Familial oculopharyngeal muscular dystrophy with distal spread
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J Neurol (1983) 230:57-64 Journal of
Neurology Springer-Verlag 1983
Familial oculopharyngeal muscular dystrophy with distal spread*
G. Vita, R. Dattola, M. Santoro, and C. Messina
Department of Neurology, University of Messina, Messina, Italy
Summary. An Italian male aged 50 years with oculopharyngeal muscular dystrophy is reported. Eleven of his relatives, over a period of three generations, had ptosis, dysphagia, nasal voice and difficulty in walking.
The distribution of muscle weakness in the propositus and in one of his sisters was proximal in the upper, but distal in the lower limbs, confirming the existence of a relationship between oculopharyngeal dystrophy and distal myopathy. The first muscle biopsy appeared normal except for some round-cell coliections, whereas the second one, 5 years later, showed marked dystrophic changes. Some patients with oculopharyngeal dystrophy may apparently pass through a secondary muscular inflammatory stage.
Key words: Oculopharyngeal muscular dystrophy - Myopathy, distal - Myopathy, inflammatory - EMG - Muscle biopsy
Zusammenfassung. Es wird fiber einen 50j~ihrigen Italiener mit einer oculo- pharyngealen Muskeldystrophie berichtet. Es zeigte sich, dal3 in der Familie 11 drei verschiedenen Generationen angehfrige Individuen eine Ptosis, Dys- phagie, eine n~iselnde Sprache und Schwierigkeiten beim Gehen aufwiesen.
Die Verteilung der Muskelschw~iche beim Propositus und einer ebenfalls untersuchten Schwester war an den oberen Extremit~iten proximal, an den unteren jedoch distal, wodurch eine Beziehung der oculopharyngealen Dys- trophie und einer distalen Myopathie bestatigt wurde. Eine erste Muskelbiopsie zeigte lediglich einige Ansammlungen von Rundzellen, w/ihrend eine zweite Biopsie, die ftinf Jahre sp~iter durchgefiihrt wurde, ausgepr~igte Zeichen eines dystrophischen Prozesses ergab. Diese Befunde sprechen dafiir, dab vereinzelte Patienten mit oculopharyngealer Dystrophie sekund~ire entziindliche Muskel- symptome aufweisen k6nnten.
* Supported in part by Fidia Research Laboratories, Abano Terme. This paper was presented in the Clinico-Pathological Conference at the Fifth International Congress on Neuromuscular Diseases, Marseilles, September 1982
Offprint requests to: Dr.Vita, Department of Neurology, Policlinico Universitario, Messina 98100, Italy
58 G.Vita et al.
O c u l o p h a r y n g e a l m u s c u l a r d y s t r o p h y is a c o n d i t i o n d o m i n a n t l y inhe r i t ed , wi th
onse t in adu l t life a n d s low p rog re s s ion . The m a j o r c o m p l a i n t s a re p tos is ,
d y s p h a g i a and p r o x i m a l l imb weaknes s [1, 2, 4, 7, 13, 14].
T h e p r e sen t r e p o r t gives the f ind ings in a m a n a f fec ted by o c u l o p h a r y n g e a l
d y s t r o p h y , wi th e m p h a s i s o n s o m e u n u s u a l c l inical a n d h i s t o p a t h o l o g i c a l aspects .
A 50-year-old Italian male was referred to the neurology clinic with dysphagia, hoarseness, fatiguability in phonation and occasional nasal regurgitation of fluids. These symptoms appeared when he was 45 and became gradually worse. Neurological examination revealed mild right ptosis, moderate weakness of the orbicularis oris muscle, nasal voice, with no elevation of right- side soft palate. Mild symmetrical wasting and weakness of biceps and triceps muscles were noted. Leg muscles were wasted and weak, particularly in the anterior compartment. Difficulty in walking because of mild bilateral foot drop was observed. The Achilles reflexes were depressed. The results of routine blood and urine analyses were unremarkable. The findings of a CSF examination were normal. His serum creatine kinase was within normal limits. Lactate dehydrogenase was increased to 115 U/I (normal 22-52). Quantitative determinations of serum immunoglobulin G, A and M levels by radial immunodiffusion gave normal results.
Electromyographic study of right biceps, deltoid, first dorsal interosseous, and of left tibialis anterior and extensor digitorum brevis muscles showed motor unit action potentials (MUPs) of low amplitude and short duration with an increased number of polyphasic potentials. There was an interference pattern at full effort. Biceps and extensor digitorum brevis muscles revealed some fibrillation potential at rest. Peroneal nerve conduction velocity was normal (50 m/s). There was neither a response to edrophonium nor a myotonic response. Paraffin-embedded sections of left biceps muscle biopsy appeared normal (Fig. 1 a), but with a few foci of mononuclear cells infiltration (Fig. 1 b and c). Some necrosis and myophagia were seen. On this basis, an inflammatory myopathy was suspected and alternate day high single dose of prednisone was started with no significant clinical response.
Five years later the patient was readmitted to the hospital with some deterioration. Examination showed ptosis of medium degree on the right side, nasal voice and difficulty in swallowing. Extra-ocular movements were full, but movement of the soft palate was decreased. There was generalized muscular wasting. Deltoid, biceps, triceps, pectoralis major, quadriceps, gastrocnemius and hamstring muscles were weak (grade 3-4 by Medical Research Council criteria). Dorsiflexion and eversion of the foot were bilaterally poor for marked weakness of tibialis anterior and peronei muscles (grade 1). Gowers' manoeuvre was present. The patient's gait was waddling with steppage. Biceps, triceps and brachioradialis reflexes were absent. Patellar and Achilles reflexes were hypo-active. Laboratory investigations showed a slightly increased level of serum creatine kinase (74 U/l). Myoglobin concentration was 145 ng/ml as determined by radio-immunoassay (normal 10-55). Contrast cineradiography of the oesophagus revealed retention of a large amount of barium sulphate in the piriform recess. Tracheal aspiration was noted (Fig. 2). Physical examination of the heart and ECG gave normal results.
A second EMG study (left deltoid, tibialis anterior and first dorsal interosseous muscles) revealed some fibrillation potentials at rest. In the deltoid muscle low amplitude and 9.85 ms + 3.7 (SD) in mean duration MUPs (with 20% polyphasic potentials) were recorded; there was an interference pattern at full effort. In the tibialis anterior low amplitude and 10.45 ms + 3.5 in duration MUPs were detected with 20% polyphasic potentials; the full effort pattern was transitional. Finally, in the first dorsal interosseous muscle low amplitude and 9.4ms + 3.7 in duration MUPs were recorded with 16% polyphasic potentials; the full effort pattern was of reduced interference with disproportion in comparison to the feeble effort made by the patient.
Right biceps muscle biopsy had clear evidence of a dystrophic process. There was a marked variability in fibre size, due to the presence of atrophied and hypertrophied fibres, with marked proliferation of perimysial and endomysial connective tissue and some fatty infiltration (Fig. 3 a). Numerous splitting fibres, internal nuclei and foci of necrosis and phagocytosis were noted.
Familial oculopharyngeal muscular dystrophy 59
Fig. l a - c . Paraffin-embedded sections of left biceps muscle stained with H &E. a Normal- looking appearance of the muscle with few isolated hypotrophic fibres, 80. b, e Two foci of mononuclear cells infiltration are seen, 180
Vacuoles were present in some fibres. Inflammatory changes were not seen. Myosin ATPase- stained sections showed no selective fibre type involvement (Fig. 3 b). No ragged red fibres were detected with Gomori trichrome stain.
During the second hospitalization, the history given by the patient with the help of some of his relatives revealed 12 members of his family, over a period of three generations, affected by ptosis, dysphagia, nasal voice and difficulty in walking.
The family members in the pedigree (Fig. 4) were as follows: II-1. Died aged 40 years. She is remembered as a woman in good health. 1I-2. Suffered from a gait disturbance and nasal voice. Died at the age of 70 years. 11-3 and 11-4. Nothing is known by their descendants.
III-2. Reported to have nasal voice and limb muscular weakness from the age of 55 years. She died at age 83 years.
11I-3. Died at the age of 30 years. At that time she was suffering from nasal voice. Ill-5. Had nasal voice, difficulty in swallowing, gait disturbance. She died at age 65 years with
60 G.Vita et al.
Fig. 2. Radiological evidence of tracheal invasion of barium
1II-6. Living in Canada in apparently good health. He is now 70 years of age. III-9. Died aged 80 years. Nasal voice was present. III-10. Reported to have nasal voice. She died aged 80 years. IV- 1. Propositus. IV-3. Now 60 years of age and for some years experienced difficulty in climbing stairs, nasal
voice, dysphagia, nasal regurgitation of fluids. Examination showed a steppage gait, no movement of soft palate, diffuse muscular wasting and weakness with marked involve- ment of the muscles in the anterior compartment of the legs. Tendon reflexes were absent.
IV-5. Reported to have difficulty in walking, nasal voice, dysphagia and nasal regurgitation. IV-8. Living in Canada and developed nasal voice from the age of 20. He is now 45 years old. IV-11. Aged 52 years and reported to suffer from nasal voice and gait disturbance. IV-12. Died aged 40 years with bone tumour (?). He had nasal voice. Generation V. Among the members of the fifth generation, no neurological symptoms are
present. They are all less than 40 years old.
Familial oculopharyngeal muscular dystrophy 61
Fig. 3a and b. Cryostat 10-~tm sections of right biceps muscle, x 70. a H &E. b Myofibrillar ATPase pH 4.6
The clinical course of our patient's condition, the lack of response to steroid therapy and the family history, together with EMG and muscle biopsy findings, are against a diagnosis of polymyositis, but are highly suggestive of oculo- pharyngeal muscular dystrophy. Such dystrophy is characterized by autosomal dominant inheritance, ophthalmoparesis, dysphagia and proximal limb weakness,
62 G. Vita et al.
I I I ~ ?
,v ~1 61
[ ] MALE 0 FEMALE ~ , ~ DEAD m o AFFECTED
1 ~ ) RELIABLY REPORTED TO BE AFFECTED
Fig. 4. Family pedigree. Question marks are for members who are also thought to be affected as the condition is inherited with autosomal dominant pattern. Only one member in the first generation should have been affected, but we do not know which one
with late onset and slow progression of the symptoms. All these criteria were met by our patient, although the distribution of weakness was distal in the lower extremities. A similar pattern was noted in his sister. A distal pattern of involve- ment has been observed in addition to features of oculopharyngeal muscular dystrophy, these cases being grouped under the term of oculopharyngodistal myopathy . Recently, Fukuhara et al.  have suggested that there might be an aetiological or nosological link between oculopharyngeal dystrophy and distal myopathy, as they observed a family in which one member suffered from oculopharyngeal syndrome and another from distal myopathy.
More than half of the reported cases of oculopharyngeal muscular dystrophy have occurred among Canadians of French origin. Barbeau  traced the descent of these patients from a common ancestor. Our patient 's family appears to have no French relatives. Patients of Italian origin have been hitherto reported by Lewis (1966), cited by Szobor , by Campanella et al. , and by Rebeiz et al. (1967), cited by Little and Perl . In the family described here 12 cases of oculo- pharyngeal syndrome occurred in three generations. Two of them were examined in detail, but the remaining ten are only reliably reported by their relatives to be affected. Among these ten members, eight had died before our study, one is living in Canada, and another one refused cooperation. Members II-1, II-3, II-4, and III-6 were probably also affected by the disease, which is an autosomal dominant disorder with complete penetrance . The first one died at the age of 40 years and we can suppose that the disease would have occurred later in life. About the other three as well as the two members of the first generation, nothing or little is reported by the members of the family with whom we spoke.
Electromyographic findings in our patient are all suggestive of a myopathic disorder. MUPs mean duration was reduced (but not significantly) in deltoid and first dorsal interosseous muscles. An increased incidence of polyphasic potentials
Familial oculopharyngeal muscular dystrophy 63
was recorded in both muscles. With maximal effort there were a full interference pattern and a decreased mean amplitude (1.5 mV), with a clear disproportion in comparison to the feeble effort of the patient. In the tibialis anterior, which was clinically the muscle most affected, myopathic EMG findings were more evident. MUPs mean duration was significantly decreased ( -26% compared to Buchthal's normal values) , and an increased number of polyphasic potentials was recorded. There was a reduced mean amplitude (750 gV) at full effort.
Inflammatory cell infiltration is not uncommon in muscular dystrophies , and sometimes it can create diagnostic problems. In facioscapulohumeral dystrophy with inflammation, cortisone therapy is not followed by long-term benefit . A secondary immune response triggered by underlying muscular degeneration has been proposed as a cause of the inflammatory response . Rosenberg et al.  reported a patient with familial ptosis, ophthalmoplegia and limb girdle weakness, whose biopsy showed evidence of polymyositis. Recently, Bosch et al.  have described a similar case. Our report confirms the concept that certain patients with oculopharyngeal muscular dystrophy may pass through a secondary muscular "inflammatory" stage, as has been noted in other dys- trophies .
In our case the second muscle biopsy showed marked evidence of a dystrophic process. The changes were prominent, and included fibrosis, fibre size variability, splitting, necrosis and phagocytosis. Such extensive involvement is somewhat surprising. Changes such as fibrosis, myophagia and basophilia, which are ordinarily considered hallmarks of the dystrophies, are rare in oculopharyngeal muscular dystrophy . It is even more surprising when it is considered that onset of the disease had occurred in our patient 10 years before and that the first muscle biopsy, performed 5 years after onset, showed only mild inflammatory changes. It may be that the observed dystrophic features were more pronounced than those expected, as a consequence of the previous inflammatory process. However, the patient reported by Bosch et al.  had a second biopsy, performed in a muscle different from the first one, showing only mild pathological changes.
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Received January 30, 1983