Journal of the Neurological Sciences, 1983, 60: 151-156 151 Elsevier

N U C L E A R I N C L U S I O N S IN O C U L O P H A R Y N G E A L D Y S T R O P H Y

An Ultrastructural Study of Six Cases

M. COQUET, J. M. VALLAT, C. VITAL, M. FOURNIER, M. BARAT, J. M. ORGOGOZO, J. JUL1EN and P. LOISEAU

Centre de Microscopie Electronique, UniversitO de Bordeaux H; Clinique Neurologique et Service de RkOducation Fonctionnelle, H6pital Pellegrin ; Service de Neurologie, H6pital Haut-LOv~que ; et Service de M(decine, H6pital Pasteur ~ Langon, Bordeaux (France)

(Received 25 October, 1982) Revised, received 13 January, 1983) (Accepted 24 January, 1983)

SUMMARY

Nuclear inclusions in striated muscle from patients with oculopharyngeal dystrophy have been detected recently. We carried out ultrastructural examinations of biopsy specimens on 5 patients with oculopharyngeal dystrophy and we also reexamined a former case. In these 6 cases we found filamentous inclusions in a few nuclei. These inclusions seem to be characteristic of this disease as they have never been seen elsewhere.

Key words: M u s c l e b i o p s y - M u s c u l a r d y s t r o p h y - N u c l e a r inc lus ions

INTRODUCTION

Oculopharyngeal dystrophy (OPD) was characterised in 1962 by Victor et al. This type of ocular myopa thy is distinguished by its late onset and accompanying dysphagia. It is a hereditary disease with autosomal dominant inheritance. Initial ultrastructural examination of muscle only showed nonspecific changes : Spiro et al. (1973), Fournier et al. (1974), Julien et al. (1974), Neville and Brooke (1974), Man et al. (1976). Recently Tom6 and Fardeau (1980) have detected specific nuclear inclusions in skeletal muscle specimens f rom 3 patients belonging to 3 unrelated

Correspondence to Dr. M. Coquet, Centre de Microscopie l~lectronique, Universit6 de Bor- deaux II, 146, rue L6o Saignat, 33076 Bordeaux Cedex, France.

0022-510X/83/$03.00 © 1983 Elsevier Science Publishers B.V.

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families. Such inclusions were reported in another case by Tom6 et al. (1980) and in cases reported by Leroy et al. (1981), Martin et al. (1983) and Mikol (1982). We therefore obtained muscle biopsy specimens from 5 patients with OPD and reexamined specimens from a former patient.

MATERIAL AND METHODS

Six cases in all were examined. Five were from the South West of France and cases 1 and 2 were first cousins. The fifth patient lived in Bordeaux but was of Armenian extraction. From case 1 an autopsy specimen was obtained while in the other 5 biopsies from the deltoid (cases 2, 3, 4, 6) or peroneus brevis muscle (case 5) were taken.

Three specimens were taken at each biopsy. One was fixed in formalin and embedded in paraffin, one was frozen and prepared for histoenzymatic examination, and the third was fixed in glutaraldehyde, treated with osmic acid, embedded in epon and prepared for electron microscopy by the normal methods.

Case 1 The disease of this 77-year-old woman began at the age of 48 with bilateral ptosis. Vertical

movement of the eyeballs was restricted and she was dysphagic. Other muscles were not affected. She died from choking. The levator palpebrae was taken 4 hours after death and fixed in glutaraldehyde. This case has already been reported by Fournier et al. (1974).

Case 2 A 67-year-old woman came to us with ocular symptoms which had started at the age of 48 with

bilateral ptosis. Over the following years the extra-ocular muscles became affected and she had dif- ficulties in swallowing. On clinical examination no other muscles seemed to be affected. She had two sisters and a first cousin with the same symptomatology. (This cousin was case 1).

Case 3 A 56-year-old woman whose ptosis began in her forties presented with bilateral ptosis and

complained of eating difficulties. On clinical examination there was a marked restriction of vertical movement of the eyeballs, and muscular weakness in the pelvic girdle. She also complained of difficulties in swallowing. A brother and one of her cousins had similar clinical symptoms.

Case 4 A 64-year-old man was suffering from bilateral ptosis which had begun 10 years previously. He

had dysphagia and a weakness of the pelvic girdle musculature. The extra-ocular muscles were not affected. His mother had the same symptomatology.

Case 5 A 72-year-old man presented with bilateral ptosis and complained of swallowing difficulties.

The symptoms started around the age of 40. Skeletal muscles were not affected. Several family members had ocular myopathy, but since they did not live in France they could not be examined

Case 6 A 65-year-old man came to us with bilateral ptosis which had began at the age of 50. He had

no swallowing difficulties. On examination he showed signs of restricted extra-ocular movement. limb-girdle weakness, and especially pelvic girdle muscle disorders. In addition he had a generalised absence of tendon reflexes. Both his father and his uncle on his father's side definitely had ptosis but it is difficult to ascertain whether they had difficulties in swallowing since they died suddenly several years ago.

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RESULTS

(a) In the 5 skeletal muscle specimens filaments were observed in some nuclei. These filamentous inclusions were sparse and were seen in 2 - 3 ~ of the nuclei. They were found mainly in normal fibres. In case 6, however, they were seen in severely atrophied fibres, where myofibrils were sparse and disorganised (Fig. 1). Under low magnification these inclusions were weakly osmophilic in the nucleus, while the chromatin was pushed to the periphery. Under higher magnification, these inclusions took the form of straight tubular filaments with an external diameter of 8.5 nm. They were either randomly organised or arranged in palisade structures (Figs. 2 and 3). There were no signs of inclusions in the nuclei of other cells in the muscle specimens. Histoenzymatic preparations were correctly performed on cases 3, 4 and 6. Rimmed vacuoles were observed only in a few fibres from case 6.

(b) In the extra-ocular specimen taken post-mortem from case 1 the same inclusions were seen. There were numerous mitochondria, and the myofibrils in these fibres were less numerous. The mitochondria were artificially swollen but the inclusions were clearly to be seen in one nucleus (Fig. 4).

Fig. 1. Case 6. Highly atrophied muscle fibre with some myofilaments remaining. Inclusions can be seen in one nucleus in the form of a more electron-transparent zone. × 7420.

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Fig. 2. Case 5. Normal muscle fibre with the presence of many filaments in one nucleus, x 24.750.

Fig. 3. Case 6. A nuclear inclusion formed of filaments randomly organised or sometimes in palisade × 72,000.

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Fig. 4. Case 1. Levator palpebrae with visible nuclear inclusion. × 3900. Detail: Filaments arranged in pseudopalisades, x 55,000.

COMMENTS

Nuclear inclusions were found in our 6 cases. Nuclear inclusions are rarely seen in muscle fibres. The only well known ones are the cases of "inclusion body myositis" of which a few cases have been reported (Carpenter et al. 1978; Tom6 et al. 1981; Julien et al. 1982; Mikol et al. 1982). The structures seen were quite different from those observed in this study. Such intranuclear filaments have so far only been seen in cases of OPD (the 3 initial cases of Tom6 and Fardeau 1980, one case of Tom6 et al. 1980, cases of Leroy et al. 1981, one of Martin et al. 1982 and one of Mikol 1982). They may be unnoticed unless specifically looked for as in case 1 which was reported by Fournier et al. (1974). Although their origin is unknown it is important to acknowledge their existence. They have never been seen in cases other than OPD, suggesting that they may be specific. Their detection in a case where the diagnosis is not clear, especially in the early stages of the disease, could be an important factor in establishing a diagnosis of OPD.

ACKNOWLEDGEMENTS

We would like to thank Mrs. J. Rochet and Mrs. A. Gue for their technical assistance, Mr. S. Senon and Miss. M. Blasco for their photographic expertise and Mrs. C. Goegel for typing the manuscript.

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