Journal of

Neurology

J. Neurol. 217, 201--206 (1978)

© by Springer-Verlag 1978

Further Investigations on Benign Myopathy with Autosomal Dominant Inheritance* W. F. Arts 1, J. Bethlem I , and W. S. Volkers 2 1The Muscle Research Center, Department of Neurology, Academic Hospital at the University of Amsterdam, Wilhelmina Gasthuis, le Helmersstraat 104, Amsterdam, The Netherlands 2Department of Human Genetics, University of Leiden, The Netherlands

Summary. Six members of a family suffered from benign myopathy over four generations. The clinical, laboratory, electromyographic, histological and genetic data were consistent with benign myopathy with autosomal dominant inheritance. Congenital torticollis was a feature in one patient. Linkage studies revealed no linkage between the locus of this myopathy and the locus of any of 17 genetic markers investigated. This family was of Polish descent, which indicates a widespread occurrence of this benign hereditary myopathy. The data presented are a strong argument in favor of a specific new disease entity. Key words: Myopathy benign - Autosomal dominant inheritance - Contractures - Linkage studies.

Zusammenfassung. In 4 Generationen einer Familie litten 6 Glieder an einer gutartigen Myopathie. Die klinischen Daten, Laboratoriumsbefunde, der elektromyographische und histologische Befund sowie die genetischen Besonderheiten waren mit der Annahme einer gutartigen Myopathie von autosomal dominantem Erbgang vereinbar. Bei einem Patienten lag ein angeborener Torticotlis vor. Es tieB sich keine Koppelung zwischen dem Lokus dieser Myopathie und dem Lokus irgendeiner der 17 untersuchten genetischen Lokalisationen feststellen. Da die beschriebene Familie aus Polen stammte, "weist dies auf die starke Verbreitung dieser gutartigen heredit~iren Myopathie hin. Die hier vorgelegten Elemente sprechen sehr for eine eigenst~indige neue Erkrankung. Introduction In 1976 Bethlem and van Wijngaarden described three families in which 28 patients suffered from benign myopathy with autosomal dominant inheritance. The onset was in early infancy, progression was slow, and many patients reached *

Supported by a grant from the Princess Beatrix Foundation

0340-5354/78/0217/0201/$01.20

202

W.F. Arts et al.

a very old age. The patients had moderate weakness a n d a t r o p h y of the muscles of the t r u n k a n d extremities, the p r o x i m a l muscles being more involved than the distal muscles, a n d the extensors more t h a n the flexors. Early flexion contractures of the elbow a n d i n t e r p h a l a n g e a l joints of the last four fingers, a n d p l a n t a r flexion c o n t r a c t u r e s of the ankles were c o n s t a n t findings in these patients. Moreover, 4 of the 28 patients had congenital torticollis. The serum creatine p h o s p h o kinase (CPK) activity was usually n o t elevated. Electromyography was equivocal, while m o t o r c o n d u c t i o n velocities of the peripheral nerves were n o r m a l . The histopathological findings were nonspecific, being characterized by m a r k e d v a r i a t i o n in muscle fiber diameter, m o d e r a t e increase of the n u m b e r of fibers with i n t e r n a l nuclei, l o b u l a t e d type I fibers a n d m a r k e d increase of fatty tissue. There was a n o r m a l d i s t r i b u t i o n of type I a n d type II fibers, while electronmicroscopy did n o t reveal a n y abnormalities. Genealogical investigations disclosed no relationship between these three D u t c h families. Their ancestors had lived in the N e t h e r l a n d s at least from the b e g i n n i n g of the 18th century. The p u r p o s e of this paper is to present a new pedigree with this benign m y o p a t h y . This family was of Polish descent. In addition, the results of the genetic linkage studies are given.

Case Histories The pedigree (Fig. 1) shows 6 members affected through 4 generations. Patient I V 1 (the index case, 16 years old at the time of examination).

His motor milestones were slightly delayed; he never could run and was very poor at gymnastics. There was no progression of the symptoms. On examination, he had slight weakness of the flexor muscles of the head and of the shoulder and pelvic girdles. The extensors of the upper arms were weaker than the flexors, leading to a flexion contracture of the elbows. In the forearms, there was a paresis of the extensor digitorum communis muscles, giving rise to a flexion contracture of the interphalangeal joints. Gowers' sign was positive. There was weakness of the extensor muscles of feet and toes, resulting in slight equinovarus of the feet. The

I

I

2

?t

Fig. 1. I family member affected o diagnosis based on anamnestic data 0 diagnosis based on complete investigation at congenital torticollis t deceased

Benign Hereditary Myopathy

203

muscles of the forearms and lower legs were slightly atrophic. The tendon reflexes were normal, while the plantar responses were flexor. No fasciculations or signs of myotonia were seen. Sensory functions were normal. Laboratory investigations revealed a serum CPK level of 367 IU/1 (normal upper limit in our laboratory 50 IU/I); pyruvate kinase (PK) level was 70 IU/1 (normal upper limit 17 IU/I). The creatinine/creatine ratio in the urine was decreased. Electromyographic findings were within normal limits. The motor conduction velocities of the ulnar, median and peroneal nerves were normal. Biopsy of the right triceps showed a marked variation of the muscle fiber diameter, while 8% of the fibers had internal nuclei. There were many ringed fibers and sacroplasmic masses. No increase of endomysial fat or connective tissue was present. The type I and the type II fibers had a normal mosaic pattern. Electronmicroscopy did not reveal any abnormalities. Patient I V 2 (younger brother of the index case, 13 years old). He was born with a left torticollis. Like his older brother, he had delayed motor milestones, and he had difficulty running, getting up from a supine position and climbing stairs. From the age of 11 years, he developed an abnormal accumulation of subcutaneous fat in the lower half of the body, leading to a feminine appearance of the legs. There was no progression of the muscular weakness. On examination there was marked weakness of the flexors of the head. There was a left torticollis, due to a shortening of the left sternocleidomastoid muscle, while on the right side this muscle was normal. There was generalized weakness of the muscles of the shoulder and pelvic girdles. He had a waddling gait and marked lumbar lordosis. Gowers' sign was positive. There was moderate weakness of the proximal and distal muscles of the arms and legs. The extensors were more involved than the flexors. No contractures were present. The deep tendon reflexes of the arms were decreased while those of the legs were brisk and equal on both sides. The plantar responses were flexor. No other neurological abnormalities were noted. Laboratory investigations revealed a serum CPK level of 194 IU/1, and PK level of 26 IU/1. The creatinine/creatine ratio in the urine was markedly decreased. No electromyographic abnormalities were noted, while the motor conduction velocities of the ulnar, median and peroneal nerves were normal.

Fig. 2. Patient IV 2, biopsy from the left quadriceps femoris muscle, × 32500. A small rod is seen between otherwise normal myofilaments

204

W.F. Arts et al.

Biopsy from the left quadriceps femoris showed a marked variation in muscle fiber diameter with a normal mosaic pattern of the type I and type II fibers. Ten per cent of the muscle fibers had internal nuclei. There was a very marked increase of the endomysial fatty tissue without proliferation of the connective tissue. Electronmicroscopy revealed occasional fibers with a few small and centrally located rods (Fig. 2). Small foci displaying streaming of the Z bands were also seen. Case I V 3 (youngest brother of the index case, i1 years old). His motor development was normal. No neurological symptoms were mentioned. Like his brother IV 2, he developed an abnormal amount of fatty tissue in the lower half of the body from age 10. On examination, no neurological abnormalities were found. Patient III 2 (mother of IV 1, 2 and 3, 43 years old). She had been very poor in running and jumping for as long as she could remember. She was removed from high school for alleged malingering at gymmastics. From early infancy, full extension of the fingers and elbows was not possible. Slight progression of her symptoms was observed, especially after the pregnancy of her youngest child. In spite of these complaints, she was fully able to perform her daily activities as a housewife. On examination she showed slight weakness of the flexors of the head, the muscles of the shoulder girdle, upper arms, pelvic girdle, upper legs and the extensors of the last four fingers and of the feet and toes. There were flexion contractures of both elbows and of the interphalangeal joints of the last four fingers. The triceps reflexes were absent and the knee jerks were decreased, while the other deep tendon reflexes were normal. The plantar responses were flexor. No other abnormal neurological signs were found. Laboratory investigations revealed a serum CPK level of 115IU/1, and a PK level of 12IU/1. The creatinine/creatine ratio was markedly decreased. Electromyography revealed complex motor unit potentials of short duration. Biopsy of the right quadriceps femoris disclosed marked variation in the diameter of the muscle fibers, 45% of which had internal nuclei. There was a normal distribution of type I and type II fibers. A large part of the muscle tissue was replaced by fat tissue and a small amount of connective tissue. No electronmicroscopic examinations were made. III 3 lived in Australia and was not available for examination. I I I 4 according to anamnestic data, suffered from the same neuromuscular disease as the other members of the family. Like his 3 children (IV 4, 5 and 6), he lived in West Germany and was not available for examination. The children were reported not to have any muscular weakness.

H 6 (grandmother of the index case) was 68 years old and of Polish descent. When she was 19 years old she came to the Netherlands, while the other members of the family stayed in Poland. As a 6 year old child~ she used to walk to the village school, but she had to leave the house 30 min earlier than her brothers and sisters because she could not walk as fast as they could. She was always poor at gymnastics, bad at skipping, and could never run. There was only very slight progression of these symptoms, but a more marked increase of her muscular weakness was observed after each of her three pregnancies. On examination she had weakness of the flexors of the head, and mild paresis of the muscles of the shoulder and pelvic girdles. There was a flexion contracture of both elbows, more marked on the left than on the right, although there was no obvious decrease in strength of the triceps muscles. The extensors of the hands and fingers were paretic, especially the extensor digitorum communis muscles, giving rise to a flexion contracture of the interphalangeal joints of the last four fingers. There was also marked weakness of the extensors of the feet and toes. The deep tendon reflexes of the arms and legs were brisk and symmetrical. No other abnormal neurological signs were observed. Nothing is known of her 10 brothers and sisters. I 1 (great grandfather of the index case). According to his daughter (II 6), he was also suffering from the disease. Notwithstanding his muscular weakness, he was able to perform almost all daily activities as a farmer. He died at the age of 58 years from an unknown cause.

Benign Hereditary Myopathy

205

Linkage Studies Blood and urine were taken from II 6, III 1 and their husbands, and from IV 1, 2 and 3. These were investigated for the presence of 17 genetic markers, including several blood groups and various enzymes. Manual calculations did not reveal significant linkage between the locus of this m y o p a t h y and the locus of any of the markers investigated. Close linkage could be excluded with the blood group systems AB0 and Kell, serum alpha-2-globulin group specific component (Gc), and the erythrocyte enzyme cholinesterase-2 (E 2).

Discussion The neuromuscular disease present in this family was characterized clinically by onset in early infancy, although the patients were not born as floppy babies. There was" no or only slight progression of the muscular weakness but moderate deterioration occurred after pregnancy. The disease runs a benign course; all patients were able to perform their daily duties. Patient II 6 has already reached an old age (68 years). In addition to a limb-girdle type of muscular weakness, the extensor digitorum communis muscle was invariably involved. Flexion contractures of the elbows, the interphalangeal joints of the last four fingers and of the ankle joints were found frequently. There was no relationship between the contractures and the severity or duration of the muscular weakness. Patient IV 2 was the most severely affected, but unlike his older brother IV 1, he had no contractures. The contractures of II 6 were also not more severe than t.hose of her grandson IV 1. In addition, the absence or presence of the deep~ tendon reflexes was not correlated with the severity or duration of the muscular weakness. Congenital torticollis due to unilateral shortening of a sternocleidomastoid muscle was present in one patient. A moderate increase of the serum CPK and PK activities was frequently found. Muscle pathology was non-specific, and consisted mainly of a marked variation of the muscle fiber diameter and, in two cases, of a very marked increase of the endomysial fatty tissue. There was a normal distribution of type I and type II fibers; no lobulated type I fibers were seen. All the clinical findings mentioned above are consistent with a diagnosis of benign hereditary m y o p a t h y as described by Bethlem a n d van Wijngaarden (1976). The finding of an elevated CPK and PK activity in all patients investigated, in contrast to the finding of only one of nine patients investigated with an elevation of C P K activity in the three families described earlier, does not argue against this diagnosis. A possible explanation of these apparently conflicting findings would be a decrease of CPK activity during the course of the illness, as occurs in several other neuromuscular disorders. The only patient with an elevated C P K activity in the families of Bethlem and van Wijngaarden was a boy aged 14 years. The eight patients with normal CPK values ranged from 24 to 51 years of age. A tendency toward a decrease of CPK activity with age also appears to exist in the family described here. The possibility of a relationship

206

w.F. Arts et al.

between the muscular weakness and the abnormal subcutaneous accumulation of fatty tissue in patient I V 2 - - w h e t h e r as an additional sign or as a disease genetically linked with benign m y o p a t h y - - w a s considered. However, the finding of the same lipid accumulation in the lower half of the body in IV 3, who had no sign of muscular weakness whatsoever, argued strongly against this supposition and m a d e the combination of signs in patient I V 2 appear coincidental. Systematic linkage studies in all available family members of three generations did not reveal significant close linkage between the locus of any of the genetic markers investigated and the locus of benign myopathy. Only three Dutch families with this benign myopathy have been described to date. The fact that this new family originated from Poland seems of particular importance, indicating that this is an ubiquitous disease and favors the assumption that this myopathy is a new and specific disease entity.

Reference Bethlem, J., van Wijngaarden, G. K.: Benign myopathy, with autosomal dominant inheritance - a report on three pedigrees. Brain 99, 91--100 (t976) Received June 3, 1977

Further investigations on benign myopathy with autosomal dominant inheritance.

Journal of Neurology J. Neurol. 217, 201--206 (1978) © by Springer-Verlag 1978 Further Investigations on Benign Myopathy with Autosomal Dominant I...
596KB Sizes 0 Downloads 0 Views