Acta neurol. scandinav. 65, 458-467, 1982

Department of Neurology, Brain Research Institute, Niigata University, and Hamagumi Children’s Hospital, Niigata, Japan

Oculopharyngeal muscular dystrophy and distal myopathy

INTRAFAMILIAL DIFFERENCE IN THE ONSET AND DISTRIBUTION OF MUSCULAR INVOLVEMENT

NOBUYOSHI F U X ~ R A , TOSHIHIDE KUMAMOTO, TADAO TSUBAKI, TOSHIO MAYUZUMI AND HATSUMI NITTA

A family is reported which included a patient with a variant form of oculopharyngeal muscular dystrophy. The patient’s son suffered from in- fantile muscular dystrophy with a distal distribution in the lower extremi- ties and no oculopharyngeal symptoms. Case 1, the father, showed ble- pharoptosis, but no limitation of ocular movements. Case 2, the son, showed early onset of weakness and more rapid progression of muscle involvement than the father. In both patients EMG, muscle biopsies and elevated serum CPK indicated the myopathic nature of the disorder. A muscle biopsy specimen in Case 2 showed abundant rimmed vacuoles and abnormal filaments 13-19 nm in diameter in the sarcoplasm, usually re- ported to occur in inclusion body myositis. The findings indicate that oculo- pharyngeal muscular dystrophy and distal myopathy are related in their etiology and distal myopathy and inclusion body myositis are regarded as variant forms of the same disease.

Key words: Distal myopathy - inclusion body myositis - oculopharyngeal muscular dystrophy - rimmed vacuoles.

The muscle involvement in hereditary neuromuscular diseases usually shows an identical course and distribution within a family, although the involve- ment may vary greatly in different families. We report a family which in- cluded a patient (the father) with oculopharyngeal muscular dystrophy (Vic- tor et al. 1962) or late-onset descending ocular myopathy (Lees & Liversedge 1962). The son suffered from infantile muscular dystrophy with a distal dis- tribution in the lower extremities and no oculopharyngeal symptoms.

CASE HISTORIES

Case 1 Patient M.M., born 1941, was first seen in November 1970. His parents were not related. He was healthy until the age of 23, when he noticed slowly pro- gressive ptosis and wasting of proximal muscles. Since the age of 26, he com- plained of difficulty in swallowing water and had frequent attacks of cough-

0001-6314/82/050458-10 $02.50/0 @ 1982 Munksgaard, Copenhagen

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ing and increased salivation. The onset of dysphagia was accompanied al- most simultaneously by muscular weakness at the hips which interfered with going up and down stairs. At the age of 31, he became aware of dysarthria being further worsened and was admitted to the University Hospital for neu- rological evaluation. General physical examination was unremaikable except for mild flexion contracture in the hand and finger joints. His intelligence was normal. Optic fundi were unremarkable. There was bilateral ptosis of the eyelids, but movements of the external ocular muscles were full. Pupils were normal. Mild weakness of a11 the facial muscles was revealed. The masseter was strong. The soft palate and tongue were normal, but voice was nasal and swallowing was mildly affected. The sternocleidomastoid was mildly weak on the right side. There was weakness and wasting of muscles with more marked involvement in proximal segments, especially in the upper extremi- ties. Fasciculation or myotonic phenomena were not observed. There was winging of the scapulae. He walked with a waddling gait. Deep tendon re- flexes were absent in the upper extremities and normal in the lower ones. Pathological reflexes were not present. Coordination and sensation were normal.

Laboratory findings: Significant laboratory data included slight elevation of serum CPK (89.8 units; normal below 20 units). Urinary excretion of creatine and creatinine was 122 mg/day and 0.37 g/day, respectively. CSF was normal. Thyroid function was normal. There were no data suggestive of collagen disease. The electrocardiography was normal. The ptosis and dysphagia were unaffected by 10 mg of edrophonium chloride (Tensilon). Fluoroscopic examination revealed marked stasis of barium in the vallecula of recessus pirifonnis and tracheal aspiration of barium. The needle electro- myography (EMG) showed polyphasic motor unit potentials (MUPs) of low amplitude (200-300 pV) and of short duration in several muscles including the orbicularis oculi, sternocleidomastoideus, biceps brachii, triceps brachii and extensor carpi radialis. Spontaneous activity or myotonic discharges were not revealed. The motor nerve conduction velocity (NCV) was 44 d s e c in the left posterior tibia1 nerve. A muscle biopsy was taken from the left deltoideus.

Course: This patient was temporarily diagnosed as having chronic poly- myositis and administration of prednisolone (40 mdday) was tried, but pro- duced no significant change in the muscle strength and the dosage of the drug gradually tapered and discontinued. During the next few years, wasting and weakness of his muscles became more prominent, especially in the shoulder girdles and upper extremities. However, he was still able to work with his hands as a worker in a gas station although with extreme difficulty. He suf- fered from bronchopneumonia two or three times. Several efforts became necessary to swallow water and food, which were frequently regurgitated

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through his nose. Coughing was weak. When seen in 1978 (Fig. 1A) and 1980, he was still able to walk a few steps without assistance, but was unable to raise his right arm above a horizontal level. There was ptosis, but external ocular movement was normal. Limitation of movement of the soft palate, decreased volume of the tongue and moderate dysarthria were noted. Deep tendon reflexes were absent.

Case 2 Patient Y.M. was a 9-year-old son of Case 1. The parents, well aware of the possibility that this child would develop wasting of muscles, noted slight clumsiness in the gait of their son at the age of 2. His elder brother had also had clumsy gait, but died following an accident at the age of 1 year and

Fig. 1 . A . Patient M.M., aged 37, showing blepharoptosis and diffuse wasting of limb muscles, especially in the scapulohumeral regions. B . Patient Y.M., uged 9, showing the

deformity o f the right foot.

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8 months. The patient visited our out-patient clinic at the age of 6 , when it was noted that he dragged his right leg very slightly and ran very slowly. His intelligence was normal and no cardiopulmonary abnormalities were re- vealed. He showed neither facial weakness nor ophthalmoplegia. He did not show dysphagia or dysarthria. Muscle bulk and strength were normal and pseudohypertrophy of calves was not revealed. Gowers’ sign was negative. Fasciculation or myotonic phenomena were also not revealed. Deep tendon reflexes were normal except at the right ankle, where they were decreased. Pathological reflexes were not revealed. Coordination and sensation were normal. He again visited the out-patient clinic 3 months later, when his right leg was noted to be very slightly slender and mild weakness was noted in his right hamstring muscles, gastrocnemius and peroneus. The EMG performed in the right rectus femoris and bilateral anterior tibialis showed polyphasic MUPs of low amplitude (100-200 pV) and of short duration. Motor NCV in the right and left posterior tibial nerves was 40.4 d s e c with distal latency of 5.0 msec and 48.8 d s e c with the distal latency of 5.4 msec, respectively. Sensory NCV in the sural nerves was 57.8 d s e c and 61.9 d s e c , respectively. Serum CPK was 128 mU/ml (normal below 80 mU/ml). At the age of 8, the patient (Fig. 1B) became unable to stand up on his toes. His feet showed a deformity of pes equinovarus. With increasing age, weakness of his muscles became definite. A muscle biopsy was performed at the left quadriceps femoris at the age of 9, when he showed mild weakness of the facial muscles and very slight ptosis of the eyelids. However, ophthalmoplegia or dysphagia were still not revealed. Mild wasting of muscles was noted in the shoulder girdles and legs. Muscular weakness was most prominent in the peroneal muscles, but the other muscles showed more weakness in the proximal seg- ments, especially in the shoulder girdles. He was unable to raise his arms to a horizontal level and was also unable to stand up by himself even by the manoeuvre of Gowers. He walked with a steppage gait and there was an in- crease of lumbar lordosis. Deep tendon reflexes were absent.

MUSCLE BIOPSY

Muscle specimens were rapidly frozen in dry-ice-cooled isopentane and an- other small piece of the specimen in Case 2, removed in an isometric device, was fixed in phosphate-buffered 2.5 % glutaraldehyde and postfixed with 1 % osmium tetroxide. Cryostat sections and araldite-embedded ultra-thin sections were processed and examined by the previous methods (Fukuhara ef al. 1980).

The most striking abnormalities in both patients were increased endomysial connective tissue and replacement of muscle by adipose tissue (Fig. 2), though much more marked in Case 1. There was a marked variation of fiber size.

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Some small angulated fibers were seen, but most of the atrophic fibers were round in their contour. The mean fiber diameters were 92.3 pm k 46.0 (SD) in Case 1 and 32.2 pm 24.2 (SD) in Case 2, respectively. There was a considerable number of hypertrophic fibers in both patients. The atrophy and hypertrophy factors (Dubowitz & Brooke 1973) in Case 1 were 833 and 17,167, respectively. 21 % of fibers in Case 2 showed that the diameters were 50 % or more greater than the standard value for the age (Brooke & Engel 1969). Most of the hypertrophic fibers belonged to type I1 fibers. There were a few-splitting fibers and some fibers showing distortions of their archi- tecture, but ring fibers or sarcoplasmic masses were not revealed. With Go- mori trichrome stain, 1.7 % of fibers in Case 1 and 11.4 % in Case 2 con- tained rimmed vacuoles (Dubowitz & Brooke 1973, Fukuhara et al. 1980) which were seen mostly in type I fibers. Some of the vacuoles contained acid phosphatase positive granules. Inflammatory cells were absent.

Electron microscopic observation in Case 2 showed autophagic vacuoles (Fig. 3), which consisted of a conglomeration of glycogen granules, multi- laminated membranous structures, dense bodies, and amorphous, granular or fibrillar material. A mass of randomly oriented filaments 13-19 nm in diameter (Fig. 4) were frequently observed within the cytoplasm abutting on those autophagic vacuoles. These abnormal filaments sometimes looked tubu- lar (Fig. 5 ) according to the plane of section, but were not seen in the nuclei.

DISCUSSION

The mode of inheritance in this family seems to be autosomal dominant, but precise classification is uncertain. The results of EMG, muscle biopsies and elevated serum CPK obviously showed the myopathic nature of the illness.

In our Case 2, somewhat more rapid clinical course with the initial in- volvement of the muscles in the legs and earlier onset with the development of contracture of ankle joints might suggest distal myopathy (Magee & De Jong 1965, Van der D e Willebois et al. 1968, Sasaki et al. 1969, Kratz & Brooke 1979, Miller et al. 1979, Kumamoto et al. 1982) as the most probable diagnosis. However, the neurological findings in his father weighed against this diagnosis. The patterning of the muscle involvement of Case 1 may vaguely resemble the facioscapulohumeral type of muscular dystrophy, but ptosis or difficulty in swallowing was never seen in that type of muscular dystrophy except terminally (Vignos 1967). In the facioscapulohumeral type of muscular dystrophy, the peroneal muscles are frequently affected and such cases are sometimes called facioscapuloperoneal dystrophy (Ricker & Mertens 1968, Kazakov et al. 1974), but the initial involvement of the per- oneal muscles in Case 2 is quite unusual for such a disease (Ricker & Mertens 1968). The mode of onset in Case 1 with the initial involvement in the

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pharyngeal muscles and levator palpebrae would make us assume that he had oculopharyngeal muscular dystrophy (Victor et al. 1962, Peterman et al. 1964, Barbeau 1966, Szobor 1973) or descending ocular myopathy (Lees & Liversedge 1962), although these diseases were differently named by various authors. Szobor (1973) reported eight patients with oculopharyngeal syn- drome from five generations. His patients all showed ptosis and dysphagia and showed no limitations of the external ocular movements. The patterning of muscular involvement in the major types of muscular dystrophy is distinc- tive and characteristic, but their clinical features sometimes overlap each other. For example, cases were recognized which had the features of distal myopathy in addition to those of oculopharyngeal muscular dystrophy (Lakin & Locke 1961) and were grouped under the term of oculopharyngodistal myopathy (Satoyoshi et al. 1971, Goto et at. 1973, Morimatsu et al. 1976, Satoyoshi & Kinoshita 1977). Limb muscles in oculopharyngodistal myopathy are more markedly involved in the distal segments, whereas those in oculo- pharyngeal muscular dystrophy are in the proximal ones as in our Case 1. The affected members in the same family usually share the same features in the initial part, progression and distribution of muscle involvement. How- ever, Case 2 showed obvious difficulty in walking already at the age of 6. In contrast, his father did not have such an early onset of weakness and a rapid advance of muscle involvement, and was still able to walk although with difficulty 17 years after the initial symptom. Anyway, the degree of difference in our cases was too great to be explicable in terms of a variant form of oculopharyngodistal myopathy. However, to the best of our knowledge, no case reports describing a family in which a member with oculopharyngeal muscular dystrophy and another one with distal myopathy were seen suggest that such cases are rare, but also suggest that there might be an etiologica1 or nosological link between oculopharyngeal muscular dystrophy and distal myopathy .

Histological features of our cases were also much more interesting. A muscle biopsy specimen in Case 2 showed abundant rimmed vacuoles (Dubo- witz & Brooke 1973, Fukuhara et al. 1980). Rimmed vacuoles were very frequently seen in the muscles of oculopharyngeal muscular dystrophy (Du- bowitz & Brooke 1973) or of distal myopathy (Fukuhara et al. 1980, Kuma- moto et al. 1982). Distal myopathy was suggested to be etiologically different from other major types of muscular dystrophies because of showing rimmed vacuoles and increased activity of acid-phosphatase in the skeletal muscles (Fukuhara et al. 1980, Kumamoto et al. 1982). In this concept, these two dis- eases were suspected to be related in their etiology to each other. Both dis- eases were also reported to be associated sometimes with slightly reduced nerve conduction velocities (Takahashi et al. 1966, Sasaki et al. 1969, Goto et al. 1973) and sometimes to demonstrate in the EMG somewhat neuropathic

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features mixing in myopathic features although the myopathic ones were prevailing (Takahashi et al. 1966, Van der De Willebois et al. 1968, Stdberg & Ekstedt 1969, Morimatsu et al. 1976, Miller et al. 1979, Edstrom et al. 1980, Kumamoto et al. 1982). Of particular interest were the ultrastructural findings on the skeletal muscle in Case 2 that showed abnormal filaments in the sarcoplasm, previously reported to occur in inclusion body myositis (Yunis & Samaha 1971, Carpenter et al. 1978). Marked similarities between the clinical and pathological features in distal myopathy and inclusion body myositis were already reported (Fukuhara et al. 1980, Vaccariu et al. 1981). Therefore it was concluded that distal myopathy and inclusion body myositis were variant forms of the same disease.

ACKNOWLEDGEMENTS

This study was supported by Grant No. 82-02-34 from NCNMMD of the Ministry of Health and Welfare, Japan. The authors wish to express their appreciation to Dr. H. Norimatsu, Hamagumi Children’s Hospital, who performed the muscle biopsy in Case 2. Thanks are also given to Miss M. Ohno and Miss R. Sato for their assistance.

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Received June 30, N . Fukuhara, M.D. accepted August 31, 1981 Department of Neurology

Brain Research Institute Niigata University Niigata 951 Japan