J. Path. Baet., 94: 139-147. Shy, G. M., W.K. Engel, J. E. Somers and T. Wanko (1963) Nemaline myopathy - - A new congenital myopathy, Brain, 86: 793-810. Wolburg, H., W. Schlote, H.D+ Langohr, J. Peiffer, K.H. Reiher and R.W. Heckt (1982) Slowly progressive congenital myopathy with cytoplasmic bodies - - Report of 2 cases and a review of the literature, Clin. Neuropath., 1 : 55-66.