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Unusual course of nemaline myopathy
Neuromusc.Disord,,Vol.2. No.5/6,pp.413-.418,1992 Printedin GreatBritain
0960-8966192$5.00+ 0.00 PersamonPreu Ltd
CASE REPORT UNUSUAL
COURSE
OF NEMALINE
MYOPATHY
I. HAUSMANOWA-PETRUSEWICZ,A. FIDZIANSKAand B. BADURSKA Neuromuscular Unit Medical Research Center, Department of Neurology, Polish Academy of Sciences, Warsaw Medical School, IA Banacha, 02-097 Warsaw, Poland (Received 11 June 1991; revised 29 April 1992; accepted 2 October 1992)
Abstraet--A boy with onset features common for a moderate form of congenital nemaline myopathy, after some years developed scapulo-humeral syndrome. Extra- and intrafusal muscle fibers overloaded with rods and indicating focal degenerati¢e changes were seen in the first biopsy. The biopsy was later repeated and revealed an improvement in muscle architecture with a dramatically decreased number of rods. This transformation suggests that rods, as well as Zline streaming, might be a reversible anomaly of Z-discs. Key words: Rods, congenital myopathy, scapulo-peroneal syndrome.
INTRODUCTION
Congenital nemaline myopathy (CNM) is now classified into three main forms [1, 2]: fatal neonatal form, moderate and adult onset. The moderate form is characterized by muscle hypotonia and weakness, delayed developmental milestones, nonprogressing or slowly progressing course. The clinical expression has a wide range and the correct diagnosis can only be made on the basis of a muscle biopsy. The case reported here is an example of very rare clinical features which could'develop in nemaline myopathy. Also, the morphological findings - - decisive for diagnosis - - seem to have implications rather different from those accepted in the literature.
t[actures, pes equinus, ankle reflexes were absent, tSe walking and lumbar hyperlordosis. All routine tests including serum biochemical examination, CSF, EEG and ECG were normal. A quantitative electrophysiological examination of muscles was performed with concentric needle electrodes (CNEMG) revealed in deltoid, biceps br., quadriceps femoris and tibialis anterior mm. at maximal effort interference pattern and at slight contraction, short potentials and increased percentage of polyphasic potentials. Motor and sensor conduction velocities in peripheral nerves were normal except for the sural nerve (34, 6 m s-I). Biopsy of biceps brachii sin. permitte~d a diagnosis of rod myopathy to be made (see below for details). Course
CASE REPORT
K.R. was born in 1971, at term after an uneventful pregnancy and delivery. He started walking at 15 months, and was always more clumsy than peers. Parents were not related and healthy. The only elder brother was healthy. The parents observed at 5 yr an unsteady and waddling gait, he could not run and had difficulty in rising from the floor. He was admitted to our department for the first time in 1978. The neurological state in October 1978 was a 7-yr-old boy with hypomimic, "sleepy" face (Fig. 1), generalized moderate floppiness and no facial weakness. The most striking feature was muscle atrophy of both the anterior and posterior compartments of the leg muscles, ankle con413
He was followed up in our Muscle Clinic. The ankle contractures gradually become more pronounced, and because of progressing gait difficulties he had two operations (tenotomy) and was treated in rehabilitation centers. Since 1983 the weakness of the proximal muscles of the upper extremities has appeared. In Autumn 1985 the atrophy of the shoulder girdle muscles, the difficulty in raising the arms, "terracing" of shoulders on abducation, and winging scapulae became very evident (Fig. 2). The face had a much less "sleepy" expression, the orbicularis oris became hypertrophic. There was no difficulty with e~e closure and he was able to purse his lips with no sign of a transverse smile. The findings in the lower extremities were generally the same as before except that the peroncal muscles had
414
I. HAUSMANOWA-PETRUSEWICZ et al.
For electron microscopy, muscle specimens were fixed in glutaraldehyde in phosphate buffer and postfixed in 1% osmium tetroxide in the same buffer. They were then dehydrated and embedded in the spurr low-viscosity epoxy resin. Thick sections were stained with methylene blue for light microscopy. Thin sections doublestained with uranyl acetate and lead citrate were examined with a JEM'-7 electron microscope. Results
Fig. 1. Patient at 7 yr -- "sleepyfac~".
"q
Fig. 2. Patient at 16 y r -
"terracing" of shoulders.
become weaker. EMG examination revealed more pronounced myopathic changes, the motor and sensory conduction velocity was normal except for the sural nerves which were within scar tissue (after surgery ) . The up-to-date condition is the same, the boy is ambulatory and able to work. The second muscle biopsy (right biceps br.) was taken in June 1990, i.e. 12 yr after the first, and is discussed below. MORPHOLOGICALEXAMINATIONOF MUSCLE Methods Muscle tissue was rapidly frozen in isopentane cooled to - 160°C in liquid nitrogen. Transverse sections of 6/am were cut and stained according to the techniques of Dubowitz [3].
In the first biopsy taken from the left biceps muscle, two populations of muscle fibers were observed using routine stains. Small, polygonal or round-shaped muscle fibers measuring 5-7/am in diameter were frequently arranged in small groups (Fig. 3a) or scattered among larger fibers of 15-20 /am in diameter. No necrotic or regenerating fibers were observed. Endomysial connective tissue was not increased. On histochemical examination, all muscle fibers showed a subdivision into two types with N A D H diaphorase and the pH 9.4, 4.6, 4.3 ATPase reactions. Predominance of type 1 fibers was evident, small muscle fibers belonged only to type 1 (Fig. 3b). The nemaline rods stained red were readily demonstrable with the Gomori trichrome stain (Fig. 4a) in 90% of fibers of both types. The distribution of rods within individual fibers varied. In some of them, rods formed focal aggregates mainly subsarcolemmal. In others, they occupied about half the diameter of the fiber. In the most severely affected fibers they extended diffusely across the whole fiber (Fig. 4b). The largest rod was about 2.5/am long and 0.4/am wide. A lattice structure with a characteristic periodic pattern was seen in some rods. Periodicity perpendicular to the axis measured approximately 17/am. There appeared to be rods in some of the intrafusal fibers (Fig. 5). Except for the rods, areas of filamentous disarray showed focal Z-line streaming. Motor end-plates as well as intramuscular nerves appeared unremarkable. In the second biopsy the diameter of muscle fibers looked normal except for a few small round muscle fibers with well preserved architecture. Small muscle fibers, as in the first biopsy, belonged to type 1. In contrast to the muscle fibers in the first biopsy, which were heavily loaded with rods, a few rods were detected in the second biopsy. They were rarely observed in trichrome stained sections at the light microscopic level, but were mogt deafly visible in toluidine
Unusual Course of Nemaline Myopathy
-
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~'
415
" ~'~
~,
. .<. .
' L:~" t
#"
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-,
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1
Fig. 3. Biceps brachii (first biopsy). (a) Small polyglonal or round-shaped muscles are scattered among larger fibers. HE x 448. (b) Small muscle fibers belonging to type 1. ATPase pH 9.4 x 100.
Fig. 4.Biceps brachii (first biopsy). (a) Nemaline rods seen within muscle fibers. Trichrome × 448. (b) Rods extend diffusely across the whole fiber, x 8000.
blue stained spurr sections. In electron micrographs, it was readily apparent that the rods were small (the longest extended two sarcomeres), arranged mainly alongside muscle fibers and the myofibrils had well preserved architecture (Fig.
6). Comments
The number of congenital nemaline myopathies (CNM) described in the literature is growing since the first report by Conen et al. [4] and Shy et al. [5]. We do not intend to repeat a review of described cases but only to add some
observations. Our case does belong to the moderate congenital form, according to the classification of Martinez and Lake [1] and Shimamura and Nonaka [2]. This form is characterized by hypotonia and weakness from early infancy, delayed developmental milestones, nonprogressive or slowly progressive course and the presence of rods as a major pathological feature. Two problems in the present study seem to be of special interest: namely quite dramatical changes in clinical features and the decreasing number of-rods in muscle biopsies with age. Wallgren-Pettersson believes that clinical fea-
416
I. HAUSMANOWA-PETRUSEWICZ et al.
Fig. 5. Biceps brachii (first biopsy), Rods seen within intrafusal muscle fibers. × 4600.
Fig. 6. Biceps brachii (second biopsy). Peripherally located small rods. Note the well preserved architecture of muscle ceil. × 6400.
tures of CNM are uniform but the severity varies widely [6]. Not all authors agree with this statement, e.g. Dubowitz stresses the clinical variety of CNM [7] Our case showed quite an unusual transformation of clinical features. At 7 yr, during the first admission as a patient of our department, the diagnosis of a congenital myopathy was made even at the first examination, of course
specific diagnosis was only possible on the basis of a biopsy. If we had not seen him before, at his later admission, on the basis of clinical features, the diagnosis of scapulo-peroneal dystrophy would have been the first choice. This is the first case with such clinical features in our series of 14 cases of nemaline myopathies. The rods in scapulo-peroneal syndrome or in facio-scapulohumeral syndrome" are, however, described by
Unusual Course ofNemaline Myopathy Wijngarden and Bethlem [8]. Dubowitz [7], Walton and Gardner-Medwin [9] mention that FSH syndrome might turn out to be another myopathy, i.e. CNM. The other intriguing finding is a dramatically decreased number of rods in the second biopsy (performed at 19 yr) as compared to the first biopsy (performed at 7 yr). Nemaline rods stained red by the trichrome method were present in a number of muscle fibers, however, their number varied widely between the first and second biopsy. In ME these structures showed bi-directionai periodicity and, in cross-sections, the lattice arrangement which is typical of nemaline rods [10]. Their presence in the muscle of our patient define the disease because until this time no other myopathy has been reported in which accumulation of rods is a major pathological feature. In moderate CNM the number of rods appears to increase with age, as pointed out by Shimamura and Nonaka [2] on the basis of comparison between patients of different ages. A longitudinal bioptic study performed in the same patients would have been of more value. The repeated biopsies in patients diagnosed during the first biopsy as nemaline myopathy are, of course, very few. Most of the repeated biopsies were done because rods were not found and a second biopsy permitted the correct diagnosis [l 1]. Quite a large series of follow-up patients with moderate CNM is described by WallgrenPettersson e t al. [6]. According to this data, in all repeated biopsies but one, the number of rods obviously increased as compared with the first biopsy (the biopsies were repeated after 5-25 yr). The rods located subsarcolemmally in the first biopsies were placed more centrally in the second biopsies. The muscles fibers in the course of the disease became functionally deficient because the Z-line structure is gradually disrupted by the production of increasing numbers of nemaline bodies. We are aware of a reservation towards comparisons of two biopsies always taken from different sites, even of the same muscle. However, we have to accept this situation otherwise all longitudinal morphological studies have to be disregarded. In our case the extremely numerous rods, also in intrafusal fibers, were observed in the first biopsy. The presence of rods in intrafusal fibers was challenged in the 1970s [12] but admitted later [13]--nevertheless they are rarely found. Two morphological findings are most evident in our case: some fiber hypotrophy and the
417
presence of rods. Common morphological changes in the first and second biopsies were variation in fiber size and the presence of a small number of muscle fibers belonging to type i. The number of small muscle fibers appears to decrease with age, because there were few at the age of 19 yr, the diameter of all muscle fibers, including the small ones, distinctly increased. An increased diameter of muscle fibers becomes evident with age and is parallel to the decreasing number of nemaline rods, which at 19 yr is quite small in comparison with the great number of rod loaded fibers in the 7-yr-old child. Also, individual muscle fibers previously indicating focal degenerative changes appear to be essentially of normal architecture. However, it is well known that the number of rods varies widely between muscles and between different sites in the same muscle [14]. The fact that all fibers in the second biopsy improved their cytoarchitecture suggests that the rods, as well as the Z-line streaming, represent a proliferative but reversible anomaly of the Z-disc, and this raises the possibility that an inborn defect might be, in some cases, improved during postnatal maturation. This statement is in agreement with the idea of muscle adaptive ability [15-17]. According to this idea, in highly biologically active muscle most of the myofilament abnormalities depend on rapidly remodeling contractile apparatus, and that some of the so-called "degenerative" changes seen in myopathic muscle are the consequence of reorganization of contractile apparatus in order to reduce the numbeI of sarcomeres or to produce new ones. Such abnormalities although appearing in myopathic muscle are not "pathological" p e r se but are an adaptive response of the pathologically altered muscle or a reaction of the normal muscle to pathological stimuli. REFERENCES
I. MartinezB A, Lake B D. Childhood nemaline myopathy. A review of clinical presentation in relation to prognosis. Dev Med Child Neurol 1987;29:815-820. 2. ShimamuraCh, Nonaka I. Nemalinemyopathy:comparative musclehistochemistryin the severe neonatal, moderatecongenitaland adult-onset forms.Ped Neurol 1989; 5: 25-31. 3. DubowitzV. Muscle Biopsy: A Practical Approach, 2nd Edn. London: Bailliere, 1985. 4. Cohen P E, Murphy E G, Donohue W L. Light and elL~ctronmicroscopic studies of myogranulesin a child with hypotoniaand muscleweakness.Can MedAssoc J 1963; 89: 983-986. 5. Shy G M, Engel W K, Somers J E, Wanko T. A new congenital myopathy.Brain 1963;79: 793-810.
418
I. HAUSMANOWA-PETRUSEWICZet al.
6. Wallgren-Pettersson C, Rapola J, Doumer M. Pathology of nemaline myopathy. A follow-up study. J Neurol Sci 1987; 83: 243-257. 7. Dubowitz V. Muscle Disorders in Children. London: W B Saunders, t978: 51, 77. 8. Wijngarden G K, Bethlem J. The facioscapulo-humeral syndrome. In: Kakulas B A, ed. Clinical Studies in Myology. New York: Elsevier, 1973: 498-501. 9. Walton J, Gardner-Medwin D. The Muscular Dystrophies. In: Walton J, ed. Disorder o f Voluntary Muscle. Edinburgh-London: Churchill Livingstone, 1988: 533. 10. Engel A G, Gomer M R. Nemaline (Z disc) myopathy: observations on the origin, structure and solubility properties of the nemaline structures. J Neuropathol Exp Neurol 1967; 26: 6017619. 11. Nienhuis A W, Coleman R F , Brown W J, Munsat T L, Pearson C H. Nemaline myopathy. A histopathologic and histochemical study. Am J Clin Pathol 1967; 48: 112.
12. Karpati G, Carpenter S, Andermann A. A new concept of childhood nemaline myopathy. Arch Neuro11971; 24: 291-304. 13. Stoessl A J, Hahn A F, Malott D, Jones D T, Silver M D. Nemaline myopathy with associated cardiomyopathy. Arch Neurol 1985; 42: 1084-1093. 14. Shafiq S A, Dubowitz V, Peterson H C, Milhorat A T. Nemaline myopathy: report of a fetal case with histochemical and electron microscopic studies. Brain 1967; 90:817-828.
15. Jakubiec-Puka A. Reconstruction of the contractile apparatus of striated tfiuscle. 1. Muscle maintained in extension. J Muscle Res Cell Motil 1985; 6:385-40 I. 16. Jakubiec-Puka A, Carraro U. Adaptive remodelling of contractile apparatus of the electrostimulated muscle. XIXth Europ Conf Muscl Contr Cell Motil, Brussels, 10-13 September 1990, abstracts p. 68. 17. Jakubiec-Puka A, C.arraro U. Remodelling of the contractile apparatus of striated muscle stimulated electrically in a shortened position. J Anat 1991; 178: 83-100.
0960-8966192$5.00+ 0.00 PersamonPreu Ltd
CASE REPORT UNUSUAL
COURSE
OF NEMALINE
MYOPATHY
I. HAUSMANOWA-PETRUSEWICZ,A. FIDZIANSKAand B. BADURSKA Neuromuscular Unit Medical Research Center, Department of Neurology, Polish Academy of Sciences, Warsaw Medical School, IA Banacha, 02-097 Warsaw, Poland (Received 11 June 1991; revised 29 April 1992; accepted 2 October 1992)
Abstraet--A boy with onset features common for a moderate form of congenital nemaline myopathy, after some years developed scapulo-humeral syndrome. Extra- and intrafusal muscle fibers overloaded with rods and indicating focal degenerati¢e changes were seen in the first biopsy. The biopsy was later repeated and revealed an improvement in muscle architecture with a dramatically decreased number of rods. This transformation suggests that rods, as well as Zline streaming, might be a reversible anomaly of Z-discs. Key words: Rods, congenital myopathy, scapulo-peroneal syndrome.
INTRODUCTION
Congenital nemaline myopathy (CNM) is now classified into three main forms [1, 2]: fatal neonatal form, moderate and adult onset. The moderate form is characterized by muscle hypotonia and weakness, delayed developmental milestones, nonprogressing or slowly progressing course. The clinical expression has a wide range and the correct diagnosis can only be made on the basis of a muscle biopsy. The case reported here is an example of very rare clinical features which could'develop in nemaline myopathy. Also, the morphological findings - - decisive for diagnosis - - seem to have implications rather different from those accepted in the literature.
t[actures, pes equinus, ankle reflexes were absent, tSe walking and lumbar hyperlordosis. All routine tests including serum biochemical examination, CSF, EEG and ECG were normal. A quantitative electrophysiological examination of muscles was performed with concentric needle electrodes (CNEMG) revealed in deltoid, biceps br., quadriceps femoris and tibialis anterior mm. at maximal effort interference pattern and at slight contraction, short potentials and increased percentage of polyphasic potentials. Motor and sensor conduction velocities in peripheral nerves were normal except for the sural nerve (34, 6 m s-I). Biopsy of biceps brachii sin. permitte~d a diagnosis of rod myopathy to be made (see below for details). Course
CASE REPORT
K.R. was born in 1971, at term after an uneventful pregnancy and delivery. He started walking at 15 months, and was always more clumsy than peers. Parents were not related and healthy. The only elder brother was healthy. The parents observed at 5 yr an unsteady and waddling gait, he could not run and had difficulty in rising from the floor. He was admitted to our department for the first time in 1978. The neurological state in October 1978 was a 7-yr-old boy with hypomimic, "sleepy" face (Fig. 1), generalized moderate floppiness and no facial weakness. The most striking feature was muscle atrophy of both the anterior and posterior compartments of the leg muscles, ankle con413
He was followed up in our Muscle Clinic. The ankle contractures gradually become more pronounced, and because of progressing gait difficulties he had two operations (tenotomy) and was treated in rehabilitation centers. Since 1983 the weakness of the proximal muscles of the upper extremities has appeared. In Autumn 1985 the atrophy of the shoulder girdle muscles, the difficulty in raising the arms, "terracing" of shoulders on abducation, and winging scapulae became very evident (Fig. 2). The face had a much less "sleepy" expression, the orbicularis oris became hypertrophic. There was no difficulty with e~e closure and he was able to purse his lips with no sign of a transverse smile. The findings in the lower extremities were generally the same as before except that the peroncal muscles had
414
I. HAUSMANOWA-PETRUSEWICZ et al.
For electron microscopy, muscle specimens were fixed in glutaraldehyde in phosphate buffer and postfixed in 1% osmium tetroxide in the same buffer. They were then dehydrated and embedded in the spurr low-viscosity epoxy resin. Thick sections were stained with methylene blue for light microscopy. Thin sections doublestained with uranyl acetate and lead citrate were examined with a JEM'-7 electron microscope. Results
Fig. 1. Patient at 7 yr -- "sleepyfac~".
"q
Fig. 2. Patient at 16 y r -
"terracing" of shoulders.
become weaker. EMG examination revealed more pronounced myopathic changes, the motor and sensory conduction velocity was normal except for the sural nerves which were within scar tissue (after surgery ) . The up-to-date condition is the same, the boy is ambulatory and able to work. The second muscle biopsy (right biceps br.) was taken in June 1990, i.e. 12 yr after the first, and is discussed below. MORPHOLOGICALEXAMINATIONOF MUSCLE Methods Muscle tissue was rapidly frozen in isopentane cooled to - 160°C in liquid nitrogen. Transverse sections of 6/am were cut and stained according to the techniques of Dubowitz [3].
In the first biopsy taken from the left biceps muscle, two populations of muscle fibers were observed using routine stains. Small, polygonal or round-shaped muscle fibers measuring 5-7/am in diameter were frequently arranged in small groups (Fig. 3a) or scattered among larger fibers of 15-20 /am in diameter. No necrotic or regenerating fibers were observed. Endomysial connective tissue was not increased. On histochemical examination, all muscle fibers showed a subdivision into two types with N A D H diaphorase and the pH 9.4, 4.6, 4.3 ATPase reactions. Predominance of type 1 fibers was evident, small muscle fibers belonged only to type 1 (Fig. 3b). The nemaline rods stained red were readily demonstrable with the Gomori trichrome stain (Fig. 4a) in 90% of fibers of both types. The distribution of rods within individual fibers varied. In some of them, rods formed focal aggregates mainly subsarcolemmal. In others, they occupied about half the diameter of the fiber. In the most severely affected fibers they extended diffusely across the whole fiber (Fig. 4b). The largest rod was about 2.5/am long and 0.4/am wide. A lattice structure with a characteristic periodic pattern was seen in some rods. Periodicity perpendicular to the axis measured approximately 17/am. There appeared to be rods in some of the intrafusal fibers (Fig. 5). Except for the rods, areas of filamentous disarray showed focal Z-line streaming. Motor end-plates as well as intramuscular nerves appeared unremarkable. In the second biopsy the diameter of muscle fibers looked normal except for a few small round muscle fibers with well preserved architecture. Small muscle fibers, as in the first biopsy, belonged to type 1. In contrast to the muscle fibers in the first biopsy, which were heavily loaded with rods, a few rods were detected in the second biopsy. They were rarely observed in trichrome stained sections at the light microscopic level, but were mogt deafly visible in toluidine
Unusual Course of Nemaline Myopathy
-
I I'I"~", I
<
~'
415
" ~'~
~,
. .<. .
' L:~" t
#"
:
I. i--, .,, .d.--
-,
-'
I -I. , 7
"
1
Fig. 3. Biceps brachii (first biopsy). (a) Small polyglonal or round-shaped muscles are scattered among larger fibers. HE x 448. (b) Small muscle fibers belonging to type 1. ATPase pH 9.4 x 100.
Fig. 4.Biceps brachii (first biopsy). (a) Nemaline rods seen within muscle fibers. Trichrome × 448. (b) Rods extend diffusely across the whole fiber, x 8000.
blue stained spurr sections. In electron micrographs, it was readily apparent that the rods were small (the longest extended two sarcomeres), arranged mainly alongside muscle fibers and the myofibrils had well preserved architecture (Fig.
6). Comments
The number of congenital nemaline myopathies (CNM) described in the literature is growing since the first report by Conen et al. [4] and Shy et al. [5]. We do not intend to repeat a review of described cases but only to add some
observations. Our case does belong to the moderate congenital form, according to the classification of Martinez and Lake [1] and Shimamura and Nonaka [2]. This form is characterized by hypotonia and weakness from early infancy, delayed developmental milestones, nonprogressive or slowly progressive course and the presence of rods as a major pathological feature. Two problems in the present study seem to be of special interest: namely quite dramatical changes in clinical features and the decreasing number of-rods in muscle biopsies with age. Wallgren-Pettersson believes that clinical fea-
416
I. HAUSMANOWA-PETRUSEWICZ et al.
Fig. 5. Biceps brachii (first biopsy), Rods seen within intrafusal muscle fibers. × 4600.
Fig. 6. Biceps brachii (second biopsy). Peripherally located small rods. Note the well preserved architecture of muscle ceil. × 6400.
tures of CNM are uniform but the severity varies widely [6]. Not all authors agree with this statement, e.g. Dubowitz stresses the clinical variety of CNM [7] Our case showed quite an unusual transformation of clinical features. At 7 yr, during the first admission as a patient of our department, the diagnosis of a congenital myopathy was made even at the first examination, of course
specific diagnosis was only possible on the basis of a biopsy. If we had not seen him before, at his later admission, on the basis of clinical features, the diagnosis of scapulo-peroneal dystrophy would have been the first choice. This is the first case with such clinical features in our series of 14 cases of nemaline myopathies. The rods in scapulo-peroneal syndrome or in facio-scapulohumeral syndrome" are, however, described by
Unusual Course ofNemaline Myopathy Wijngarden and Bethlem [8]. Dubowitz [7], Walton and Gardner-Medwin [9] mention that FSH syndrome might turn out to be another myopathy, i.e. CNM. The other intriguing finding is a dramatically decreased number of rods in the second biopsy (performed at 19 yr) as compared to the first biopsy (performed at 7 yr). Nemaline rods stained red by the trichrome method were present in a number of muscle fibers, however, their number varied widely between the first and second biopsy. In ME these structures showed bi-directionai periodicity and, in cross-sections, the lattice arrangement which is typical of nemaline rods [10]. Their presence in the muscle of our patient define the disease because until this time no other myopathy has been reported in which accumulation of rods is a major pathological feature. In moderate CNM the number of rods appears to increase with age, as pointed out by Shimamura and Nonaka [2] on the basis of comparison between patients of different ages. A longitudinal bioptic study performed in the same patients would have been of more value. The repeated biopsies in patients diagnosed during the first biopsy as nemaline myopathy are, of course, very few. Most of the repeated biopsies were done because rods were not found and a second biopsy permitted the correct diagnosis [l 1]. Quite a large series of follow-up patients with moderate CNM is described by WallgrenPettersson e t al. [6]. According to this data, in all repeated biopsies but one, the number of rods obviously increased as compared with the first biopsy (the biopsies were repeated after 5-25 yr). The rods located subsarcolemmally in the first biopsies were placed more centrally in the second biopsies. The muscles fibers in the course of the disease became functionally deficient because the Z-line structure is gradually disrupted by the production of increasing numbers of nemaline bodies. We are aware of a reservation towards comparisons of two biopsies always taken from different sites, even of the same muscle. However, we have to accept this situation otherwise all longitudinal morphological studies have to be disregarded. In our case the extremely numerous rods, also in intrafusal fibers, were observed in the first biopsy. The presence of rods in intrafusal fibers was challenged in the 1970s [12] but admitted later [13]--nevertheless they are rarely found. Two morphological findings are most evident in our case: some fiber hypotrophy and the
417
presence of rods. Common morphological changes in the first and second biopsies were variation in fiber size and the presence of a small number of muscle fibers belonging to type i. The number of small muscle fibers appears to decrease with age, because there were few at the age of 19 yr, the diameter of all muscle fibers, including the small ones, distinctly increased. An increased diameter of muscle fibers becomes evident with age and is parallel to the decreasing number of nemaline rods, which at 19 yr is quite small in comparison with the great number of rod loaded fibers in the 7-yr-old child. Also, individual muscle fibers previously indicating focal degenerative changes appear to be essentially of normal architecture. However, it is well known that the number of rods varies widely between muscles and between different sites in the same muscle [14]. The fact that all fibers in the second biopsy improved their cytoarchitecture suggests that the rods, as well as the Z-line streaming, represent a proliferative but reversible anomaly of the Z-disc, and this raises the possibility that an inborn defect might be, in some cases, improved during postnatal maturation. This statement is in agreement with the idea of muscle adaptive ability [15-17]. According to this idea, in highly biologically active muscle most of the myofilament abnormalities depend on rapidly remodeling contractile apparatus, and that some of the so-called "degenerative" changes seen in myopathic muscle are the consequence of reorganization of contractile apparatus in order to reduce the numbeI of sarcomeres or to produce new ones. Such abnormalities although appearing in myopathic muscle are not "pathological" p e r se but are an adaptive response of the pathologically altered muscle or a reaction of the normal muscle to pathological stimuli. REFERENCES
I. MartinezB A, Lake B D. Childhood nemaline myopathy. A review of clinical presentation in relation to prognosis. Dev Med Child Neurol 1987;29:815-820. 2. ShimamuraCh, Nonaka I. Nemalinemyopathy:comparative musclehistochemistryin the severe neonatal, moderatecongenitaland adult-onset forms.Ped Neurol 1989; 5: 25-31. 3. DubowitzV. Muscle Biopsy: A Practical Approach, 2nd Edn. London: Bailliere, 1985. 4. Cohen P E, Murphy E G, Donohue W L. Light and elL~ctronmicroscopic studies of myogranulesin a child with hypotoniaand muscleweakness.Can MedAssoc J 1963; 89: 983-986. 5. Shy G M, Engel W K, Somers J E, Wanko T. A new congenital myopathy.Brain 1963;79: 793-810.
418
I. HAUSMANOWA-PETRUSEWICZet al.
6. Wallgren-Pettersson C, Rapola J, Doumer M. Pathology of nemaline myopathy. A follow-up study. J Neurol Sci 1987; 83: 243-257. 7. Dubowitz V. Muscle Disorders in Children. London: W B Saunders, t978: 51, 77. 8. Wijngarden G K, Bethlem J. The facioscapulo-humeral syndrome. In: Kakulas B A, ed. Clinical Studies in Myology. New York: Elsevier, 1973: 498-501. 9. Walton J, Gardner-Medwin D. The Muscular Dystrophies. In: Walton J, ed. Disorder o f Voluntary Muscle. Edinburgh-London: Churchill Livingstone, 1988: 533. 10. Engel A G, Gomer M R. Nemaline (Z disc) myopathy: observations on the origin, structure and solubility properties of the nemaline structures. J Neuropathol Exp Neurol 1967; 26: 6017619. 11. Nienhuis A W, Coleman R F , Brown W J, Munsat T L, Pearson C H. Nemaline myopathy. A histopathologic and histochemical study. Am J Clin Pathol 1967; 48: 112.
12. Karpati G, Carpenter S, Andermann A. A new concept of childhood nemaline myopathy. Arch Neuro11971; 24: 291-304. 13. Stoessl A J, Hahn A F, Malott D, Jones D T, Silver M D. Nemaline myopathy with associated cardiomyopathy. Arch Neurol 1985; 42: 1084-1093. 14. Shafiq S A, Dubowitz V, Peterson H C, Milhorat A T. Nemaline myopathy: report of a fetal case with histochemical and electron microscopic studies. Brain 1967; 90:817-828.
15. Jakubiec-Puka A. Reconstruction of the contractile apparatus of striated tfiuscle. 1. Muscle maintained in extension. J Muscle Res Cell Motil 1985; 6:385-40 I. 16. Jakubiec-Puka A, Carraro U. Adaptive remodelling of contractile apparatus of the electrostimulated muscle. XIXth Europ Conf Muscl Contr Cell Motil, Brussels, 10-13 September 1990, abstracts p. 68. 17. Jakubiec-Puka A, C.arraro U. Remodelling of the contractile apparatus of striated muscle stimulated electrically in a shortened position. J Anat 1991; 178: 83-100.