Benign muscular dystrophy with autosomal dominant inheritance
Neuromuscular Disorders. Vol. 1, No. 4, pp. 267-273, 1991 0960-8966/91 $3.00 + 0.00 Printed in Great Britain .~ 1992 Pergamon Press plc BENIGN MUSCULAR DYSTROPHY WITH AUTOSOMAL DOMINANT INHERITANCE HANNU SOMER,* t VEIKKO LAULUMAA, LEO PALJXRVI,** JUHANI PARTANEN,tt ANTTI LAMMINEN,+ + HELENA PIHKO,I[ HANNU SARIOLAjl and MATTI HALTIA Departments of *Neurology, ~Diagnostic Radiology, Pathology, and IChildren's Hospital, University of Helsinki, 00290 Helsinki 29; and Departments of rNeurology, **Pathology, and ~Clinical Neurophysiology, University of Kuopio, Kuopio, Finland (Received I November 1990; accepted 8 April 1991) Abstraet--A slowly progressive myopathy was discovered in a family in four successive generations. Eight patients (four female, four male) from three generations were examined and they showed muscle weakness affecting predominantly proximal, but also distal, muscles. Two patients had unequivocal findings in childhood, the others showed myopathy in their twenties or thirties. Working ability was lost in physically demanding jobs in the thirties, but activities of daily living were still preserved. Elbow contractures, tight heel cords and contractures of the interphalangeal joints were frequent. Serum CK activity was usually mildly elevated and electromyographic examinations revealed myopathic changes. Histopathological changes were compatible with moderately advanced muscular dystrophy in two patients, the six others had mild myopathic changes. Key words: Muscular dystrophy, medical genetics, genetic counselling, creatine kinase, contracture, electromyography. INTRODUCTION Although X-linked muscular dystrophies can now be defined by accurate molecular genetic methods , other muscular dystrophies are still classified on the basis of clinical findings and the mode of inheritance . Muscular dystrophy with autosomal dominant (AD) inheritance is rare and difficult to classify. The first clinical descriptions contained little clinical information [3,4]. Subsequent reports include patients with relatively benign myopathy [5-8], and adult onset cases classified as limb-girdle muscular dystrophy [9-11]. We describe a family where muscle symptoms occurred in four successive generations with a variable clinical picture illustrating the difficulties in clinical definition. PATIENTS AND METHODS All affected individuals belong to a family which has been living in the eastern part of Finland for several generations. There is no t Author to whom correspondence should be addressed. consanguinity in the family (Fig. 1). Several family members of the III generation have moved to other parts of the country and five of them sought medical help independently because of increasing muscle problems in their twenties. Several other family members were then invited for clinical examination. Electromyographic examinations. Six patients underwent routine needle electromyographic studies on multiple muscles in the upper and lower extremities. Nerve conduction velocities were measured in two or three nerves using standard techniques. Two patients had more than one EMG examination. Subject II-2 had a quantitative EMG examination. Muscle biopsy. Muscle biopsies were taken with a conchotome from tibialis anterior muscle (five patients) or from vastus lateralis muscle (five patients). Two patients had a biopsy taken from both muscles. Cryostat sections were stained with haematoxylin--eosin, periodic acid- Schiff stain (PAS), as well as for NADH- tetrazolium-reductase and ATPase after pre- incubations at pH 10.4, 4.6 and 4.3. Chemical analyses. Creatine kinase activities were measures spectrophotometrically. The ref- erence values have changed during the follow-up and they also differ between men and women. An 267 268 H. SOMER et al. ++ 1 2 4 5* 6* 7 8 9 10 11" 12" 13 14 15 16 17 " 19 20 Symbots: [ ] 0 unaffected E~]. O. unaffected by clinical examination by history [ ] ~ affected I affected by clinical examination by history ' ~ proband Fig. 1. Pedigree data. upper normal limit is given in parentheses in the text. Magnetic resonance imaging (MR1). MRI studies were carried out in five patients with a low-field resistive magnet operating at a field strength of 0.02 Tesla (Acutscan TM Instru- mentarium Corp., Helsinki). Cross-sectional images of the thighs and legs were obtained using a partial saturation (PS) pulse sequence with a repetition time (TR) of 1000 ms and an echo time of 60 ms. Section thickness was 10 mm. RESULTS Pedigree analysis. The family consists of 34 living members (Fig. 1). Information concerning the deceased members from generation I was obtained from subject 11-2. Her mother (1-2) died at the age of 42 yr. She had suffered from mild muscle weakness. The maternal aunt (1-4) walked with the help of a cane already in adolescence. Walking difficulties progressed. She lived in a nursing home for two decades and was severely disabled some years before her death at the age of 67 yr. We have examined 14 family members from three generations. The diagnosis of muscular dystrophy is based on findings in clinical exam- ination, associated with abnormalities either in serum enzyme analysis, EMG or histopatho- logical examination. The actual onset was difficult to define and the progression appeared to be slow. Subject 1II-3 had delayed motor mile- stones, but he was able to serve the ordinary military service and he then worked as a con- struction worker, until muscle weakness manifested in his early thirties. Seven members of the paediatric age group were studied. Subject IV-3 is described in detail below. Subject IV- 10, a 10-yr-old girl was found to have a mild distal myopathy of which she and her mother were unaware. One subject (IV-12), an 8-yr-old girl showed a mild elevation of serum CK activity (214 UI-~; normal < 150 UI-~), but the clinical examination was normal and no further exam- inations were carried out. Case histories Subject 111-6. The proband was born after an uneventful pregnancy. She learned to walk at the age of 2 yr, but she always walked on her toes. Around the age of 20 she could walk 3 miles. She worked as a trained domestic aid for several years. Muscle weakness then caused increasing AD Muscular Dystrophy 269 (a) Fig. 2. (a) The proband (III-6) showed mild muscular atrophy in the distal leg muscles, and a tight heel cord in the right leg. Contractures are present in both elbows. (b) The proband's brother (11I-3) showing muscular atrophy in the shoulder girdle region, elbow contractures and tight heel cords. (c) Case IV-3 (son of 1II-3 showing pronounced muscular atrophy in the scapular region. Fig. 3. (a) Muscle biopsy from tibialis anterior muscle (patient II-2) showing a myopathic picture with increased fibre size variation, internal nuclei and some endomysial fat cells (HE, 180 ). (b) Muscle biopsy from vastus lateralis muscle of the proband (11I-6) showing increased variability in fibre size, round and atrophic fibres, central nuclei, clumps of pyknotic nuclei and increased amounts of endomysial connective tissue and fat cells (HE, 500 x ). (c) Muscle biopsy from vastus lateralis muscle (patient IV-3) showing advanced atrophy of most of the muscle fibres and endomysial fibrosis (paraffin section, Van Gieson staining, 180 ). 270 H. SOMER et al. Table 1. Clinical features Subject Age at Examined Muscle Muscle Deep tendon Flexion onset (yr) at (yr) weakness atrophy reflexes contractures I1-2 50s 61 SH, PF III-3 1st 41 SH, PF SH, PF Ili-4 20s 30 SH, PF, SH, DF, DF, DL DL III-5 10s 33 SH, PF, SH DF, DL 111-6 late 20s 31 SH, PF, DE, DL DF, DL III-7 10s 25 SH, PF SH IV-3 Ist 15 SH, PF, SH, DF, DL DF, DL IV-10 10 10 DF, DL DF, DL +/+ + / + E,A / E,A (+)/(+) E,A (+)/(+) E, IF / S,E, IF, A + / + A (SH) Scapulohumeral muscles, (A) achilles tendon contractures, (DF) distal forearm muscles, (E) elbow contractures, (DL) distal leg muscles, (S) shoulder contractures, (PF) pelvifemoral muscles; and (IF) interphalangeal joint contractures. difficulties in holding a baby or lifting household objects. Clinical examination at the age of 31 yr showed an obese woman with short stature (149 cm). She walked on her toes [Fig. 2(a)] with a waddling gait. She had bilateral elbow contrac- tures (20-30*) and her heel cords were tight with some asymmetry. Distal leg muscles showed mild muscular atrophy [Fig. 2(a)]. Muscle weakness was more prominent in the proximal than in the distal muscles with no facial weakness. Muscle biopsy was compatible with muscular dystrophy [Fig. 3(b)]. Examination at the age of 36 yr showed mild progression. She had retired be- cause of muscle weakness. Subject 11-2. The proband's mother was called for examination because muscular dystrophy was discovered in her children. She had mild proximal muscle weakness in both upper and lower extremities. Muscle biopsy showed mild myopathic changes [Fig. 3(a)]. Subject 111"-3. The pregnancy was uneventful, but the birth at 42 gwk was prolonged causing slight asphyxia. At the age of 1 yr he could not get into the sitting position, but could sit and stand supported. His CK was 84 UI-1 (normal < 50 U1- i). He walked at the age of 2 yr, but he never learned to run. Retardation in his early motor development was attributed to birth asphyxia. He was investigated again at the age of 5 because of generalized muscle weakness [Fig. 2(c)]. Severe dystrophic changes were seen in the muscle biopsy [Fig. 3(c)]. Muscle weakness progressed slowly. Joint contractures appeared around the age of 10 yr. At the age of 15 he walked unsupported, but did not manage stairs without help. He had hypertrophic calves and severe atrophy around the shoulder region. Contrac- tures were present in shoulders, elbows, fingers and ankles. His CK was 840 U1- i (normal < 270 U l - l ) . A summary of the clinical findings in the eight affected family members is given in Table 1. Creatine kinase analysis. Serum CK activity was mildly elevated in the eight clinically affected subjects. No significant change was noticed during the follow-up. Cardiological examinations. Clinical exam- ination included cardiac auscultation, thoracic X-rays and standard ECG recordings in all 11 subjects (eight affected, three unaffected) with no signs ofcardiomyopathy or cardiac arrhythmias. Two patients (111-3 and 111-6) had M-mode and two-dimensional echocardiography with normal results. Electromyographicfindings. The proband (III- 6) showed increased polyphasicity in all muscles studied (upper extremities: m. deltoideus, exten- sor digitorum communis, opponens pollicis, abductor poUicis brevis; lower extremities: vastus lateralis, rectus femoris, tibialis anterior). There was some low-amplitude and short-duration potentials in the extensor digitorum communis and tibialis anterior muscles. Sensory conduction velocities in the median and sural nerves were normal as well as the amplitude of the responses. Motor conduction velocities and F-response latencies were normal in the median and peroneal nerves. The findings in the other family members studied were similar with a few exceptions. Members 111-7 and 11-2 showed occasional mild findings of fibrillation activity but myotonic discharges or fasciculations were observed in none. Members 111-4, I1-2 and 111-7 showed also occasional increase of the MUP amplitude. In patients 11I-4 and 111-7 there were an increased number of satellite potentials in some muscles. Increased polyphasicity was confirmed with A D Muscular Dys t rophy Table 2. Laboratory Features 271 Subject s-Creatine Electromyographic findings Histopathological findings kinase act. II-2 female 347 U1-' Polyphasic potentials in SH, Increased variation in fibre size, fibrillation, occasional positive IN, RF, a few RRF, infiltration waves in DL of fat cells I11-3 male 236 UI ~ n. st. Increased variation of fibre size, IN, increased amount of connective tissue III-4 female 223 UI ~ Polyphasic potentials in several Increased variation in fibre size, muscles IN, SF, MEF, increased amount of connective tissue 1II-5 male 608 U1 ~ Polyphasic potentials in several Increased variation in fibre size, muscles IN, RF 1II-6 female 164 U1-~ Polyphasic potentials, low Increased variation in fibre size, amplitudes in several muscles IN, RF, SF, MEF, increased amounl of fat and connective tissue II1-7 male 580 UI ~ Positive waves in SH and DL, Increased variation in fibre size, polyphasic potentials in several IN muscles IV-3 male 840 U1-~ n. st. Increased variation in fibre size, increased amount of fat and connective tissue IV-10 female 487 U1 t Polyphasic potentials in several Some atrophic fibres, IN muscles Muscle biopsies were taken from vastus lateralis, muscle (Ili-3; III-4; 1II-6; IV-3; IV-10) and from tibialis anterior muscle (11-2; Ili-5; III-6; III-7; IV-3). s-Creatine kinase activity: normal < 270 U1 ~ men, < 150 U1 -~ women. (n. st.) Not studied, (RF) ring fibres, (IN) internal nuclei, (SF) split fibres, (RRF) ragged red fibres, (SH) scapulohumeral muscles, (MEF) moth-eaten fibres, and (DL) = distal leg muscles. Fig. 4. (a) M R image of the thigh muscle from the p roband (III-6) showing a t rophy and fatty infiltration bilaterally in the rectus femoris muscles and in the semimembranosus and biceps femoris muscles. Note relative sparing of the gracilis and semitendinosus muscles. (b) M R image of the thigh muscles f rom the p roband ' s daughter (IV-10) showing a t rophy and fatty infiltration in the rectus femoris muscles. The hamstrings, adductors and the gracilis and sartorius muscles are relatively spared. quantitative EMG in members 11-2 and IV-10. In patient III-7 distal muscles of the upper extrem- ity (m. interosseus dorsalis I and opponens pollicis) had no distinct EMG alterations. Histopathological findings. Muscle biopsies showed increased variation in fibre size and internal nuclei [Fig. 3(a)-(c)] in all patients. Ring fibres were detected in three, and moth-eaten fibres two biopsies, one biopsy showed also occasional ragged red fibres (Table 2). The proband's biopsy [Fig. 3(b)] showed marked fibre size variation as well as an increased amount of fat and connective tissue; changes compatible with a moderate degree of muscular dystrophy. In the proband the changes were similar in the tibialis anterior and the vastus lateralis muscle, but in general the findings were more severe in the vastus lateralis muscle. Rim- med vacuoles were not detected in any of the biopsies. Histopathological changes were most prominent in patient IV-3 [Fig. 3(c)], who had onset already at infancy. Muscle biopsy at the 272 H. SOMER et al. age of 5 showed even more pronounced changes than in case III-6. Magnetic resonance imaging studies. MR images of the five patients examined showed increased signal intensity of muscles with a similar pattern of muscle involvement. In thigh muscles, the quadriceps femoris was affected most, whereas the gracilis and sartorius muscles and the hamstrings were relatively spared [Fig 4(a)-(b)]. In the legs, the gastrocnemius showed increased signal intensity as a sign of atrophy and fatty degeneration. DISCUSSION Characteristic features in this family were generalized muscle weakness and frequent joint contractures without cardiomyopathy or myo- tonia. The disease manifested in both sexes and appeared in successive generations suggesting AD transmission. The pedigree data and the clinical findings exclude such entities as facio- scapulohumeral muscular dystrophy, myotonic dystrophy, Emery-Dreifuss syndrome and auto- somal dominant humeroperoneal myopathy. The diagnosis of muscular dystrophy was achieved only with delay in the present family. Patients had clearly grown accustomed to the symptoms and to their slow progression. Serum creatine kinase activity was elevated in all affected family members, but the elevations were often marginal. Magnetic resonance imaging showed a fairly similar pattern of selective muscle sparing and involvement in all five patients. This is in-keeping with recent reports of its usefulness in evaluating muscle disorders [12,13]. The possibility for a form of muscular dys- trophy being inherited in AD fashion was first suggested two decades ago, but these reports [3,4] contained little information about the clinical picture. Bethlem and van Wijngaarden  then described slowly progressive muscle weakness and frequent flexion contractures in three pedigrees, a condition now often referred to as "Bethlem myopathy". The first symptoms appeared always around the fifth year of life. Others have found similar families [6-8,14], and report on problems in differential diagnosis from congenital mus- cular dystrophy, Emery-Dreifuss syndrome and rigid spine syndrome. Adult onset AD muscular dystrophy has been clearly documented in two recent American studies [9,10]. Transmission in AD fashion is also a possibility in some large pedigrees, where the disease is manifesting only in females [15-17] or males . Chutkow et al.  reviewed the previous pedigrees and conclude their "adult onset limb- girdle muscular dystrophy" a separate entity from those manifesting already in childhood. We were also inclined to consider our patients as cases of adult onset of muscular dystrophy  since five sibs independently reported the onset of their symptoms in late twenties or thirties. A thorough examination, however, revealed two new cases of muscular dystrophy in the next generation. One of them had unequivocal signs and symptoms during the first years of his life. If the age of onset is excluded, our patients re- semble more "Bethlem myopathy"  than adult onset limb-girdle dystrophy as described by Chutkow et al. . The concept of limb-girdle muscular dys- trophy was created to distinguish patients with proximal limb-girdle weakness from facioscap- ulohumeral dystrophy and from Duchenne dystrophy . The mode of inheritance was considered autosomal recessive . It now appears that some of the cases may have sub- stantial distal muscle involvement and facial weakness [10,11], and the syndrome can be inherited in AD fashion as well [9-11]. One may therefore ask, are muscular dystrophies with AD inheritance homogeneous enough to constitute just one entity? Patients with "Bethlem myo- pathy" showed often, although not invariably, flexion contractures. Many of the affected family members in Gilchrist et al.'s study  also had tight heel cords, but contractures were not reported by Chutkow et al. . Rimmed vacuoles have, however, been described in oculopharyn- geal muscular dystrophy and in other slowly progressive muscular dystrophies . At the moment there appears to be no lab- oratory finding specific to any of the muscular dystrophies inherited in AD fashion. They do have clinical differences, but there is substantial variability even within the same family. 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