MYOPATHY WITH MULTIPLE MINICORE Report of Two Siblings Two ...

Journal of the Neurological Sciences, 1980, 48 : 81--92

81

~) Elsevier/North-Holland Biomedical Press

MYOPATHY WITH MULTIPLE MINICORE Report of Two Siblings

JOSI~ R. RICOY I, ANA CABELLO t and GABRIELA G O I Z U E T A 2

tDepartment ~[' Pathology ( Neuropathology ) and 2Service ~[' NeuroloKv, "l°de Octubre" Ho.~pital, Complutense Uniw'rsiO' School ~f Medicine, Madrid (Spain) (Received 17 March, 1980) (Accepted 7 May, 1980)

SUMMARY

Two cases of non-progressive congenital hypotonia are described in siblings, male and female, aged 5 and 9 years, respectively, .which morphologically correspond to myopathy with multicore or minicore. The study of these 2 cases is compared with those described in the literature, with special emphasis on the analysis of the histochemical picture. The disease in all the cases is defined by the presence of multiple small loci of loss of cross striation with loss of activity of myofibrillar ATPase and oxidative enzymes. Furthermore, a predominance and hypotrophy of type | fibers and in some cases hypertrophy of type II is constantly recorded, which is interpreted as an alteration in muscle maturation. We review other myopathies described with focal loss of cross-striation which associate central nuclei with the myofibrillar lesion, considering them to be myopathy with multicore or minicore.

INTRODUCTION

A . G . Engel et al. (1971) were first to describe a non-progressive congenital myopathy found in a 13-year-old male and a female studied at 6 and 11 years old. The underlying morphostructure was the presence of lesions similar to core, but of smaller size and greater in number; in accordance with these characteristics they were named multicore. Reprints requests and correspondence to: J. R. Ricoy, M.D., Ciudad Sanitaria "1 ° de Octubre", Dpto. Anatomia Patol6gica (Neuropatologia), Carretera de Andalucia, Kin. 5, Madrid 26, Spain.

82 In 1974. Currie et al.. having regard to the size of the lesions, called them minicore. In this report, we present the study of two siblings affected by this myopathy and we review the cases described as such, together with others which we believe to correspond to the same entity. From the review of the histochemical picture we conclude that in these patients a disturbance in muscle maturation coexists with the characteristic lesion (multicore or minicore). CASE REPORTS Case 1

A 5-year-old boy with no familial antecedents of neuromuscular disease except for his only sister (Case ll). The mother reports diminished fetal movements during pregnancy. He was a hypotonic child during the neonatal period and the hypotonia has persisted till the present day: however, postural development and growth were normal. From the age of 3, the parents noticed a slight clumsiness of movement, a tendency, to fall over easily and backwardness at play with his fellows. On current examination, a slight generalized hypotonia is found, with moderate weakness in the girdle muscles and generalized reduced tendon reflexes. There is no muscular atrophy. The facial and ocular muscles are normal. He has polythelia of the right hand. Cardiological examination, including a vectorcardiogram, is normal. Serum enzymes including CPK are normal. An EMG is also normal. A biopsy was performed of the rectus femoris muscle of the left quadriceps. Case 11

A 9-year-old girl, the older, only sister of the boy in Case I. The parents noticed backwardness in postural development and clumsy movements dating from the first few months of her life. In her early childhood she had frequent respiratory infections. After the age of 3, the parents noticed a gradual improvement in the clumsiness, her movements being the same as other children her age. On examination a slight generalized hypotonia is to be found with mild weakness in the girdle muscles and generalized reduced reflexes. The facial and extrinsic eye muscles are normal. She has a slight lumbar hyperlordosis. The tests carried out on her brother also gave negative results in her case. A biopsy was performed of the rectus femoris of the left quadriceps. MATERIAL A N D M E T H O D S

Under local anesthesia of the skin and subcutaneous tissue, a cylindrical portion of muscle, approximately 1 by 0.5 cm, was removed. Immediately after removal a fragment was separated out which was in turn cut into 1-mm cubes and fixed with paraformaldehyde-glutaraldehyde at 2~] for 3 h at 4°C. It was then washed in cacodylate buffer, postfixed in osmium tetroxide, dehydrated in graded alcohols and embedded in epoxy-resin. The blocks were trimmed, cut with an LKB ultramicrotome and examined with a Hitachi H-12 electron microscope. The semi-thin sections were stained with toluidine blue and examined under a light microscope. For the remainder of the biopsy material, a transversely-orientated block was shaped which was immediately frozen in isopentane cooled in liquid nitrogen, transferred to liquid nitrogen and cut with a cryostat. The sections thus obtained were processed with the following techniques: hematoxylin-eosin, trichrome according to Engel and Cunningham, PAS, Sudan III-IV, ATPase without preincubation and preincubated at pH 4.6 and 4.3, phosphorylase, phosphofructokinase, succinic dehydrogenase, NADH-tetrazolium reductase and alpha-glycerophosphate-dehydrogenase.

83 The remaining fragment of the biopsy was fixed in formol, embedded in paraffin and processed with the H E and P T A H techniques. RESULTS

The results are tabulated in Table 1. The biopsy from Case I did not show interstitial abnormalities, adipose tissue replacement, fibrosis or degenerative muscle fibers. The biopsy from Case II revealed an extensive endomysial adipose replacement which effaced the boundaries of the fascicles; there was no fibrosis. The rest of the changes observed were similar in both cases. There was a moderate number of central nuclei and the fiber size was variable with an abnormal coefficient of variability in Case I1 (287). In the sarcoplasm irregular basophilic areas were observed which did not displace the myofibrillar material. Using histo-enzymatic techniques, there was a good differentiation of fiber types, with correct enzymatic correspondence. Type I fibers had diameters which varied from 10 to 30 lam and in both cases this type was clearly predominant. Type II fibers had diameters larger than those of type I and appeared to be markedly reduced in number. As regards subtypes of type II fibers, in neither case were there type II-C fibers; there was a predominance of type II-A in both cases with deficiency of type B. In both cases, using N A D H - t e t r a z o l i u m reductase, areas devoid of enzyme activity were observed, less than 15 ~tm in diameter, as well as small areas of positive granular accumulations. Similar results were obtained with succinic dehydrogenase; both changes were more frequent in the type I fibers, though not exclusive to them. Pale areas were also observed with PAS and ATPase at pH 9.4. However, there was TABLE 1 BIOPSY F I N D I N G S IN T H E T W O P R E S E N T E D CASES

Cases

Endomysial adipose tissue Central nuclei Basophil accumulation '!,, Type 1 % Type II x Type 1 x Type 11 Oxidative enzymes : No activity (focal) Granular accumulation ATPase: No activity (local) ". Type II-A ",, Type II-B ",, Fype II-C

1

II

_.'v~....,, 67,. 92 8 21 + 4 26 + 9

+ 14",, 23". 90 10 20 ± 4 33 + 6

65",, 73,, 56",, 75 25 0

17". 45'!, 27",, 90 10 0

84 no strict c o r r e l a t i o n between those a r e a s lacking in o x i d a t i v e e n z y m e activit? and those lacking in activity tbr m y o f i b r i l l a r A T P a s e . In b o t h cases m u l t i p l e small losses o f transverse striation o f the fiber" \sere seen with p h o s p h o t u n g s t i c acid h e m a t o x y l i n a n d in semi-thin sections. In the u l t r a s t r u c t u r a l e x a m i n a t i o n , a l m o s t all the fibers showed multiple foci o f m y o f i b r i l l a r d i s o r g a n i s a t i o n . In these zones, the Z - d i s k has been t r a n s f o r m e d into

Fig, 1. Light-microscopic findings. Intense basophil areas in cellular sarcoplasm (~t; HE, × 1000). Focal defects of ATPase activity (h: ATPase, pH 9.4, × 100). Focal defects wilh oxidative enzyme reactions together with areas intensely positive (c and d: NADH TR, × 400).

85 irregular masses of dense material situated axially with respect to the main axis of the myofibrils. The intermyofibrillar spaces appeared to have collapsed, without the presence of sarcoplasmic organelles within them, and with a marked absence of mitochondria and reticulum. These loci involved the 4-10 adjacent myofibrils and extended over 2 - 5 consecutive sarcomeres. There is an abrupt transition between these areas and normal zones. In the small lesions, dense collections of particularly thick myofilaments are seen between the bands. There are other areas with focal accumulations of mitochondria and enclosed saclike formations. In both cases, the satellite cells are very obvious.

Fig. 2. In semithin sections there are multiple defects of fiber striation (toluidine blue, × 1000).

DISCUSSION We know of 18 cases described in 10 publications (Engel et al. 1971; M u k o y a m a et al. 1973 ; Bonnette et al. 1974; Currie et al. 1974; Tanimura et al. 1974; De Lumley et al. 1976; Heffner et al. 1976; Lake et al. 1977; Dubowitz 1978; Taratuto et al. 1978) which we shall discuss together with the 2 we furnish in this study. The cases reported by Dubowitz (1978) comprise 2 brothers and a sister with myopathy with multicore and extensive whorled fibers; we cannot evaluate these cases exhaustively as the information published is incomplete, as are the cases reported by Fardeau et al. (1977). The basic morphostructural picture is the same

86

Fig. 3, Electron-microscopic l'indings. Focal disruption of myofilaments with streaming of Z-b~tnd (a: x 12.800:h: x 11,600).

87

Fig. 4. Electron-microscopic findings. Focal disintegration of myofilamcnts and Z-band (a: × ~)600). Some areas with myofibrill~lr lesions show abundance of mitochondria and rcticulum (h: × 9600).

88 in all the cases described and forms the basis for differentiation of the disease (multicore or minicore). In Table 2 the cases are arranged according to the patient's age at the time of the study, together with the alterations present in each case. Eleven of the cases are males and 4 are females. In 3 families, apart from the 2 described by Dubowitz (1978), there are siblings affected (Cases I and 3, 4 and 5, 6 and 11); there are familial antecedents in only 2 cases (Cases 2 and 14). The disease is congenital in all cases except in Case 15 (Bonnette et al. 1974), in whom the disease appeared in adult life and behaved like a progressive, crippling myopathy. In the remaining cases the disease is not progressive or only slowly so (Cases 2, 7 and 8). Facial involvement is described in 4 cases (Cases 3, 7, 8 and 12); the involvement of extrinsic ocular muscles in another 4 (Cases 3 and 12 with facial involvement and Cases 1 and 13 without weakness of facial muscles). Weakness of the skeletal muscles is generalized in the young patients (Cases 2 and 4), and confined to the proximal zones in the older ones. In 12 cases there are mild electromyographic abnormalities (Cases 2, 3, 5, 7, 8, 9, 10, 11, 12, 13, 14 and 15), minimal changes which conform to the SSAP pattern (short duration, small amplitude, excessively abundant potentials) being the most frequent (Engel and Warmolts 1973). The CPK levels are slightly abnormal in 5 cases. The associated somatic alterations are not serious or particularly frequent; branch block and arthromyogryposis (Case 2), torticollis (Cases 4 and 5), cardiac septal defect (Case 13.), polythelia (Case 6), hyperlordosis (Case 11). Morphologically in almost all cases there is a variable proportion of central nuclei and a pronounced variability in the diameter of the fibers. The endomysial connective tissue is reported as increased in 6 cases and there is endomysial replacement in 3 cases. Furthermore, rod-like Z-bodies have been described (Case 10), whorled fibers (Case 5) and enlarged end-plates with numerous expansions (Cases 7 and 8). With regard to fiber types, in all the cases studied, there was a predominance of type I fibers and a constant feature is the disproportion in size of the fibers with hypotrophy of type I and hypertrophy of type II. The most frequent histochemical alterations found are the areas lacking in oxidative enzyme activity, almost a constant in the cases studied histochemically and present in a variable but high percentage of fibers. Less frequently, clusters of oxidative enzyme positive granules are described. Similarly, areas lacking in myofibrillar ATPase activity are almost invariably found. The most common and most easily demonstrated light-microscopic findings are the small multiple loci of loss of cross-striation and streaming of the Z-line. This alteration corresponds ultrastructurally to loci of myofibrillar disorganisation, which can extend to 2 4 consecutive sarcomeres (Case 2) and even as many as 5 (Cases 6 and 11), from 10 to 40 !am (Case 3), from 4 to 8 adjacent sarcomeres in 10 adjoining myofibrils (Cases 4 and 5) and some may even be central and elliptical up to 100 !am in diameter. Equally invariable is the decrease or absence of mitochondria in the areas of myofibrillar lesions. Apart from these alterations, the triads

x T y p e 11

+

+

+ +

3/4 M

2

+ +

+ + P D

1 5 M

3

+ +

+ +

90'111

N

N

90'~,,

5 10°,; 72 28 -

2 5 M

5

65'!o 73'~; 56'!,, +

26

22°i, 92 8 21

1 5 M

6

+

+ P D

+

1 ? M

7

OR MIN1CORE

5 10,, 80 20 -

1 5 M

4

AS MULTICORE

+

+ P D

+

2 ? M

8

+ +

100!!0

few all 0

6/8 M

9

DISEASE

+ +

+

N

5 15'!o P D -

2 7 F

13a

+

+

+ 60 40

+

F

8

10

17°, 45°0 .27'~,, +

33

+ 14"~; 90 10 20

2 9 E

1l

+ +

+

+

_+

10 F

12

+ 510

85°,,

N

1 15~Io p D -

+ s

2 11 F

13b

+ +

+

-

5 15°~i P D

1 13 M

14

34'~i, + 811. +

92q

some 85d, + 9 9 q 15d, l q 45q, 471 d, 5 2 r d

46 M

15

p = p r e d o m i n a n c e . D = deficiency, d = d e l t o i d , q = q u a d r i c e p s , r = right, 1 = left, - = d i m i n i s h e d . + = p r e s e n t . ? = n o t r e p o r t e d , N = n o r m a l , s = soleus. ( ' a s e s 1 a n d 3: L a k e et al. 1977: C a s e 2: D e L u m l e y et al. 1976: C a s e s 4 a n d 5: H e f f n e r et al. 1976; C a s e s 6 a n d 11: p r e s e n t r e p o r t ; C a s e s 7 a n d 8: C u r r i e et al. 1974: C a s e 9: T a r a t u t o ct al. 1978: C a s e 10: T a n i m u r a et al. 1974; C a s e I2: M u k o y a m a et al. 1973: C a s e s 13 a n d 14: Engel et al. 1971 : C a s e 15: B o n n e t t e et al. 1974.

Oxidative enzymes : N o a c t i v i t y (focal) Granular accum. A T P a s e : N o activity (focal) Loss o f c r o s s s t r i a t i o n s

+ 65 35

2 1 M

1

Cases

IN I5 C A S E S D E S C R I B E D

E n d o m y s i a l c o n n e c t i v e tissue E n d o m y s i a l a d i p o s e tissue C e n t r a l nuclei i!,, T y p e 1 "o T y p e 11 Type 1

Original Case No. A g e (yr) Sex

BIOPSY FINDINGS

TABLE 2

9(I are p r o m i n e n t in o t h e r a r e a s o f the muscle fiber (Cases 3 a n d 6), there arc a c c u m u l a t i o n s o f s a r c o t u b u l a r profiles (Cases 2, 4, 5, 1 l, 13, 14 a n d 15) a n d in one case m i t o c h o n d r i a l a b n o r m a l i t i e s such as crystalline inclusions (Case 15). In c o n c l u s i o n , the most c o m m o n features which typify m y o p a t h y with multiple m i n o c o r e are as follows: higher p r o p o r t i o n o f males affected (2.75 : 1), s p o r a d i c o r familial p r e s e n t a t i o n with scant p e n e t r a t i o n , generally congenital a p p e a r a n c e a n d n o n - p r o g r e s s i v e e v o l u t i o n shown by generalized muscle w e a k n e s s which is later limited to the p r o x i m a l zones, only o c c a s i o n a l l y affecting the facial m u s c u l a t u r e . T h e E M G generally shows an S S P A p a t t e r n ; the serum C P K levels are not significantly raised. M o r p h o l o g i c a l l y the disease is typified by the presence o f multiple small a r e a s o f loss o f c r o s s - s t r i a t i o n a n d s t r e a m i n g o f the Z - l i n e : these areas corr e s p o n d histologically to decreased activity o f m y o f i b r i l l a r A T P a s e a n d oxidative e n z y m e s : u l t r a s t r u c t u r a l l y they c o r r e s p o n d to m y o f i b r i l l a r d i s o r g a n i s a t i o n a n d a b s e n c e o f m i t o c h o n d r i a . A p a r t f r o m these c h a r a c t e r i s t i c m o r p h o l o g i c a l a l t e r a t i o n s , o t h e r c o n s t a n t findings are the presence o f central nuclei a n d the p r e d o m i n a n c e , with h y p o t r o p h y , o f type I fibers together with h y p e r t r o p h y o f those o f type 11. This picture bears a m a r k e d similarity to that o f the m y o p a t h i e s with central nuclei a n d h y p o t r o p h y o f type I fibers (Engel et al. 1968) a n d in a certain sense to that o f congenital d i s p r o p o r t i o n o f types ( B r o o k e et al. 1972). These aspects are evidence o f an early onset o f the disease a n d show the coexistence o f m a t u r a t i o n a l t e r a t i o n s in this process, as can also occur in o t h e r muscle diseases with early onset (Sarnat a n d Silbert 1976). Nevertheless, on s t u d y i n g s u b t y p e s o f the type II fibers, I I - C fibers were n o t seen ; their presence w o u l d be a sign, in o u r o p i n i o n , o f a m a t u r a t i o n defect. In fact both in out" cases as well as those o f L a k e et al. (1977) there are no TABLE 3 BIOPSY FINDINGS IN 4 CASES O F

MYOPATHY

WITH FOCAL LOSS OF CROSS-STRIATIONS

Case No.

(l)

(2)

Sex Age (yr) Relationship Hypotonia Facial muscle involvement Extraocular muscle involvement Evolution Loss of cross-striation Oxidative enzymes : No activity (focal) ATPase: No activity (focal) Central nuclei !'(, Type I % Type 11

F 14

M 6

~3)

14)

? ? + benign

F 1/10 - siblings + + + + + benign benign

'? 9 + + + benign

+

+

+

+

? ?

+ +

+ +

+ +

+

+

+

+

? ')

P D

P D

1O0 0

P = predominance, D = deficiency. Case 1 : Engel 1977; Cases 2 and 3: Van Wijngaarden et al. 1977; Case 4: Schotland 1969.

91 type I I - C fibers a n d the I I - A fibers are p r e d o m i n a n t in spite o f these being the last to be d i s t i n g u i s h a b l e in n o r m a l d e v e l o p m e n t ( S a r n a t a n d Silbert 1976). T h e d i f f e r e n t i a t i o n o f the m u l t i c o r e structures f r o m those k n o w n as central core presents no serious difficulty, t a k i n g into a c c o u n t the small size a n d great n u m b e r o f the f o r m e r , as was p o i n t e d out in the first d e s c r i p t i o n (Engel et al. 1971). T h e d i f f e r e n t i a t i o n between m y o p a t h y with m u l t i c o r e a n d those cases o f m y o p a t h y with focal loss o f c r o s s - s t r i a t i o n described b y Engel (1967), S c h o t l a n d (1969) a n d Van W i j n g a a r d e n et al. (1977) is m o r e c o m p l i c a t e d . The characteristics o f the latter are shown in T a b l e 3. In o u r o p i n i o n , these c o r r e s p o n d to m y o p a t h y with m u l t i p l e minicore, given that the m o r p h o s t r u c t u r a l a l t e r a t i o n which typifies this disease (multiple focal loss o f c r o s s - s t r i a t i o n ) is present in all cases: the o c c a s i o n a l a s s o c i a t i o n o f central nuclei with these a r e a s o f m y o f i b r i l l a r lesion, which is c o n s i d e r e d to be c h a r a c t e r i s t i c (Van W i j n g a a r d e n et al. 1977) may, in o u r o p i n i o n , be a s s u m e d to be fortuitous+ especially c o n s i d e r i n g the high incidence o f central nuclei in m y o p a t h y with m u l t i c o r e . Bethlem et al. (1978) r e c o n s i d e r the cases p r e v i o u s l y p u b l i s h e d by Van W i j n g a a r d e n et al. (1977) a n d c o n c l u d e t h a t there is no essential difference between m u l t i c o r e a n d focal loss o f cross-striations, considering the latter s i m p l y a m o r e a d v a n c e d p h a s e o f the former. F u r t h e r m o r e , with reference to the d e n o m i n a t i o n o f this disease, we believe the n a m e m y o p a t h y with m u l t i p l e m i n i c o r e expresses m o r e clearly the m o r p h o l o g i c a l aspect o f the lesion t h a n the simple d e s i g n a t i o n o f m u l t i c o r e (Engel et al. 1971) or m i n i c o r e ( C u t t l e et al. 1974). ACKNOWLEDGEMENTS W e wish to t h a n k Dr. E. G u t i 6 r r e z a n d Dr. J . L . T r u e b a for p r o v i d i n g the clinical s t u d y ; also Ms. R e i g o s a a n d T o r r e a n d Mr. R o m e r o , M o t a , Sfinchez a n d M a n d e z for their technical assistance. REFERENCES Bethlem, J., W. F. Arts and K. P. Dingemans (1978) Common origin of rods, cores, miniature cores and focal loss of cross-striations, Arch. Neurol. (Chic.), 35:555 566. Bonnene, H., R. Roelofs and W. H. Olson (1974) Multicore disease Report of a case with onset in middle age, Neurology (Minneap.), 24:1039 1044. Brooke, M. H., H. E. Neville and J.S. Burks (1972) Congenital fiber type disproportion A common neuromuscular disease+ Neurology (Minneap.), 22:401 (Abstract). Currie, S., M. Noronha and D. Harriman (1974) +'Minicore" disease. In: W. G. Bradley (Ed.), Abstracts ~1 Papers presented at the 3rd h+ternational Congress on Muscle Diseases, Newcastle upon 7~l'ne, September, 1974 (International Congress Series, No. 334), Excerpta Medica, Amsterdam, 1974, p. 12.

De Lumley, L., J. M. Vallat and G. Catanzano (1976) l~tude clinique et ultrastructurale d'un cas de myopathie congOnitale fi foyers multiples, Ann. P~;diat., 23:333 336. Dabowitz, V. (1978) Muscle Disorders it+ Childhood (Major Problems in Clinical Pediatrics, Vol. 16). Saunders, London, pp. 70 107. Engel, A.G., M.R. Gomez and R.V. Groover (t971) Multicore disease A recently recognized congenital myopathy associated with multifocal degeneration of muscle fiber, Proc. Mayo Clin., 46:666 681. Engel. W. K. (1967) Muscle biopsies in neuromuscular diseases, Pedial. Clin. Norlh Amer., 14:963 995.

92 Engel, W. K. and J. R. Warmolts (1973) The motor unit Diseases affecting it ill toto or in portxt>, lt~: J. E. Desmedt (Ed.), New Developments hi Fh'ctromyography cmd ClhTical N~'urc~ph.l~xiologl', IoI. /. Karger, Basel, pp. 141 177. Engel, W. K., G . M . Gold and G. Karpati (1968) Type I fiber hypotrophy and central Iluclei, "tr~h. Neurol. (Chic.), 18:435 444. Fardeau, M., J. Godet-Guillain, F. Tome, P. Dreyfus and C. Bitlard (1977) Difficulties and limits in the classification ot" congenital myopathies. In: W.A. Den Hartog Jager, G.W. Bruyn and Ar P.J. Heijstee (Eds.), Neurolo~tv (Procs. of l l t h World Congress of Neurology, Amsterdam, 1977) (Intern. Congress Series, No. 434), Excerpta Medica, Amsterdam, pp. 144 161. Heffiaer, H., M. Cohen, P. Duffner and G. Daigter (1976) Multicore disease in twins, J. Neurol. Neurosurg. Po'chiat., 39:602 606. Lake, B. D., N. Cavanagh and ,I. Wilson (1977) Myopathy with minicore in siblings, Neurop~th. app/. Neutwhiol., 3 : 159 167. Mukoyama, M., Y. Matsuoka, H. Kato and 1. Sobue (1973)Multicore disease, Clin. Neurol. ~ 7?~kio), 13:221 227. Sarnat, H. B. and S. W. Silbert (1976) Maturational arrest of fetal muscle in neonatal myotonic dystrophy A pathologic study of four cases, Arch. Neurol. (Chic.), 33:466 474. Schotland, D . k . (1969) An electron microscopic study of target fibers, target-like fibers and related abnormalities in human muscle, J. Neuropath. exp. Neurol., 28: 214- 228. Tanimura, R.. H. Suzuki, J. Yokota, M. Segawa and Y. Kukuyama (1974) Multicore myopathy, Clh~. Neurol. (Tokio), 14:613 622. Taratuto. A. L., Z. M. Sfaello, C. Rezzonico and R.C. Morales (1978) Multicore disease Report of a case with lack of fibre type differentiation, Neuropgidiat., 9:285 297. Van Wijngaarden, G. K., J. Bethlem. K. P. Dingemans, C. Co6rs, N. Telerman-Toppet and J. M. Gerard (1977) Familial focal loss of cross striations, J. Neurol., 216: 163-~172.