In a new, typical case of Schwartz-Jampel syndrome (SJS) the origin of the disorder was found to be purely myogenic. Concentric needle EMG showed abundant and persistent spontaneous activity, maximal at insertion, and uninfluenced by local curarization. Single-fiber EMG showed rather stable, sometimes intermittent, discharge series with occasional amplitude and/or frequency fluctuations. It could be demonstrated that this activity did not consist of complex repetitive discharges, but of independent activity of individual muscle fibers. This contrasts with findings by other investigators that have been published in this Light microscopic studies of quadriceps and intercostal muscles showed no abnormalities, whereas electron-microscopic findings were in accordance with earlier studies in SJS. Endplate analysis revealed no specific changes; the postsynaptic structures gave the impression of an accelerated-maturation. Key words: Schwartz-Jampel syndrome myotonia single-fiber EMG electron microscopy complex repetitive discharges MUSCLE & NERVE 13516-527 1990
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SCHWARTZ- JAMPEL SYNDROME: 1. CLINICAL, ELECTROMYOGRAPHIC, AND HISTOLOGIC STUDIES FRANK SPAANS, MD, PIERRE THEUNISSEN, MD, AD REEKERS, MD, LEO SMIT, MD, and HENK VELDMAN
About 30 cases of Schwartz- Jampel syndrome (chondrodystrophic myotonia) have been reported since the first description in 1962.28 Prominent clinical features .are muscle stiffness, myotonia, shortness of stature, skeletal abnormalities and a peculiar facies. Hypertrophic muscle bulks are often present. Other frequently occurring symptoms are blepharophimosis, blepharospasm, strabismus, puckered lips, receding chin, laryngeal stridor, high-pitched voice, high-arched palatum and excessive sweating. In most patients with the Schwartz- Jampel syndrome (SJS) intelligence is normal, but several cases with mental retardation have been de~cribed.~,~,~~,'~.'~,~' The disorder is
From the Department of Clinical Neurophysiology, University of Limburg, Maastricht (Dr. Spaans); the Department of Pediatrics. De Wever Hospital, Heerlen (Dr. Theunissen); the Rehabilitation Center for Children Franciscusoord, Valkenburg (Dr. Reekers); and the Laboratory for Neuromuscular Diseases, Department of Neurology, University Hospital Utrecht (Dr. Smit and Mr Veldman), The Netherlands. Address reprint requests to Prof. Spaans at the Department of Clinical Neurophysiology, University Hospital, Postbox 1918,6201 BX Maastricht, The Netherlands. Acknowledgments: We thank Dr. R. Visser for initial examination of the quadriceps muscle biopsy, Dr. C. Schrander-Stumpel for the anthropometric examination, Prof. J. v. Engelshoven for radiological advice, and Philips Medical Systems for the MRI examination. Accepted for publication August 14, 1989 CCC 0148-639X/90/060516-12$04.00 0 1990 John Wiley & Sons, Inc.
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usually autosomal and recessively inherited, but dominant inheritance has also been suggested in one family report.12 Clinical symptoms are obvious within the first 3 years of life or even at birth6; most cases described were under 10 years of age. Little information is available about the rognosis, but from reports on older children 12,13,8and two sisters, one 47 and the other 51 years of age,4 the course does not seem progressive or only slowly so. One case of an 16-year-old SJS patient with spinal cord compression resulting from spinal column deformities has been reported.31 Abundant spontaneous activity has been found in all on EMG studies but its character has been variously described and opinion differs as to its origin. Recently we carried out extensive electromyographic and histologic studies in a new case of this rare disorder. Results of these studies will be correlated with in vitro electrophysiological studies (article to follow).l 8 CASE HISTORY
The patient is a boy born with breech presentation after an uneventful pregnancy at a gestational age of 36 weeks. He is the second child of unrelated parents. Birth weight was 2935 g, length 47 cm. The Apgar score was 6 after 1 minute and 9 after 5 minutes. The neonatal period was complicated by poor sucking and slight muscle rigidity. At 9
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months the boy developed a laryngeal stridor, intermittent rigidity and a limited mobility of the neck. He had a masklike facies, epicanthal folds, a receding chin, upturned nose and a long philtrum. The neck was short, with strongly hypertrophic musculature. Shoulder and upper arm muscles were also hypertrophic and firm on palpation. Movements were scarce and slow. Excitement caused muscle hypertonia and frequently laryngeal stridor, hypersalivation and excessive sweating. Ophthalmological and audiological investigations revealed no abnormalities. Routine laboratory studies, muscle enzymes, calcium, phosphate and alkaline phosphatase were normal. Metabolic screening, including mucopolysaccharide excretion, was normal. Chromosome analysis showed a normal male karyotype, 46 xy. EMG studies, however, were markedly abnormal (see below). Family history revealed no cases of muscle disease. From the age of 20 months the boy could stand alone and walk without support. Language and speech development were normal; the voice, however, was unusually high-pitched. Only at the age of 4 years did he learn to roll over and crawl, sit up directly from a supine position and stand up without using Gower's maneuver. These and other activities could only be performed at low speed and at the cost of much energy. Myotonia did not decrease during physical activity (no warm-up phenomenon). During locomotion there was toe-walking and the arms were held in semiflexion (Fig. 1A). Arm-hand function was impaired by muscle rigidity and the differentiation of manipulation was poorly developed. There was a slight flexion contracture of the right elbow, but no other apparent contractures. Forceful closure of the eyes (e.g., during hair-washing or crying) caused a pronounced blepharospasm (Fig. 1D). Mental development was within normal limits. Length growth was according to the third percentile (P3), but below P3 when related to mid-parental length. Arm span was too short compared with body height. A moderate thoracic kyphosis became apparent. Radiographs, however, showed no evidence of abnormal osseous or epiphyseal developments. Magnetic resonance imaging (MRI) of neck, shoulder, and arm musculature showed that the hypertrophic aspect of these structures was due to true muscle hypertrophy (Fig. 2). MATERIAL AND METHODS
Various EMG studies were performed at 15 months, 17 months, and at 4
Electromyography.
Schwartz-Jarnpel Syndrome
years 2 months. A Medelec MS6 electromyograph (Medelec Ltd, Old Woking, Surrey, UK) was used for the first two studies and a Viking electromyograph (Nicolet Biomedical Instruments, Madison, WI, USA) for the third study. The parents and the only (older) brother were investigated once. For concentric needle EMG (CNEMG), the frequency range of the amplifiers was 2 Hz to 8 kHz or 10 kHz, and for single-fiber EMG (SFEMG), 500 Hz to 16 kHz or 20 kHz. Nerve conduction studies were performed with surface electrodes for stimulation and recording (frequency range 16 Hz or 20 Hz to 1600 Hz or 2000 Hz). Both CNEMG and SFEMG were stored on magnetic tape (Racal Store 4 DS FM recorder, Racal Recorders Ltd, Southampton, UK) at a speed of 15 intsec. Light and Electron Microscopy. At 17 months a needle biopsy was taken from the left quadriceps muscle and prepared for routine light and electron-microscopic investigation. Five age-matched control specimens of quadriceps muscle were studied. At 4 years 4 months, an intercostal muscle biopsy was performed. During this procedure, tissue was also obtained for in vitro electrophysiological studies (see Lehmann-Horn et al. this issue"). Fresh muscle specimens, obtained by intercostal muscle biopsy, were quickly frozen and cooled in liquid nitrogen for light microscopic investigation. Two parts of the biopsy were initially immersed in Bretag solution,20 containing 10 FM TTX, for 1 and 4 hours respectively and subsequently fixated in periodate lysine paraformaldehyde (PLP). Light microscopic studies included routine histological and histochemical staining procedures including alizarin red for calcium. Indoxyl acetate was used as substrate demonstrating acetylcholinesterase activity. Intramuscular nerves and endplates were visualized by the Pestronk and Drachrnan method.** Acetylcholine receptors (AChR) in endplate regions were localized with a two-step monoclonal antibody technique, as described p r e v i o u ~ l y .Electron ~~ microscopic studies included muscle fiber morphology by routine procedures. The structure of 34 endplates was analysed. AChR was localized at the endplates with the aid of a monoclonal antibody te~hnique.~'Results of measurements of fiber size and distribution and electron microscopic images of endplate morphology were compared with findings in intercostal muscle of two age-matched controls.
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A
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FIGURE 1. Patient with SJS at the age of 4 years and 6 months. (A) Walking; the forefoot hits the floor first; pedes plani; moderate thoracic kyphosis; hypertrophic arm musculature; both arms directed forward with about 30" elbow flexion. ( 8 ) Short neck; hypertrophic shoulder and neck musculature. (C) Receding chin, long philtrum, upturned nose. (D) Blepharospasm: attempt to open the eyes after forceful closure; epicanthus.
FIGURE 2. Magnetic resonance imaging showing a transverse section at the level of the 4th thoracic vertebra. The hypertrophic aspect of the shoulder musculature (Fig. 1) appears to be due to an increase of muscle tissue (grey), and not to pseudohypertrophy (fat and connective tissue are white on these images). At the dorsal side, the infraspinate and subscapularis (separated by the scapula: subtle black line) can be recognized, as well as the trapezius, rhomboideus, and erector spinae. The deltoid is also clearly hypertrophic. The blurring at the ventral side is due to respiration movements.
RESULTS Electromyography
CNEMG. Performed at 15 months, 17 months, and at 4 years 2 months, CNEMG showed persistent spontaneous activity in all investigated limb and facial muscles. On all occasions it was so abundant that no individual action potentials could be identified (Fig. 3). Needle displacements induced outbursts of activity with amplitudes ranging u p to 3 mV. These discharges sounded like electrical myotonia, but with a less pronounced crescendo-descrescendo character. When the needle electrode was kept still, the spontaneous activity showed little fluctuation. Electrical silence never occurred. Due to the boy’s immobility and poor cooperation, motor unit activity could only be recorded incidentally. MUPs could not be measured properly, but did not appear abnormal (Fig. 3C). Peroneal motor and median sensory nerve conduction were normal. Both parents and the brother of our patient had no EMG abnormalities. At 17 months the effect of cururimtion on the spontaneous activity was studied during general anesthesia (necessary because of a muscle biopsy). Owing to the possible risk of malignant hyperthermia in SJS,2gno halothane or succinylcholine were used. Simultaneous CNEMG recordings were performed in the left abductor pollicis brevis (APB), both flexor carpi radialis (FCR) muscles, and the left tibialis anterior (TA). Regional neuromuscular curare block was performed by the intravenous technique of Torda and K l ~ n y r n u s Cuffs . ~ ~ were applied around both upper arms and inflated to above the systolic pressure. D-tubocurarine was administered intravenously in the left forearm until supramaximal stimulation of the median nerve no longer elicited a muscle response from the thenar. It took 20 minutes, during which 250 pg of d-tubocurarine was administered, to achieve complete neuromuscular blockade. At that time there was still spontaneous activity in the left APB and FCR, and the amount of activity in the left FCR was no different from that in the right FCR (also ischemic) or in the left TA (not ischemic), thus demonstrating that the spontaneous activity was uninfluenced by curare or ischemia. SFEMG Studies were performed at 4 years 2 months. Individual muscle fiber discharge series, at rates from 30 to 80 Hz, could be recognized (Fig. 4). Some discharge series showed occasional crescendo-decrescendo fluctuations and others varied only slightly in amplitude. Some fibers discharged intermittently (Fig. 4A). Brief frequency
Schwartz-Jarnpel Syndrome
changes were noted in a number of discharge series (Figs. 4C and 5). A triggering and averaging technique was used to detect time-locking between SF potentials, but this was never encountered (Fig. 5A). In one recording a double potential occurred for a few seconds (Fig. 5B). Jitter measurements on this transient “double potential” gave an MCD (mean consecutive difference) value of about 260 psec (normal maximal MCD value for the interpotential intervals of two fivers belonging to the same motor unit is 55 psec; for two ephaptically coupled fibers it is typically 5 p s e ~ ) . ~ * Myopathic features were absent in cross sections of both muscle biopsies and there was no excess of internal nuclei. Measurements in the quadriceps muscle biopsy at 17 months showed a type 1 fiber diameter of 19 t 3 pm (mean ? SD) and a type 2 diameter of 17 3 pm. Five age-matched controls measured 18 k 4 pm for type 1 and 19 k 4 pm for type 2 fibers. Type 1 versus type 2 fiber distribution was 1: 1 in patient as well as in controls. In intercostal muscle (at 4 years 4 months), the fiber-type distribution showed a mosaic pattern with a 73% predominance of type 1 fibers, which corresponded to data in our two intercostal controls. Intercostal muscle fiber diameters measured 32.2 -+ 7.9 pm for type 1 and 32.6 k 8.3 p,m for type 2 fibers. In control muscles these values were 30.1 -t- 7.3 for type 1 and 24.7 t 6.7 for type 2 fibers. Additional examination of the intercostal muscle did not show accumulation of calcium or inorganic iron. Acetylcholinesterase activity was normally confined to the endplate regions and its extinction at shorter staining times was similar to that in controls. With the combined staining method for intramuscular nerves and endplates, there was a normal innervation pattern and no signs of sprouting or collateral innervation. AChR markings were strictly confined to the sickle-shaped regions on the postsynaptic membranes and each fiber showed a single endplate region. Light Microscopy.
*
Electron Microscopy
Muscle Fibers. Morphological alterations were seen in most muscle fibers, though some focal distribution seemed to be present. The prominent features were increase of subsarcolemmal sarcoplasm, vacuoles between bundles of myofibrils and abrupt loss of filaments, together with disarray of the Z disks. The quadriceps biopsy already re-
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FIGURE 3.Concentric needle EMG biceps brachii; ongoing spontaneous activity recorded with a single amplifier. (A) Traces 1 and 3: needle displacement causes bursts of activity with amplitudes up to 3 mV (cat.: 1 sec, 1 mV). Subsequently, the activity shows slight amplitude variations, but never stops. Traces 7 and 8 contain a number of volitional MUPs with higher amplitudes than the spontaneous activity. They are shown in greater detail in (C) (cal.: 10 msec, 500 FV). (6)Within the spontaneous activity, no individual potentials can be identified with CNEMG. The global activity nevertheless shows some rhythmicity (about 70 Hz) (cal.: 10 msec, 200 pV).
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C FIGURE 4. Single-fiber EMG biceps brachii. Ongoing spontaneous activity recorded with a single arnplifier. (A) Needle insertion in trace 1. All subsequent changes occurred without displacement of the needle or other mechanical stimuli (cal.: 500 rnsec, 500 (LV). (B) Detail of (A), first part, second trace (cal.: 50 rnsec, 500 KV). In traces 1 and 5 of Fig. 38,probably the same muscle fiber is discharging at a rate of about 45 Hz. Note the gradual reduction of interpotential intervals in the first part of both discharge series. In traces 7 and 8, a lower SF potential can be identified discharging at a rate of about 70 Hz. ( C ) Another part of recording (A) in greater detail (cal.: 10 msec, 200 pV). The two highest single-fiber potentials discharge at frequencies of about 50 Hz and 65 Hz respectively.
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FIGURE 5. (A) Trace 3 (cal.: 10 msec, 200 JLV)shows ongoing SF activity in the biceps brachii. Trigger level top left. Trace 6 (cal.: 2 msec, 200 k V ) shows the result of averaging 50 discharges of the highest potential. Its shape is that of a typical SF potential without coupling to any other potential. (B) A double potential was seen for a few seconds. With triggering on the first potential, and averaging only 50 times, the amplitude of the second potential decreased (trace 6) and vice versa (trace 7). This indicates a considerable interval variation between the two potentials, which was confirmed by jitter measurements (see text). The interdischargeintervals are about 15 msec in (A) and about 20 msec in (6). The averaged signal, however, shows no previous or subsequent discharges of the main potential, indicating that the corresponding muscle fibers do not discharge with strict regularity.
vealed these features, though streaming and disarray of myofibers were rare. The subsarcolemmal sarcoplasm consisted of loose stroma with accumulation of mitochondria and abundant thin filaments. Increased subsarcolemmal space was most prominent in the vicinity of the nuclei and endplates. Clusters of glycogen particles were present. Accumulation of myelinoid material was found occasionally under the sarcolemma which focally filled up the peripheral sarcoplasm (Fig. 6). There were membrane-bounded vacuoles between the bundles of myofibrils, mostly empty, sometimes filled with fine granular material or electron-dense whorls (Fig. 7). T h e vacuoles were anything from half to the full intersarcomere distance in size. Normally shaped mitochondria were present; occasionally they were elongated or branched. Calcium deposits were absent. Myofibril bundles showed marked interrup-
522
Schwartz-Jampel Syndrome
tions with disappearance of the 2 disks, involving one or more sarcomeres (Fig. 8). In these areas many glycogen particles and branched and elongated mitochondria were present, as well as the vesicles described earlier. Endplates. The presynaptic terminals varied in size and content, but Schwann-cell covering appeared normal. The postsynaptic area was enlarged and deep secondary clefts were visible in the loose postsynaptic stroma. Extensive branching of these clefts occurred with some fibers, in others they were practically unbranched. The invaginations in the primary clefts occurred at regular intervals and the postsynaptic densities were normally present. Localization of the AChR at the postsynaptic membrane was normal. There were no signs of focal degeneration or remodelling of the endplates. Results of quantitative measurements at neuromuscular junctions: mean nerve
MUSCLE 8, NERVE
June 1990
FIGURE 6. Accumulation of rnyelinoid material was occasionally present under the sarcolemrna (bar
*
terminal area (NTA) measured 4.05 pm2 (SD 2.481, mean presynaptic membrane length (PSM) 4.75 pm (SD k 1.51) and mean postsynaptic area (PSA) of folds and clefts measured 7.89 pm2 (SD t 3.76). Results in two controls were: NTA 5.33 pm2 (SD k 4.08) and 8.26 pm2 (SD 2 7.02), PSM 5.02 pm (SD 2.08) and 6.19 pm (SD 2.6’7, PSA 7.68 pm2 (SD i 4.15 and 9.19 pm2 (SD 2 5.33).
*
*
DISCUSSION
Congenital myotonic syndromes include congenital inyotonic dystrophy (MyD), dominantly and recessively inherited myotonia congenita (MyC), paramyotonia congenita (PC) and chondrodystrophic myotonia (SJS). The most intensive myotonia is seen in SJS. Apart from his body height, the clinical features of our patient were all highly characteristic of SJS. Almost all published cases of SJS have been dwarfs; our patient, as well as two other cases?’ had a body height of about 2 standard deviations below the mean. Moreover, the patient was too small compared to his parents’ body height and the arm span too short compared with body height. X-ray investigations showed no evidence of abnormal osseous or epiphyseal developments. This has also been the case in some other SJS patients, for which reason the term chondrodystrophic myotonia has been criticized.’% Myotonic discharges are not identical in the various myotonic syndromes. There are differences in incidence, mean duration and amplitudefrequency pattern^,^^.^^,^^ du e probably to different underlying membrane abnormalities. For
Schwartz- Jampel Syndrome
=
1 p).
example, in MyD, in addition to typical “divebomber” discharges, prolonged runs, with falling or unchanging frequency and amplitude also occur.25 The spontaneous EMG activity in the SJS has been variously described in different patients. A number of authors re orted only “typical” myotonic discharge^.^"^"^^^ Others found sponta-
t
neous activity with little or no amplitude and/or frequency v a r i a t i ~ n . ~ ~ ” ’ “ ” ”Others ,’~ again reported a combination of both kinds of activity.5,S,16,23,27 The regular, spontaneous activity has been described as “pseudomyotonic discharges”, “bizarre high frequency discharges” and, more recently, as “complex repetitive discharges” (CRDs). True CKDs consist of a number of muscle fiber potentials which are closely time-locked as a result of ephaptic impulse transmission between their fibers.32 Usually the MCD values of interspike and interdischar e intervals are very low, typically below 5 psec!‘ CRDs are mainly encountered in chronic neurogenic disorders; overexcitable, denervated muscle fibers are activated ephaptically by the action potential of a neighboring fiber. Like single fibrillation potentials, CRDs may also occur in muscular dystrophies, metabolic myopathies and polymyositis. In CNEMG recordings it can be difficult or even impossible to recognize discharges of individual muscle fibers or groups of fibers within the large amount of spontaneous activity which occurs in the SJS. We think that only three case reports convincingly show the occurrence of CRDs in SJS.8,’6*’7T h e spontaneous activity was analyzed with SFEMG in two of them. In one report, CRDs were in fact found to be the only kind of spontaneous acti~ity.’~ This finding
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B FIGURE 7. (A) At low magnification, a number of membrane-bounded vacuoles are seen to be located between the bundles of myofibrils (bar = 1 km). (B)At higher magnification these vacuoles are empty or filled with fine granular material (Bar = 1 Km).
contrasts maximally with the EMG findings in our patient. SFEMG showed activity with obvious frequency and amplitude changes as well as more stable activity which, however, appeared to be not strictly regular (Figs. 4 and 5). Apart from one
524
SchwatTz-Jampel Syndrome
transient double potential, with a large interval variation between its components, we failed to find any sign of electrical coupling between muscle fibers (Fig. 5). There is likewise no unanimity in the litera-
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FIGURE 8. Myofibrillar architecture showed focal disarray and interruptions of the 2 disks involving one or more sarcomeres (arrows; bar = 1 pm).
ture with respect to the persistence of the spontaneous activity in SJS. In our case as in others,4,6,12714.16,21,33 the spontaneous activity never disappeared during routine recordings, though others have reported finding periods of silence.5.' 1,17 We, as well as other investigators4,6,12-14 h ave found that the activity also persisted during general anesthesia. Both myotonic discharges and CRDs originate in the muscle fibers themselves and are not abolished by curare.24 Cases of SJS, in which the spontaneous activity diminished or disappeared after c ~ r a r i z a t i o n ,must ~ ' ~ ~have been neurogenic. Like other investigation^,^,^^'^^^^ we found that there was no effect on the spontaneous activity. The different features of the spontaneous activity re-
Schwartz- Jampel Syndrome
ported in the various cases suggest that a number of different membrane abnormalities may occur within the SJS. In vitro electrophysiological studies were undertaken" to obtain more insight into the membrane dysfunction in our patient. During these studies the absence of any effect of curare has been confirmed. Since procainamide appeared to be effective in suppressing the spontaneous activity in vitro, we decided to try this drug in the case of our patient. Mobility clearly increased, with 4 x 500 mg daily, whereas clinical myotonia and fatigability diminished. T h e few MUPs that we could recognize did not appear abnormal (Fig. 3C). A number of authors others reported MUPs in SJS as being
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525
found MUPs with decreased mean duration and increased polyphasia. 1,15,23 Extreme polyphasia has been reported in the case where CRDs were observed as the only form of spontaneous activity.17 The authors found “a striking similarity between the configuration of its MUPs and the repeating units of its CRDs, suggesting an origin in the same muscle fibers.” Since CRDs are due to ephaptic coactivation of neighboring muscle fibers, this remarkable finding suggests that, in this case, compact groups of fibers should belong to the same motor unit, which means that histochemistry could be expected to show fiber-type grouping. The report, however, contains no muscle biopsy results. In our case, as in all other reported muscle histochemistry in SJS,2,6,’4-16,20,z1 signs of reinnervation such as fiber-type grouping or altered terminal innervation were absent. In view of the obvious hypertrophy of several muscles of our patient (Figs. l and 2) an increased mean muscle-fiber diameter might have been expected, but both quadriceps (judged with MRI) and intercostal muscle (viewed at surgery) were not hypertrophic. Mean fiber diameter of type 2 intercostal fibers exceeds 25% of the control value, but average increases in diameter, as reported by others,13 were not present. According to Brooke and Engel, the normal average muscle-fiber diameter at 4.5 years is 23 pm 12%, but the normal intercostal muscle, which apparently contains larger fibers, was not included in their ~ t u d i e sProliferation .~ of sarcolemmal nuclei and increase of connective tissue, reported by other^,'^"*'^ was absent. The terminal innervation pattern showed a normal, single innervation site on the muscle fibers and the marked increase of AChE activity reported by Fowler et all3 was absent.
’
*
Results of our electron-microscopic studies show many similarities to findings in other cases. Vacuoles were found between the bundles of myofibrils in many fibers. It has been suggested that they are focal dilatations of the sarcotubular system.2,10,13,16A constant finding in electron-microscopic studies in SJS are the interruptions in the sarcomeres, including Z disks, together with focal disarray of myofibrils. Z-disk streaming and disintegration is a common finding, especially in mitochondria1 myopathy and denervation atrophy.9 These features also occur in endplate myopathies in which calcium accumulates in the junctional region.’” In these cases Z disk damage may be related to calcium-activated proteases found at the Z Disorders with abnormally high calcium transients in the myofilament space, to which SJS probably belongs, may show loss of myofibrillar architecture on the basis of this mechanism. The postsynaptic structures in the present study gave the impression of an accelerated maturation, proportional to the mature aspect of the muscle fibers. However, endplate analysis revealed no specific changes in morphology and quantitative measurements revealed nothing of significance. Obviously the massive ongoing spontaneous muscle-fiber activity did not influence the morphology of the neuromuscular synapse. I n conclusion, it can be said that, although the clinical picture of the SJS is characteristic and the reported electron-microscopic findings in muscle biopsies are similar, its pathophysiology seems to be variable. The present case appears to be purely myogenic and is the first one in which it has been convincingly shown that massive, independent activity of individual muscle fibers underlies the impressive myotonic symptoms.
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2. 3.
4. 5.
dwarfism, diffuse bone disease and unusual ocular and facial abnormalities (a new syndrome). Bruin 1965; 88:313321. Aberfeld DC, Namba T, Vye MV, Grob D: Chondrodystrophic myotonia: Report of two cases. Arch Neural 1970; 22:455-462. Brooke MH, Engel WK: T h e histographic analysis of human muscle biopsies with regard to fiber typcs. 4: Children’s biopsies. Neurology (Minncapolis) 1969; 19:59 l 605. Brown, SB, Garcia-Mullin R, Murai Y: T h e Schwartz-Jampel syndrome (myotonic chondrodystrophy) in the adult. Neurology (Minneapolis) 1975; 25:365-366. Abstract. Cadilhac J, Baldet P, Greze J, Duday H: E.M.G. studies of two family cases of the Schwartz and Jampel syndrome (os-
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teo-chondro-muscular dystrophy with myotonia). Electromyogr Clin Neurophyysiol 1975; 15:5- 12. Cao A, Cianchetti C, Calisti L, de Virgiliis S, Ferreli A, Tarighcroni W: Schwarlz-Janipcl syndrome: Clinical, electrophysiological and histopathological study of. a severe variant. J N e u d Sci 1978; 35:175- 187. Carafoli E: T h e regulation of. intracellular calcium. Adu EX^ M e d Rid 1982; 151:461-472. Cruz Martinez A, Arpa J, Perez Conde MC, Ferrer MT: Bilateral carpal tunnel in childhood associated with Schwartz- Jampel syndrome. Muscle Nervr 1984; 7: 66-72. Engel AG: Pathological reaction of the Z disk. Excerpta Medzra ICS 1967; 147:398-411. Engel, WK, Vick HA, Glueck, CJ, I.evy RI: A skeletal muscle disorder associated with intermittent symptoms and a
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possible defect in lipid metabolism. N e u Engl J Med 1970; 2821697-699. 11. Fariello R, Meloff K, Murphy EG, Reilly BJ, Armstrong D: A case of Schwartz-Jampel syndrome with unusual muscle biopsy findings. Ann Neural 1978; 3:93-96. 12. Ferrannini E, Perniola T , Krajewska G, Serlenga L, Trizir M: Schwartz- Jampel syndrome with autosomal-dominant inheritance. Eur. Neural 1982; 21:137- 146. 13. Fowler WM, Layzer RB, Taylor RG, Eberle ED, Sims GE, Munsat TL, Philippart M, Wilson BW: The SchwartzJampel syndrome: Its clinical, physiological and histological expressions. J Neural Sci 1974; 22: 127- 146. 14. Greze J, Baldet P, Dumas R, Cadilhac J , Pages A, Jean R: Dystrophie osteo-chondro-musculaire de Schwartz-Jampel. Arch Franc Pkd 1975; 32:59-75. 15. Huffelen AC van, Gabreels FJM, Luypen-v.d. Horst JS van, Slooff JL, Stadhouders AM, Korten JJ: Chondrodystrophic myotonia. Neuropadiatrie 1974; 5:71-90. 16. Huttenlocher PR, Landwirth J, Hanson V, Gallagher BB, Bensch K: Osteochondro-muscular dystrophy: A disorder manifested by multiple skeletal deformities, myotonia, and dystrophic changes in muscle. Pediatrics 1969; 44:945-958. 17. Jablecki C, Schultz P: Single muscle fiber recordings in the Schwartz- Jampel syndrome. Muscle Nerve 1982; 5 5 6 4 S69. 18. Lehmann-Horn F, Iaizzo PA, Franke C, Hatt H, Spaans F: Schwartz-Jampel syndrome: 11. Na+ channel defect causes myotonia. Muscle Nerve 1990; 13:528-535. 19. Leonard JP, Salpete MM: Agonist-induced myopathy at the neuromuscular junction is mediated by calcium. J Cell B i d 1979; 82:811-819. 20. Mereu TR, Porter IH, Hug G: Myotonia, shortness of stature, and hip dysplasia: Schwartz-Jampel syndrome. Am J DiS Child 1969; 117:470-478. 21. Pavone L, Mollica F, Grasso A, Cao A, Gullotta F: Schwartz-Jampel syndrome in two daughters of first cousins. J Neural Neurosurg Psychiat 1978; 41:161- 169. 22. Pestronk A, Drachmann DB: A new stain for quantitative measurement of sprouting at neuromuscular functions. Muscle Nerve 1978; 1:70-74.
Schwartz- Jampel Syndrome
23. Pfeiffer RA, Bauer H, Petersen C: Das Syndrom von Schwartz-Jampel (Myotonia chondrodystrophica). Helv Paediat Acta 1977; 32:251-261. 24. Ricker K, Meinck HM: Verlaufsdynamik und Herkunft pseudomyotoner Entladungsserien bei Denervations-syndromen. 2 EEG-EMG 1972a; 3:170- 178. 25. Ricker K, Meinck HM: Vergleich myotoner Entladungen bei Myotonia congenita und Dystrophia myotonica. Z Neurol 1972b; 201:62-72. 26. Rude1 R, Lehmann-Horn F: Membrane changes in cells from myotonia patients. Physiological Reviews 1985; 65 :310- 356. 27. Santoro L, Camporeale F, Marolda M, Nucciotti R, Marasco E: Schwartz-Jampel syndrome. Report of a case. Acta Neural (Naples) 1984; 6: 193- 199. 28. Schwartz 0, Jampel RS: Congenital blepharophimosis associated with a unique generalized myopathy. Arch Ophthalmol 1962; 68:52-57. 29. Seay AR, Ziter FA: Malignant hyperpyrexia in a patient with Schwartz-Jampel syndrome. J Pediatr 1978; 93:8384. 30. Smit LME, Veldman H, Jennekens FGI: Immunohistochemical localization of acetylcholine receptors at human endplates using a monoclonal antibody. J Histochem Cytochem 1987; 35:613-617. 31. Smith DL, Shoumaker R, Shuman R: Compressive myelopathy in the Schwartz- Jampel syndrome. Ann Neural 1981; 10:497. 32. Stalberg E, Trontelj JV: Abnormal discharges generated within the motor unit as observed with single-fiber electromyography, in Culp WJ, Ochoa J (eds): Abnormal Nerves and Muscles as Impulse Generators. New York, Oxford University Press, 1982, pp. 443-474. 33. Taylor RG, Layzer RB, Davis HS, Fowler WM: Continuous muscle fiber activity in the Schwartz- Jampel syndrome. Electroenceph Clin Neurophysiol 1972; 33:497-509. 34. Torda TAG, Klonymus DH: Regional neuromuscular block. Acta Anaesth S c a d (suppl) 1966; 24:177- 192.
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SCHWARTZ- JAMPEL SYNDROME: 1. CLINICAL, ELECTROMYOGRAPHIC, AND HISTOLOGIC STUDIES FRANK SPAANS, MD, PIERRE THEUNISSEN, MD, AD REEKERS, MD, LEO SMIT, MD, and HENK VELDMAN
About 30 cases of Schwartz- Jampel syndrome (chondrodystrophic myotonia) have been reported since the first description in 1962.28 Prominent clinical features .are muscle stiffness, myotonia, shortness of stature, skeletal abnormalities and a peculiar facies. Hypertrophic muscle bulks are often present. Other frequently occurring symptoms are blepharophimosis, blepharospasm, strabismus, puckered lips, receding chin, laryngeal stridor, high-pitched voice, high-arched palatum and excessive sweating. In most patients with the Schwartz- Jampel syndrome (SJS) intelligence is normal, but several cases with mental retardation have been de~cribed.~,~,~~,'~.'~,~' The disorder is
From the Department of Clinical Neurophysiology, University of Limburg, Maastricht (Dr. Spaans); the Department of Pediatrics. De Wever Hospital, Heerlen (Dr. Theunissen); the Rehabilitation Center for Children Franciscusoord, Valkenburg (Dr. Reekers); and the Laboratory for Neuromuscular Diseases, Department of Neurology, University Hospital Utrecht (Dr. Smit and Mr Veldman), The Netherlands. Address reprint requests to Prof. Spaans at the Department of Clinical Neurophysiology, University Hospital, Postbox 1918,6201 BX Maastricht, The Netherlands. Acknowledgments: We thank Dr. R. Visser for initial examination of the quadriceps muscle biopsy, Dr. C. Schrander-Stumpel for the anthropometric examination, Prof. J. v. Engelshoven for radiological advice, and Philips Medical Systems for the MRI examination. Accepted for publication August 14, 1989 CCC 0148-639X/90/060516-12$04.00 0 1990 John Wiley & Sons, Inc.
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usually autosomal and recessively inherited, but dominant inheritance has also been suggested in one family report.12 Clinical symptoms are obvious within the first 3 years of life or even at birth6; most cases described were under 10 years of age. Little information is available about the rognosis, but from reports on older children 12,13,8and two sisters, one 47 and the other 51 years of age,4 the course does not seem progressive or only slowly so. One case of an 16-year-old SJS patient with spinal cord compression resulting from spinal column deformities has been reported.31 Abundant spontaneous activity has been found in all on EMG studies but its character has been variously described and opinion differs as to its origin. Recently we carried out extensive electromyographic and histologic studies in a new case of this rare disorder. Results of these studies will be correlated with in vitro electrophysiological studies (article to follow).l 8 CASE HISTORY
The patient is a boy born with breech presentation after an uneventful pregnancy at a gestational age of 36 weeks. He is the second child of unrelated parents. Birth weight was 2935 g, length 47 cm. The Apgar score was 6 after 1 minute and 9 after 5 minutes. The neonatal period was complicated by poor sucking and slight muscle rigidity. At 9
MUSCLE & NERVE
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months the boy developed a laryngeal stridor, intermittent rigidity and a limited mobility of the neck. He had a masklike facies, epicanthal folds, a receding chin, upturned nose and a long philtrum. The neck was short, with strongly hypertrophic musculature. Shoulder and upper arm muscles were also hypertrophic and firm on palpation. Movements were scarce and slow. Excitement caused muscle hypertonia and frequently laryngeal stridor, hypersalivation and excessive sweating. Ophthalmological and audiological investigations revealed no abnormalities. Routine laboratory studies, muscle enzymes, calcium, phosphate and alkaline phosphatase were normal. Metabolic screening, including mucopolysaccharide excretion, was normal. Chromosome analysis showed a normal male karyotype, 46 xy. EMG studies, however, were markedly abnormal (see below). Family history revealed no cases of muscle disease. From the age of 20 months the boy could stand alone and walk without support. Language and speech development were normal; the voice, however, was unusually high-pitched. Only at the age of 4 years did he learn to roll over and crawl, sit up directly from a supine position and stand up without using Gower's maneuver. These and other activities could only be performed at low speed and at the cost of much energy. Myotonia did not decrease during physical activity (no warm-up phenomenon). During locomotion there was toe-walking and the arms were held in semiflexion (Fig. 1A). Arm-hand function was impaired by muscle rigidity and the differentiation of manipulation was poorly developed. There was a slight flexion contracture of the right elbow, but no other apparent contractures. Forceful closure of the eyes (e.g., during hair-washing or crying) caused a pronounced blepharospasm (Fig. 1D). Mental development was within normal limits. Length growth was according to the third percentile (P3), but below P3 when related to mid-parental length. Arm span was too short compared with body height. A moderate thoracic kyphosis became apparent. Radiographs, however, showed no evidence of abnormal osseous or epiphyseal developments. Magnetic resonance imaging (MRI) of neck, shoulder, and arm musculature showed that the hypertrophic aspect of these structures was due to true muscle hypertrophy (Fig. 2). MATERIAL AND METHODS
Various EMG studies were performed at 15 months, 17 months, and at 4
Electromyography.
Schwartz-Jarnpel Syndrome
years 2 months. A Medelec MS6 electromyograph (Medelec Ltd, Old Woking, Surrey, UK) was used for the first two studies and a Viking electromyograph (Nicolet Biomedical Instruments, Madison, WI, USA) for the third study. The parents and the only (older) brother were investigated once. For concentric needle EMG (CNEMG), the frequency range of the amplifiers was 2 Hz to 8 kHz or 10 kHz, and for single-fiber EMG (SFEMG), 500 Hz to 16 kHz or 20 kHz. Nerve conduction studies were performed with surface electrodes for stimulation and recording (frequency range 16 Hz or 20 Hz to 1600 Hz or 2000 Hz). Both CNEMG and SFEMG were stored on magnetic tape (Racal Store 4 DS FM recorder, Racal Recorders Ltd, Southampton, UK) at a speed of 15 intsec. Light and Electron Microscopy. At 17 months a needle biopsy was taken from the left quadriceps muscle and prepared for routine light and electron-microscopic investigation. Five age-matched control specimens of quadriceps muscle were studied. At 4 years 4 months, an intercostal muscle biopsy was performed. During this procedure, tissue was also obtained for in vitro electrophysiological studies (see Lehmann-Horn et al. this issue"). Fresh muscle specimens, obtained by intercostal muscle biopsy, were quickly frozen and cooled in liquid nitrogen for light microscopic investigation. Two parts of the biopsy were initially immersed in Bretag solution,20 containing 10 FM TTX, for 1 and 4 hours respectively and subsequently fixated in periodate lysine paraformaldehyde (PLP). Light microscopic studies included routine histological and histochemical staining procedures including alizarin red for calcium. Indoxyl acetate was used as substrate demonstrating acetylcholinesterase activity. Intramuscular nerves and endplates were visualized by the Pestronk and Drachrnan method.** Acetylcholine receptors (AChR) in endplate regions were localized with a two-step monoclonal antibody technique, as described p r e v i o u ~ l y .Electron ~~ microscopic studies included muscle fiber morphology by routine procedures. The structure of 34 endplates was analysed. AChR was localized at the endplates with the aid of a monoclonal antibody te~hnique.~'Results of measurements of fiber size and distribution and electron microscopic images of endplate morphology were compared with findings in intercostal muscle of two age-matched controls.
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A
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FIGURE 1. Patient with SJS at the age of 4 years and 6 months. (A) Walking; the forefoot hits the floor first; pedes plani; moderate thoracic kyphosis; hypertrophic arm musculature; both arms directed forward with about 30" elbow flexion. ( 8 ) Short neck; hypertrophic shoulder and neck musculature. (C) Receding chin, long philtrum, upturned nose. (D) Blepharospasm: attempt to open the eyes after forceful closure; epicanthus.
FIGURE 2. Magnetic resonance imaging showing a transverse section at the level of the 4th thoracic vertebra. The hypertrophic aspect of the shoulder musculature (Fig. 1) appears to be due to an increase of muscle tissue (grey), and not to pseudohypertrophy (fat and connective tissue are white on these images). At the dorsal side, the infraspinate and subscapularis (separated by the scapula: subtle black line) can be recognized, as well as the trapezius, rhomboideus, and erector spinae. The deltoid is also clearly hypertrophic. The blurring at the ventral side is due to respiration movements.
RESULTS Electromyography
CNEMG. Performed at 15 months, 17 months, and at 4 years 2 months, CNEMG showed persistent spontaneous activity in all investigated limb and facial muscles. On all occasions it was so abundant that no individual action potentials could be identified (Fig. 3). Needle displacements induced outbursts of activity with amplitudes ranging u p to 3 mV. These discharges sounded like electrical myotonia, but with a less pronounced crescendo-descrescendo character. When the needle electrode was kept still, the spontaneous activity showed little fluctuation. Electrical silence never occurred. Due to the boy’s immobility and poor cooperation, motor unit activity could only be recorded incidentally. MUPs could not be measured properly, but did not appear abnormal (Fig. 3C). Peroneal motor and median sensory nerve conduction were normal. Both parents and the brother of our patient had no EMG abnormalities. At 17 months the effect of cururimtion on the spontaneous activity was studied during general anesthesia (necessary because of a muscle biopsy). Owing to the possible risk of malignant hyperthermia in SJS,2gno halothane or succinylcholine were used. Simultaneous CNEMG recordings were performed in the left abductor pollicis brevis (APB), both flexor carpi radialis (FCR) muscles, and the left tibialis anterior (TA). Regional neuromuscular curare block was performed by the intravenous technique of Torda and K l ~ n y r n u s Cuffs . ~ ~ were applied around both upper arms and inflated to above the systolic pressure. D-tubocurarine was administered intravenously in the left forearm until supramaximal stimulation of the median nerve no longer elicited a muscle response from the thenar. It took 20 minutes, during which 250 pg of d-tubocurarine was administered, to achieve complete neuromuscular blockade. At that time there was still spontaneous activity in the left APB and FCR, and the amount of activity in the left FCR was no different from that in the right FCR (also ischemic) or in the left TA (not ischemic), thus demonstrating that the spontaneous activity was uninfluenced by curare or ischemia. SFEMG Studies were performed at 4 years 2 months. Individual muscle fiber discharge series, at rates from 30 to 80 Hz, could be recognized (Fig. 4). Some discharge series showed occasional crescendo-decrescendo fluctuations and others varied only slightly in amplitude. Some fibers discharged intermittently (Fig. 4A). Brief frequency
Schwartz-Jarnpel Syndrome
changes were noted in a number of discharge series (Figs. 4C and 5). A triggering and averaging technique was used to detect time-locking between SF potentials, but this was never encountered (Fig. 5A). In one recording a double potential occurred for a few seconds (Fig. 5B). Jitter measurements on this transient “double potential” gave an MCD (mean consecutive difference) value of about 260 psec (normal maximal MCD value for the interpotential intervals of two fivers belonging to the same motor unit is 55 psec; for two ephaptically coupled fibers it is typically 5 p s e ~ ) . ~ * Myopathic features were absent in cross sections of both muscle biopsies and there was no excess of internal nuclei. Measurements in the quadriceps muscle biopsy at 17 months showed a type 1 fiber diameter of 19 t 3 pm (mean ? SD) and a type 2 diameter of 17 3 pm. Five age-matched controls measured 18 k 4 pm for type 1 and 19 k 4 pm for type 2 fibers. Type 1 versus type 2 fiber distribution was 1: 1 in patient as well as in controls. In intercostal muscle (at 4 years 4 months), the fiber-type distribution showed a mosaic pattern with a 73% predominance of type 1 fibers, which corresponded to data in our two intercostal controls. Intercostal muscle fiber diameters measured 32.2 -+ 7.9 pm for type 1 and 32.6 k 8.3 p,m for type 2 fibers. In control muscles these values were 30.1 -t- 7.3 for type 1 and 24.7 t 6.7 for type 2 fibers. Additional examination of the intercostal muscle did not show accumulation of calcium or inorganic iron. Acetylcholinesterase activity was normally confined to the endplate regions and its extinction at shorter staining times was similar to that in controls. With the combined staining method for intramuscular nerves and endplates, there was a normal innervation pattern and no signs of sprouting or collateral innervation. AChR markings were strictly confined to the sickle-shaped regions on the postsynaptic membranes and each fiber showed a single endplate region. Light Microscopy.
*
Electron Microscopy
Muscle Fibers. Morphological alterations were seen in most muscle fibers, though some focal distribution seemed to be present. The prominent features were increase of subsarcolemmal sarcoplasm, vacuoles between bundles of myofibrils and abrupt loss of filaments, together with disarray of the Z disks. The quadriceps biopsy already re-
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FIGURE 3.Concentric needle EMG biceps brachii; ongoing spontaneous activity recorded with a single amplifier. (A) Traces 1 and 3: needle displacement causes bursts of activity with amplitudes up to 3 mV (cat.: 1 sec, 1 mV). Subsequently, the activity shows slight amplitude variations, but never stops. Traces 7 and 8 contain a number of volitional MUPs with higher amplitudes than the spontaneous activity. They are shown in greater detail in (C) (cal.: 10 msec, 500 FV). (6)Within the spontaneous activity, no individual potentials can be identified with CNEMG. The global activity nevertheless shows some rhythmicity (about 70 Hz) (cal.: 10 msec, 200 pV).
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C FIGURE 4. Single-fiber EMG biceps brachii. Ongoing spontaneous activity recorded with a single arnplifier. (A) Needle insertion in trace 1. All subsequent changes occurred without displacement of the needle or other mechanical stimuli (cal.: 500 rnsec, 500 (LV). (B) Detail of (A), first part, second trace (cal.: 50 rnsec, 500 KV). In traces 1 and 5 of Fig. 38,probably the same muscle fiber is discharging at a rate of about 45 Hz. Note the gradual reduction of interpotential intervals in the first part of both discharge series. In traces 7 and 8, a lower SF potential can be identified discharging at a rate of about 70 Hz. ( C ) Another part of recording (A) in greater detail (cal.: 10 msec, 200 pV). The two highest single-fiber potentials discharge at frequencies of about 50 Hz and 65 Hz respectively.
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FIGURE 5. (A) Trace 3 (cal.: 10 msec, 200 JLV)shows ongoing SF activity in the biceps brachii. Trigger level top left. Trace 6 (cal.: 2 msec, 200 k V ) shows the result of averaging 50 discharges of the highest potential. Its shape is that of a typical SF potential without coupling to any other potential. (B) A double potential was seen for a few seconds. With triggering on the first potential, and averaging only 50 times, the amplitude of the second potential decreased (trace 6) and vice versa (trace 7). This indicates a considerable interval variation between the two potentials, which was confirmed by jitter measurements (see text). The interdischargeintervals are about 15 msec in (A) and about 20 msec in (6). The averaged signal, however, shows no previous or subsequent discharges of the main potential, indicating that the corresponding muscle fibers do not discharge with strict regularity.
vealed these features, though streaming and disarray of myofibers were rare. The subsarcolemmal sarcoplasm consisted of loose stroma with accumulation of mitochondria and abundant thin filaments. Increased subsarcolemmal space was most prominent in the vicinity of the nuclei and endplates. Clusters of glycogen particles were present. Accumulation of myelinoid material was found occasionally under the sarcolemma which focally filled up the peripheral sarcoplasm (Fig. 6). There were membrane-bounded vacuoles between the bundles of myofibrils, mostly empty, sometimes filled with fine granular material or electron-dense whorls (Fig. 7). T h e vacuoles were anything from half to the full intersarcomere distance in size. Normally shaped mitochondria were present; occasionally they were elongated or branched. Calcium deposits were absent. Myofibril bundles showed marked interrup-
522
Schwartz-Jampel Syndrome
tions with disappearance of the 2 disks, involving one or more sarcomeres (Fig. 8). In these areas many glycogen particles and branched and elongated mitochondria were present, as well as the vesicles described earlier. Endplates. The presynaptic terminals varied in size and content, but Schwann-cell covering appeared normal. The postsynaptic area was enlarged and deep secondary clefts were visible in the loose postsynaptic stroma. Extensive branching of these clefts occurred with some fibers, in others they were practically unbranched. The invaginations in the primary clefts occurred at regular intervals and the postsynaptic densities were normally present. Localization of the AChR at the postsynaptic membrane was normal. There were no signs of focal degeneration or remodelling of the endplates. Results of quantitative measurements at neuromuscular junctions: mean nerve
MUSCLE 8, NERVE
June 1990
FIGURE 6. Accumulation of rnyelinoid material was occasionally present under the sarcolemrna (bar
*
terminal area (NTA) measured 4.05 pm2 (SD 2.481, mean presynaptic membrane length (PSM) 4.75 pm (SD k 1.51) and mean postsynaptic area (PSA) of folds and clefts measured 7.89 pm2 (SD t 3.76). Results in two controls were: NTA 5.33 pm2 (SD k 4.08) and 8.26 pm2 (SD 2 7.02), PSM 5.02 pm (SD 2.08) and 6.19 pm (SD 2.6’7, PSA 7.68 pm2 (SD i 4.15 and 9.19 pm2 (SD 2 5.33).
*
*
DISCUSSION
Congenital myotonic syndromes include congenital inyotonic dystrophy (MyD), dominantly and recessively inherited myotonia congenita (MyC), paramyotonia congenita (PC) and chondrodystrophic myotonia (SJS). The most intensive myotonia is seen in SJS. Apart from his body height, the clinical features of our patient were all highly characteristic of SJS. Almost all published cases of SJS have been dwarfs; our patient, as well as two other cases?’ had a body height of about 2 standard deviations below the mean. Moreover, the patient was too small compared to his parents’ body height and the arm span too short compared with body height. X-ray investigations showed no evidence of abnormal osseous or epiphyseal developments. This has also been the case in some other SJS patients, for which reason the term chondrodystrophic myotonia has been criticized.’% Myotonic discharges are not identical in the various myotonic syndromes. There are differences in incidence, mean duration and amplitudefrequency pattern^,^^.^^,^^ du e probably to different underlying membrane abnormalities. For
Schwartz- Jampel Syndrome
=
1 p).
example, in MyD, in addition to typical “divebomber” discharges, prolonged runs, with falling or unchanging frequency and amplitude also occur.25 The spontaneous EMG activity in the SJS has been variously described in different patients. A number of authors re orted only “typical” myotonic discharge^.^"^"^^^ Others found sponta-
t
neous activity with little or no amplitude and/or frequency v a r i a t i ~ n . ~ ~ ” ’ “ ” ”Others ,’~ again reported a combination of both kinds of activity.5,S,16,23,27 The regular, spontaneous activity has been described as “pseudomyotonic discharges”, “bizarre high frequency discharges” and, more recently, as “complex repetitive discharges” (CRDs). True CKDs consist of a number of muscle fiber potentials which are closely time-locked as a result of ephaptic impulse transmission between their fibers.32 Usually the MCD values of interspike and interdischar e intervals are very low, typically below 5 psec!‘ CRDs are mainly encountered in chronic neurogenic disorders; overexcitable, denervated muscle fibers are activated ephaptically by the action potential of a neighboring fiber. Like single fibrillation potentials, CRDs may also occur in muscular dystrophies, metabolic myopathies and polymyositis. In CNEMG recordings it can be difficult or even impossible to recognize discharges of individual muscle fibers or groups of fibers within the large amount of spontaneous activity which occurs in the SJS. We think that only three case reports convincingly show the occurrence of CRDs in SJS.8,’6*’7T h e spontaneous activity was analyzed with SFEMG in two of them. In one report, CRDs were in fact found to be the only kind of spontaneous acti~ity.’~ This finding
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A
B FIGURE 7. (A) At low magnification, a number of membrane-bounded vacuoles are seen to be located between the bundles of myofibrils (bar = 1 km). (B)At higher magnification these vacuoles are empty or filled with fine granular material (Bar = 1 Km).
contrasts maximally with the EMG findings in our patient. SFEMG showed activity with obvious frequency and amplitude changes as well as more stable activity which, however, appeared to be not strictly regular (Figs. 4 and 5). Apart from one
524
SchwatTz-Jampel Syndrome
transient double potential, with a large interval variation between its components, we failed to find any sign of electrical coupling between muscle fibers (Fig. 5). There is likewise no unanimity in the litera-
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FIGURE 8. Myofibrillar architecture showed focal disarray and interruptions of the 2 disks involving one or more sarcomeres (arrows; bar = 1 pm).
ture with respect to the persistence of the spontaneous activity in SJS. In our case as in others,4,6,12714.16,21,33 the spontaneous activity never disappeared during routine recordings, though others have reported finding periods of silence.5.' 1,17 We, as well as other investigators4,6,12-14 h ave found that the activity also persisted during general anesthesia. Both myotonic discharges and CRDs originate in the muscle fibers themselves and are not abolished by curare.24 Cases of SJS, in which the spontaneous activity diminished or disappeared after c ~ r a r i z a t i o n ,must ~ ' ~ ~have been neurogenic. Like other investigation^,^,^^'^^^^ we found that there was no effect on the spontaneous activity. The different features of the spontaneous activity re-
Schwartz- Jampel Syndrome
ported in the various cases suggest that a number of different membrane abnormalities may occur within the SJS. In vitro electrophysiological studies were undertaken" to obtain more insight into the membrane dysfunction in our patient. During these studies the absence of any effect of curare has been confirmed. Since procainamide appeared to be effective in suppressing the spontaneous activity in vitro, we decided to try this drug in the case of our patient. Mobility clearly increased, with 4 x 500 mg daily, whereas clinical myotonia and fatigability diminished. T h e few MUPs that we could recognize did not appear abnormal (Fig. 3C). A number of authors others reported MUPs in SJS as being
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found MUPs with decreased mean duration and increased polyphasia. 1,15,23 Extreme polyphasia has been reported in the case where CRDs were observed as the only form of spontaneous activity.17 The authors found “a striking similarity between the configuration of its MUPs and the repeating units of its CRDs, suggesting an origin in the same muscle fibers.” Since CRDs are due to ephaptic coactivation of neighboring muscle fibers, this remarkable finding suggests that, in this case, compact groups of fibers should belong to the same motor unit, which means that histochemistry could be expected to show fiber-type grouping. The report, however, contains no muscle biopsy results. In our case, as in all other reported muscle histochemistry in SJS,2,6,’4-16,20,z1 signs of reinnervation such as fiber-type grouping or altered terminal innervation were absent. In view of the obvious hypertrophy of several muscles of our patient (Figs. l and 2) an increased mean muscle-fiber diameter might have been expected, but both quadriceps (judged with MRI) and intercostal muscle (viewed at surgery) were not hypertrophic. Mean fiber diameter of type 2 intercostal fibers exceeds 25% of the control value, but average increases in diameter, as reported by others,13 were not present. According to Brooke and Engel, the normal average muscle-fiber diameter at 4.5 years is 23 pm 12%, but the normal intercostal muscle, which apparently contains larger fibers, was not included in their ~ t u d i e sProliferation .~ of sarcolemmal nuclei and increase of connective tissue, reported by other^,'^"*'^ was absent. The terminal innervation pattern showed a normal, single innervation site on the muscle fibers and the marked increase of AChE activity reported by Fowler et all3 was absent.
’
*
Results of our electron-microscopic studies show many similarities to findings in other cases. Vacuoles were found between the bundles of myofibrils in many fibers. It has been suggested that they are focal dilatations of the sarcotubular system.2,10,13,16A constant finding in electron-microscopic studies in SJS are the interruptions in the sarcomeres, including Z disks, together with focal disarray of myofibrils. Z-disk streaming and disintegration is a common finding, especially in mitochondria1 myopathy and denervation atrophy.9 These features also occur in endplate myopathies in which calcium accumulates in the junctional region.’” In these cases Z disk damage may be related to calcium-activated proteases found at the Z Disorders with abnormally high calcium transients in the myofilament space, to which SJS probably belongs, may show loss of myofibrillar architecture on the basis of this mechanism. The postsynaptic structures in the present study gave the impression of an accelerated maturation, proportional to the mature aspect of the muscle fibers. However, endplate analysis revealed no specific changes in morphology and quantitative measurements revealed nothing of significance. Obviously the massive ongoing spontaneous muscle-fiber activity did not influence the morphology of the neuromuscular synapse. I n conclusion, it can be said that, although the clinical picture of the SJS is characteristic and the reported electron-microscopic findings in muscle biopsies are similar, its pathophysiology seems to be variable. The present case appears to be purely myogenic and is the first one in which it has been convincingly shown that massive, independent activity of individual muscle fibers underlies the impressive myotonic symptoms.
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