A family with oculopharyngeal muscular dystrophy (OPMD) is described. Histological and histochemical studies of muscle biopsy showed nonspecific myopathic changes; no "ragged-red'' fibers were seen. Electron microscopy demonstrated bizarre large mitochondria with abnormal cristae, but no intranuclear inclusion bodies. Our findings are compatible with the possibility that OPMD is a heterogeneous syndrome, and may be a manifestation of mitochondria1 myopathy. Key words: oculopharyngeal muscular dystrophy mitochondrial myopathy oculomyopathy muscular dystrophy MUSCLE 81 NERVE 14:947-952 1991
MITOCHONDRIAL ABNORMALITIES IN OCULOPHARYNGEAL MUSCULAR DYSTROPHY RACHEL PAWNER, MD, ILAN BLATT, MD, MElR MOUALLEM, MD, ElTAN BEN-DAVID, MSc, ZVI FARFEL, MD, and MENACHEM SADEH, MD
Oculopharyngeal muscular dystrophy (OPMD), a rare autosomal dominant genetic disorder, was first described by Taylor in 1915,13 and traced to a common French ancestor who settled in Quebec in the seventeenth ~ e n t u r y . 'It ~ has since been found in various ethnic groups such as the Italian, Spanish, Norwegian, and Japanese. Few cases have been reported among Jews. Victor et al.17 described 10 such patients: 1 sporadic and 9 cases in three generations of a North American family of Eastern European origin. Schotland and Rowland" found 11 cases in five Jewish families. Late adult onset of ptosis and dysphagia are characteristic, though weakness in facial, masticatory, neck, and limb muscles has also been described. The patho enetic basis for the syndrome is not well definedr5 Tome et al. have found intranuclear inclusion bodies and suggested that this is a hallmark of the However, other workers have discovered mitochondrial abnormalities.3,7,11 We present here further evidence for
mitochondrial abnormalities not described previously in a family with OPMD. CASEREPORTS
An 8 1-year-old Jewish, non-Ashkenazi man born in Buchara, Uzbekistan was hospitalized because of syncope due to bradycardia caused by propranolol. The patient has had bilateral ptosis for more than 15 years, and for 5 years has complained of progressive difficulty in swallowing solid food. Bronchitis was diagnosed because of
Case 1.
From the Department of Internal Medicine E (Drs Pauzner, Mouallem, Farfel and Sadeh), and Department of Neurology (Dr. Blatt), The Chaim Sheba Medical Center, Tel Hashomer and Department of Pathology, Beilinson Medical Center (Mr. Ben-David), affiliated with the Sackler School of Medicine, Tel Aviv University, Israel. Address reprint requests to R. Pauzner, MD, Department of Internal Medicine E,The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Accepted for publication July 18, 1990 CCC 0148-639)(/91/0100947-06 $04.00 0 1991 John Wiley & Sons, lnc.
Mitochondria in Oculopharyngeal Muscular Dystrophy
FIGURE 1. Case 1 : bilateral ptosis and contraction of the frontalis muscle.
MUSCLE & NERVE
October 1991
947
FIGURE 2. Irregular patches of absent enzyme product reaction are seen with subsarcolemmal aggregates. NADH-tetrazolium reductase ( x 250).
FIGURE 3. Electron micrograph shows thickened, dense aggregates within the mitochondria and loss of normal mitochondria1 structure (x45,OOO).
recurrent episodes of productive cough upon swallowing. T h e dysphagia had worsened during the last 2 years with a weight loss of 10 kg. Dysphonia developed as well. On physical examination, the patient weighed 52 kg and had bilateral ptosis compensated by contraction of the frontalis muscle and by holding the head backward (Fig. 1). Eye movements were limited and slow in all directions. The pupils were equal and reacted to light and accomodation. There was no eyelid fatigue or evidence of myotonia. Speech had a nasal quality, but the palate was symmetric with a central uvula and the gag reflex normal. There was mild proximal weakness of the lower limbs. An apical systolic murmur and a diastolic murmur at the left sternal border were heard. T h e rest of the physical examination was normal. Biochemical blood studies, including creatinine kinase, yielded normal results. ECG showed sinus bradycardia and right bundle branch block. A 24hour Holter recording revealed sinus bradycardia, not less than 50 beats/min. Echocardiogram demonstrated mild mitral insufficiency, moderate aortic insufficiency, and good left ventricular function. A tensilon test was negative. Nerve conduction velocity studies yielded normal values as did electromyography of limb muscles, and no myotonic discharges were observed. A sample of biopsied deltoid muscle was rap-
idly frozen in isopentan cooled in liquid nitrogen. Sections of 10 micrometers were stained with hematoxylin and eosin, modified Gomori trichrome, Sudan black B, NADH-tetrazolium reductase, succinic dehydrogenase, and ATPase at pH 9.4 and after preincubation at pH 4.6 and 4.25.4 Another portion was fixed in 3% gluteraldehyde in cacodylate buffer treated with osmic acid, embedded in epon and prepared for electron microscopy. Light microscopy revealed variability in muscle fiber size with no connective tissue, fatty, or inflammatory infiltration. With the NADH-TR and succinic dehydrogenase reactions, many “motheaten” fibers were observed. Areas devoid of oxidative enzyme reactions were present in both fiber types. Many fibers showed subsacrolemmal diformazan deposition (Fig. 2). However, with the modified Gomori trichrome stain, no ragged red fibers were seen. Small angulated fibers were absent, and there were no vacuoles. Electron microscopy revealed areas of disintegration of sarcomeres and foci of Z-disc streaming. Nuclei appeared normal, and no intranuclear filamentous inclusions were found in spite of a careful search in many fibers. Subsacrolemmal mitochondria were increased in number. All the mitochondria had an abnormal appearance- they were large with widened clumped bizarre cristae (Fig. 3). Recently, because of increasing difficulties in
FIGURE 4. Electron micrograph demonstrates aggregation of multiple dark mitochondria within an atrophied muscle (~9,000).
Mitochondria in Oculopharyngeal Muscular Dystrophy
MUSCLE & NERVE
October 1991
949
swallowing, the patient underwent cricopharyngeal m y ~ t o m y , ~which . ~ relieved the dysphagia. During the operation, a biopsy from one of the anterior neck muscles was taken and prepared for histochemical and electron microscopical studies as described above. Muscle fibers were small, atrophic, and rounded, separated by a markedly increased amount of fibrous tissue. With the NADH-TR reaction, the fibers were darkly and irregularly stained; no ragged-red fibers were observed with the modified Gomori trichrome. Electron microscopy revealed atrophied fibers with sacrolemmal foldings and a reduced number of myofibrils. Abundant dark bizarre mitochondria were observed between myofibrils (Fig. 4). At a higher magnification, the mitochondria contained dense homogeneous matrix material and convoluted cristae (Fig. 5). Other fibers possessed ringlike mitochondria enclosing an abundant amount of matrix material with almost no cristae (Fig. 6). No intranuclear inclusion bodies were observable in this biopsy either. A 75-year-old man, first cousin of patient 1, was known to have had bilateral ptosis for more than 10 years and dysphagia for 6 years. His weight was 54 kg. Physical examination revealed findings identical to those found in his cousin, except that no heart murmurs were found. T h e patient refused any investigation. Information about other members of the family is provided in Figure 7 which shows the family pedigree. Thirteen cases in four generations were affected by the disease. Autosomal dominant pattern of inheritance is obvious.
Case 2.
DISCUSSION
Oculopharyngeal dystrophy is inherited as an autosomal dominant trait becoming manifest in the fifth or sixth decade mainly by ptosis and dysphagia, with later involvement of all extraocular muscles. Many patients may develop laryngeal weakness with dysphonia, and in late stages of the disease, weakness and atrophy of other voluntary muscles. Death occurs at an advanced age as a result of starvation or aspiration pneumonia; a few cases of carcinoma of the esophagus and the stomach have been reported. l 5 The main disease to be considered in the differential diagnosis is oculocraniosomatic syndrome (OCSS), in which ptosis appears sometimes unilaterally, but which invariably shows skeletal muscle involvement, sometimes with dental and skeletal abnormalities. Associated distinguishing findings include retinitis pigmentosa, cerebellar ataxia, hearing loss, mental disturbances, endocrine abnormalities, and cardiac involvement with atrioventricular block, which occur in OCSS. Its onset is usually before the age of 30, although it may appear later until the age of 60. The syndrome is sporadic, but there are a few familial cases.15 T h e characteristic histological finding is ragged red fibers. Recently, deletions of mitochondria1 DNA were found in this syndrome. Though severe dysphagia may also occur in OCSS, our family’s age of onset and mode of inheritance fit the diagnosis of OPMD. The pathological basis of OPMD was, in the past, suspected to be neurogenic due to degeneration of vagal, glossopharyngeal, and oculomotor nuclei. Taylor named the disease “progressive va-
’’
FIGURE 5. Higher magnification of a dark subsarcolemmal large mitochondrionshows coiled cristae and dense matrix material (~40,000).
950
Mitochondria in Oculopharyngeal Muscular Dystrophy
MUSCLE & NERVE
October 1991
FIGURE 6. In this electron micrograph, mitochondria appear rounded or ring-like, encircling fine granular material (~25,000).
gus-glossopharyngeal paralysis with p t o ~ i s . ” ’ ~ Victor et al., who coined the name OPMD, proposed a myopathic basis. Muscle studies by classical histological methods showed nonspecific changes, such as decreased muscle fiber size, inter-
nal nuclei, and interstitial fibrosis. l 5 On histochemical studies, fibers appeared split, “motheaten,” and many were small and angulated. Rimmed vacuoles were also described, consisting of irregular round or polygonal clear spaces lined
I
2
5 3 ?
?
?
FIGURE 7. Pedigree of the affected family. Ages provided are either at death or at present. p p t o s i s , ?-no known details.
Mitochondria in Oculopharyngeal Muscular Dystrophy
MUSCLE & NERVE
October 1991
951
by a baso hilic ring staining red with Gomori's trichrome. Ultrastructural studies showed that the rimmed vacuoles contained membranous structures and a few glycogen granules and debris, arising from the breakdown of unidentified muscle components. Tome et al.14,16described nuclear inclusions in 33 cases. Under high magnification, these looked like tubular filaments with an external diameter of 8.5 nm, randomly organized or arranged in palisades, an appearance confirmed by others. 16- l8 Tome et al. considered this finding to be the hallmark of OPMD. Mitochondrial abnormalities in OPMD were re orted in 2 patients by Couturier et al.3Julien et al. reported a case with abnormal mitochondria that contained inclusion bodies composed of concentric lamellae of short electron-dense linear ele-
'
1:
ments. Prat et al." reported another case with mitochondrial abnormalities. Abnormal dense irregular metallic inclusions were situated within grossly destroyed mitochondria. In our family, we describe another type of morphological mitochondrial changes. T h e specificity of the mitochondrial changes is not certain. It is difficult to assess the role of mitochondrial abnormalities in the pathogenesis of the disease and to determine whether we are dealing with a primary mitochondrial myopathy. This report, as well as previous reports on mitochondrial abnormalities in OPMD, raise the possibility that OPMD is not a homogeneous disease characterized histologically by intranuclear inclusions, but a more complex syndrome.'7829Genetic, biochemical, and molecular biology studies are required to classify the disorder more precisely.
REFERENCES 1 . Carlos T, Moraes et al: Mitochondria1 DNA deletions in progressive external ophthalmoplegia and Kearns- Sayre syndrome. N Engl J Med 1989;320:1293- 1299. 2. Coquet M, Vallat JM, Vital C, Fournier H , Barat M, Orgogoo JM, Julien J, Loiseau P: Nuclear inclusions in oculopharyngeal dystrophy. An ultrastructural study of six cases. J Neurol Scz 1983;60:151-156. 3. Couturier JC, Carrier H, Brunon AM, Bady B: La myopathie oculo-pharyngee (a propos d'une observation familiale). Lyon Med 1981;245:109. 4. Dubowitz V, Brooke M: Muscle Biopsy: A Modern Approach. Philadelphia, Saunders, 1973, pp 27-28. 5. Duranceau AC, Beauchamp C, Jamieson GG, Barbeau A: Oropharyngeal dysphagia and oculopharyngeal muscular dystrophy. Surg Clin North Am 1983;63:825-832. 6. Fradet G, Pouliot D, Laroie S, St. Pierre S: Inferior constrictor myotomy in oculopharyngeal muscular dystrophy: Clinical and manometric evaluation. J Otolaryngol 1988;17:68-73. 7. Julien J, Vital C, Vallat JM, Vallat M, Leblanc H: Oculopharyngeal muscular dystrophy-A case with abnormal mitochondria and fingerprint inclusions. J Neurol Sci 1974;21:165- 169. 8. Leroy JP, Missoum A, Bastard J, Goas JY: Etude morphologique d'un cas de dystrophie oculo-pharyngee. Rev Oto Neuro Ophtal 1981;53:139- 143. 9. Martin JJ, Centerick C, Mercelis R: Nuclear inclusions in oculopharyngeal muscular dystrophy. Muscle Nerve 198215~735-737.
952
Mitochondria in Oculopharyngeal Muscular Dystrophy
of 10. Neville HE. Brooke ME: Muscle biomv in the diagnosis 0 oculopharyngeal myopathy. J Neuropath Exp Neurol 1974;33:193. 1 1 . Pratt MF, Myers PK: Oculopharyngeal muscular dystrophy: recent ultrastructural evidence for mitochondrial abnormalities. Laryngoscope 1986;96:368-373. 12. Schotland DL, Rowland LP: Muscular dystrophy features of ocular myopathy, distal myopathy and myotonic dystrophy. Arch Neurol 1964;10:433-445. 13. Taylor EW: Progressive vagus-glossopharyngeal paralysis with ptosis: contribution to group of family diseases.J Neurol Ment Dis 1915;42:129- 139. 14. Tome FMS, Fardeau H: Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropath 1980;49:85-87. 15. Tome FMS, Fardeau H: Ocular myopathies, in Engel AG, Banker BA, (eds): Myology, New York, McGraw-Hill, 1986, pp 1327-1347. 16. Tom6 FMS, Gounon P, Collin H: Intranuclear inclusions in oculopharyngeal muscular dystrophy, further studies. Neurology 1989;39(suppl 1):335. 17. Victor H, Hayes R, Adams RD: Oculopharyngeal muscular dystrophy: a familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 1962;207:1267- 1272. 18. Zeriani M, Moraes CT, Nakase H, Bonilla E, Schon EA, Rowland LP: Deletions of mitochondrial DNA in KearnsSayre syndrome. Neurology 1988;38:1339- 1346. 1
,
MUSCLE & NERVE
October 1991
MITOCHONDRIAL ABNORMALITIES IN OCULOPHARYNGEAL MUSCULAR DYSTROPHY RACHEL PAWNER, MD, ILAN BLATT, MD, MElR MOUALLEM, MD, ElTAN BEN-DAVID, MSc, ZVI FARFEL, MD, and MENACHEM SADEH, MD
Oculopharyngeal muscular dystrophy (OPMD), a rare autosomal dominant genetic disorder, was first described by Taylor in 1915,13 and traced to a common French ancestor who settled in Quebec in the seventeenth ~ e n t u r y . 'It ~ has since been found in various ethnic groups such as the Italian, Spanish, Norwegian, and Japanese. Few cases have been reported among Jews. Victor et al.17 described 10 such patients: 1 sporadic and 9 cases in three generations of a North American family of Eastern European origin. Schotland and Rowland" found 11 cases in five Jewish families. Late adult onset of ptosis and dysphagia are characteristic, though weakness in facial, masticatory, neck, and limb muscles has also been described. The patho enetic basis for the syndrome is not well definedr5 Tome et al. have found intranuclear inclusion bodies and suggested that this is a hallmark of the However, other workers have discovered mitochondrial abnormalities.3,7,11 We present here further evidence for
mitochondrial abnormalities not described previously in a family with OPMD. CASEREPORTS
An 8 1-year-old Jewish, non-Ashkenazi man born in Buchara, Uzbekistan was hospitalized because of syncope due to bradycardia caused by propranolol. The patient has had bilateral ptosis for more than 15 years, and for 5 years has complained of progressive difficulty in swallowing solid food. Bronchitis was diagnosed because of
Case 1.
From the Department of Internal Medicine E (Drs Pauzner, Mouallem, Farfel and Sadeh), and Department of Neurology (Dr. Blatt), The Chaim Sheba Medical Center, Tel Hashomer and Department of Pathology, Beilinson Medical Center (Mr. Ben-David), affiliated with the Sackler School of Medicine, Tel Aviv University, Israel. Address reprint requests to R. Pauzner, MD, Department of Internal Medicine E,The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Accepted for publication July 18, 1990 CCC 0148-639)(/91/0100947-06 $04.00 0 1991 John Wiley & Sons, lnc.
Mitochondria in Oculopharyngeal Muscular Dystrophy
FIGURE 1. Case 1 : bilateral ptosis and contraction of the frontalis muscle.
MUSCLE & NERVE
October 1991
947
FIGURE 2. Irregular patches of absent enzyme product reaction are seen with subsarcolemmal aggregates. NADH-tetrazolium reductase ( x 250).
FIGURE 3. Electron micrograph shows thickened, dense aggregates within the mitochondria and loss of normal mitochondria1 structure (x45,OOO).
recurrent episodes of productive cough upon swallowing. T h e dysphagia had worsened during the last 2 years with a weight loss of 10 kg. Dysphonia developed as well. On physical examination, the patient weighed 52 kg and had bilateral ptosis compensated by contraction of the frontalis muscle and by holding the head backward (Fig. 1). Eye movements were limited and slow in all directions. The pupils were equal and reacted to light and accomodation. There was no eyelid fatigue or evidence of myotonia. Speech had a nasal quality, but the palate was symmetric with a central uvula and the gag reflex normal. There was mild proximal weakness of the lower limbs. An apical systolic murmur and a diastolic murmur at the left sternal border were heard. T h e rest of the physical examination was normal. Biochemical blood studies, including creatinine kinase, yielded normal results. ECG showed sinus bradycardia and right bundle branch block. A 24hour Holter recording revealed sinus bradycardia, not less than 50 beats/min. Echocardiogram demonstrated mild mitral insufficiency, moderate aortic insufficiency, and good left ventricular function. A tensilon test was negative. Nerve conduction velocity studies yielded normal values as did electromyography of limb muscles, and no myotonic discharges were observed. A sample of biopsied deltoid muscle was rap-
idly frozen in isopentan cooled in liquid nitrogen. Sections of 10 micrometers were stained with hematoxylin and eosin, modified Gomori trichrome, Sudan black B, NADH-tetrazolium reductase, succinic dehydrogenase, and ATPase at pH 9.4 and after preincubation at pH 4.6 and 4.25.4 Another portion was fixed in 3% gluteraldehyde in cacodylate buffer treated with osmic acid, embedded in epon and prepared for electron microscopy. Light microscopy revealed variability in muscle fiber size with no connective tissue, fatty, or inflammatory infiltration. With the NADH-TR and succinic dehydrogenase reactions, many “motheaten” fibers were observed. Areas devoid of oxidative enzyme reactions were present in both fiber types. Many fibers showed subsacrolemmal diformazan deposition (Fig. 2). However, with the modified Gomori trichrome stain, no ragged red fibers were seen. Small angulated fibers were absent, and there were no vacuoles. Electron microscopy revealed areas of disintegration of sarcomeres and foci of Z-disc streaming. Nuclei appeared normal, and no intranuclear filamentous inclusions were found in spite of a careful search in many fibers. Subsacrolemmal mitochondria were increased in number. All the mitochondria had an abnormal appearance- they were large with widened clumped bizarre cristae (Fig. 3). Recently, because of increasing difficulties in
FIGURE 4. Electron micrograph demonstrates aggregation of multiple dark mitochondria within an atrophied muscle (~9,000).
Mitochondria in Oculopharyngeal Muscular Dystrophy
MUSCLE & NERVE
October 1991
949
swallowing, the patient underwent cricopharyngeal m y ~ t o m y , ~which . ~ relieved the dysphagia. During the operation, a biopsy from one of the anterior neck muscles was taken and prepared for histochemical and electron microscopical studies as described above. Muscle fibers were small, atrophic, and rounded, separated by a markedly increased amount of fibrous tissue. With the NADH-TR reaction, the fibers were darkly and irregularly stained; no ragged-red fibers were observed with the modified Gomori trichrome. Electron microscopy revealed atrophied fibers with sacrolemmal foldings and a reduced number of myofibrils. Abundant dark bizarre mitochondria were observed between myofibrils (Fig. 4). At a higher magnification, the mitochondria contained dense homogeneous matrix material and convoluted cristae (Fig. 5). Other fibers possessed ringlike mitochondria enclosing an abundant amount of matrix material with almost no cristae (Fig. 6). No intranuclear inclusion bodies were observable in this biopsy either. A 75-year-old man, first cousin of patient 1, was known to have had bilateral ptosis for more than 10 years and dysphagia for 6 years. His weight was 54 kg. Physical examination revealed findings identical to those found in his cousin, except that no heart murmurs were found. T h e patient refused any investigation. Information about other members of the family is provided in Figure 7 which shows the family pedigree. Thirteen cases in four generations were affected by the disease. Autosomal dominant pattern of inheritance is obvious.
Case 2.
DISCUSSION
Oculopharyngeal dystrophy is inherited as an autosomal dominant trait becoming manifest in the fifth or sixth decade mainly by ptosis and dysphagia, with later involvement of all extraocular muscles. Many patients may develop laryngeal weakness with dysphonia, and in late stages of the disease, weakness and atrophy of other voluntary muscles. Death occurs at an advanced age as a result of starvation or aspiration pneumonia; a few cases of carcinoma of the esophagus and the stomach have been reported. l 5 The main disease to be considered in the differential diagnosis is oculocraniosomatic syndrome (OCSS), in which ptosis appears sometimes unilaterally, but which invariably shows skeletal muscle involvement, sometimes with dental and skeletal abnormalities. Associated distinguishing findings include retinitis pigmentosa, cerebellar ataxia, hearing loss, mental disturbances, endocrine abnormalities, and cardiac involvement with atrioventricular block, which occur in OCSS. Its onset is usually before the age of 30, although it may appear later until the age of 60. The syndrome is sporadic, but there are a few familial cases.15 T h e characteristic histological finding is ragged red fibers. Recently, deletions of mitochondria1 DNA were found in this syndrome. Though severe dysphagia may also occur in OCSS, our family’s age of onset and mode of inheritance fit the diagnosis of OPMD. The pathological basis of OPMD was, in the past, suspected to be neurogenic due to degeneration of vagal, glossopharyngeal, and oculomotor nuclei. Taylor named the disease “progressive va-
’’
FIGURE 5. Higher magnification of a dark subsarcolemmal large mitochondrionshows coiled cristae and dense matrix material (~40,000).
950
Mitochondria in Oculopharyngeal Muscular Dystrophy
MUSCLE & NERVE
October 1991
FIGURE 6. In this electron micrograph, mitochondria appear rounded or ring-like, encircling fine granular material (~25,000).
gus-glossopharyngeal paralysis with p t o ~ i s . ” ’ ~ Victor et al., who coined the name OPMD, proposed a myopathic basis. Muscle studies by classical histological methods showed nonspecific changes, such as decreased muscle fiber size, inter-
nal nuclei, and interstitial fibrosis. l 5 On histochemical studies, fibers appeared split, “motheaten,” and many were small and angulated. Rimmed vacuoles were also described, consisting of irregular round or polygonal clear spaces lined
I
2
5 3 ?
?
?
FIGURE 7. Pedigree of the affected family. Ages provided are either at death or at present. p p t o s i s , ?-no known details.
Mitochondria in Oculopharyngeal Muscular Dystrophy
MUSCLE & NERVE
October 1991
951
by a baso hilic ring staining red with Gomori's trichrome. Ultrastructural studies showed that the rimmed vacuoles contained membranous structures and a few glycogen granules and debris, arising from the breakdown of unidentified muscle components. Tome et al.14,16described nuclear inclusions in 33 cases. Under high magnification, these looked like tubular filaments with an external diameter of 8.5 nm, randomly organized or arranged in palisades, an appearance confirmed by others. 16- l8 Tome et al. considered this finding to be the hallmark of OPMD. Mitochondrial abnormalities in OPMD were re orted in 2 patients by Couturier et al.3Julien et al. reported a case with abnormal mitochondria that contained inclusion bodies composed of concentric lamellae of short electron-dense linear ele-
'
1:
ments. Prat et al." reported another case with mitochondrial abnormalities. Abnormal dense irregular metallic inclusions were situated within grossly destroyed mitochondria. In our family, we describe another type of morphological mitochondrial changes. T h e specificity of the mitochondrial changes is not certain. It is difficult to assess the role of mitochondrial abnormalities in the pathogenesis of the disease and to determine whether we are dealing with a primary mitochondrial myopathy. This report, as well as previous reports on mitochondrial abnormalities in OPMD, raise the possibility that OPMD is not a homogeneous disease characterized histologically by intranuclear inclusions, but a more complex syndrome.'7829Genetic, biochemical, and molecular biology studies are required to classify the disorder more precisely.
REFERENCES 1 . Carlos T, Moraes et al: Mitochondria1 DNA deletions in progressive external ophthalmoplegia and Kearns- Sayre syndrome. N Engl J Med 1989;320:1293- 1299. 2. Coquet M, Vallat JM, Vital C, Fournier H , Barat M, Orgogoo JM, Julien J, Loiseau P: Nuclear inclusions in oculopharyngeal dystrophy. An ultrastructural study of six cases. J Neurol Scz 1983;60:151-156. 3. Couturier JC, Carrier H, Brunon AM, Bady B: La myopathie oculo-pharyngee (a propos d'une observation familiale). Lyon Med 1981;245:109. 4. Dubowitz V, Brooke M: Muscle Biopsy: A Modern Approach. Philadelphia, Saunders, 1973, pp 27-28. 5. Duranceau AC, Beauchamp C, Jamieson GG, Barbeau A: Oropharyngeal dysphagia and oculopharyngeal muscular dystrophy. Surg Clin North Am 1983;63:825-832. 6. Fradet G, Pouliot D, Laroie S, St. Pierre S: Inferior constrictor myotomy in oculopharyngeal muscular dystrophy: Clinical and manometric evaluation. J Otolaryngol 1988;17:68-73. 7. Julien J, Vital C, Vallat JM, Vallat M, Leblanc H: Oculopharyngeal muscular dystrophy-A case with abnormal mitochondria and fingerprint inclusions. J Neurol Sci 1974;21:165- 169. 8. Leroy JP, Missoum A, Bastard J, Goas JY: Etude morphologique d'un cas de dystrophie oculo-pharyngee. Rev Oto Neuro Ophtal 1981;53:139- 143. 9. Martin JJ, Centerick C, Mercelis R: Nuclear inclusions in oculopharyngeal muscular dystrophy. Muscle Nerve 198215~735-737.
952
Mitochondria in Oculopharyngeal Muscular Dystrophy
of 10. Neville HE. Brooke ME: Muscle biomv in the diagnosis 0 oculopharyngeal myopathy. J Neuropath Exp Neurol 1974;33:193. 1 1 . Pratt MF, Myers PK: Oculopharyngeal muscular dystrophy: recent ultrastructural evidence for mitochondrial abnormalities. Laryngoscope 1986;96:368-373. 12. Schotland DL, Rowland LP: Muscular dystrophy features of ocular myopathy, distal myopathy and myotonic dystrophy. Arch Neurol 1964;10:433-445. 13. Taylor EW: Progressive vagus-glossopharyngeal paralysis with ptosis: contribution to group of family diseases.J Neurol Ment Dis 1915;42:129- 139. 14. Tome FMS, Fardeau H: Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropath 1980;49:85-87. 15. Tome FMS, Fardeau H: Ocular myopathies, in Engel AG, Banker BA, (eds): Myology, New York, McGraw-Hill, 1986, pp 1327-1347. 16. Tom6 FMS, Gounon P, Collin H: Intranuclear inclusions in oculopharyngeal muscular dystrophy, further studies. Neurology 1989;39(suppl 1):335. 17. Victor H, Hayes R, Adams RD: Oculopharyngeal muscular dystrophy: a familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 1962;207:1267- 1272. 18. Zeriani M, Moraes CT, Nakase H, Bonilla E, Schon EA, Rowland LP: Deletions of mitochondrial DNA in KearnsSayre syndrome. Neurology 1988;38:1339- 1346. 1
,
MUSCLE & NERVE
October 1991
