Mitochondrial myopathy with multisystem abnormalities and normal ocular movements

39

Journal of the neurolo.qical Sciences, 1975, 24:39 52 ¢~, Elsevier Scientific Publishing Company, A m s t e r d a m

Printed in The Netherlands

Mitochondrial Myopathy with Multisystem Abnormalities and Normal Ocular Movements J. G. McLEOD, W. DE C. BAKER, C. D. SHOREY A ~ C. B. KERR Departments 0[' Medicine and Electron Microscopy Unit. Universi O, o['Sydney, and Prince of Wales Hospital. Sydney, N.S. W. (Australia ) (Received 17 June, 1974)

INTRODUCTION

Engel (1971) and Olson, Engel, Walsh and Einaugler (1972) drew attention to the presence of "ragged-red" fibres in the muscle biopsies of some patients with progressive external ophthalmoplegia. These "ragged-red" fibres are seen in modified trichrome stains (Engel and Cunningham 1963) and consist of subsarcolemmal collections of normal and abnormal mitochondria and lipid droplets. In 4 of their 7 patients with ophthalmoplegia Olson et al. (1972) noted other abnormal clinical and laboratory features which included short stature, ataxia, retinal degeneration, sensori-neural deafness, elevated cerebrospinal fluid (CSF) protein, abnormal electroencephalogram (EEG) and electrocardiogram (ECG). Similar abnormalities had been previously described in patients with progressive external ophthalmoplegia by Kearns and Sayre (1958), Shy, Silberberg, Appel, Mishkin and Godfrey (1967) and Drachman ( 1968 ) and the subject has been recently reviewed by Karpati, Carpenter, Larbrisseau and Lafontaine (1973). The purpose of the present report is to describe a patient with this rare syndrome which is usually associated with ophthalmoplegia, but in whom the ocular movements were entirely normal. Twenty-three percent of fibres seen on muscle biopsy had a "ragged-red" appearance, and mitochondrial abnormalities were found on electron microscopy. CASE REPORT K.S. (R.P.A.H. 335148), a w o m a n aged 27 years, was admitted to hospital following an epileptic seizure on 1 September, 1971. She was mentally retarded. There was no family history of neuromuscular disease; 2 sisters and 3 brothers were normal. She lived with foster-parents, and little information was obtainable about her early development. At the age of 8 years she was able to walk normally and to talk, although her Reprint requests to J. G. McLeod, Department of Medicine, University of Sydney, Sydney, N.S.W. 2006, Australia.

40

J . G . MCLEOD, W. I)E ('. BAKER, ( . D. SHOREY, ( . B. KERR

vocabulary was limited. She learned to read and to write. She developed secondary sexual characteristics. but had never menstruated. Her progress was otherwise uneventful until about 6 m o n t h s prior to admission when she appeared to become more dull and withdrawn, and to be clumsy and unsteady On her feet. She was brought to hospital following 3 major focal epileptic seizures. On physical examination, the patient was mentally retarded: on the Wechsler scale, her intelligence was equivalent to that of a normal 5-year-old child. She had a limited vocabulary and could read and write in a childish manner. She had a round face, with a small mandible. Height was 137 cm. Head circumference 50.5 cm. Weight 36.5 kg. Breasts were normally developed but pubic and axillary hair were scanty. There were no skeletal deformities. Palmar creases and dermatoglyphics were normal. Cardiovascular system was normal: blood pressure was t30/85 m m Hg. Visual acuity was normal in both eyes. Ophthalmoscopic examination revealed a disscmit;ated ehoriore~ tinitis in both fundi, and a post-cortical cataract in the left eye. Pupils were equal, central, circular, and reacted briskly to light and accommodation. Extraocular m o v e m e n t s were full, and there was no nystagmus. There was a mild degree of facial weakness. There was moderate bilateral sensori-nem al deafness, particularly for high frequencies. Other cranial nerves were all intact. There was no definite muscle wasting~ There was a mild generalized weakness of air muscle groups, but particularly of the shoulder and pelvic girdle musculature. She was unable to rise unaided from a chair. Coordination was normal in the upper limbs. R o m b e r g ' s test was negative. She had ~; wide-based, clumsy gait and was unable to walk heel-to-toe. Deep tendon reflexes were all present, and were increased in the right upper and lower limbs. Plantar responses were flexor. There were no sensor~ abnormalities.

Laborato O, investigations Haemoglobin concentration, white cell count, erythrocyte sedimentation rate, and urinalysis were all normal. Serum sodium, potassium, chloride, bicarbonate, calcium, phosphate, albumin, globulin, cholesterol, creatinine, bilirubin, alkaline phosphatase, lactate, creatine phosphokinase, glutamic and pyruvic oxaloacetic transaminase and lactic dehydrogenase were normal. Blood glucose, urea nitrogen, and uric acid were also within the normal range. Urinary amino-acid screening was negative. Plasma electrophoresis, and serum immunoglobulins were normal. There was a mildly diabetic response to a 5-hour glucose tolerance test. Plasma cortisol levels were 17.8 gg/100 ml and 12.6 #g/100 ml at 10 a.m. and 10 p.m. respectively. Serum thyroxin was 4.4 #g/100 ml (normal range 4.3 7.3 #g/100 ml). Plasma luteinizing h o r m o n e level was at the lower limit of the normal range. Growth hormone levels were normal and there was a normal response to insulin hypoglycaemia. Serological studies, including blood and CSF W a s s e r m a n reaction, cytomegalo-virus complement fixation test, toxoplasmosis haemaglutination and complement fixation tests, and Australia antigen titres were negative. E C G : Sinus rhythm. Intraventricular conduction defect. Radiological studies of chest and skull were normal. Bone age on radiological skeletal ,~urvey was consistent with the chronological age. The CSF was under normal pressure. There was 1 l y m p h o c y t e / m m 3. CSF protein was 347 rag/100 mt and, when repeated 2 weeks later, was 218 rag/100 ml. There was increased lgA, l g M anda-glycoprotein. CSF glucose was 65 rag/100 ml. An EEG showed generalized slow wave abnormalities with no focal features. Bilateral carotid arteriograms were normal. Pneumoencephalography revealed a minor degree of ventricular dilatation but no other abnormality. Electromyography (EMG) was performed on biceps, triceps, quadriceps and tibialis anterior muscles. There was no spontaneous fibrillation. On voluntary effort, n u m e r o u s highly polyphasic units containing brief components of short duration and with an amplitude of less than 2 3 mV were recorded. Motor and sensory conduction and mixed nerve action potentials in median, ulnar and lateral popliteal nerves were within the normal range. C h r o m o s o m e studies performed on blood and on skin fibroblast cultures were normal.

MATERIALS AND METHODS

Histological techniques Muscle biopsy was performed on the right vastus lateralis under general anaesthesia. Specimens were prepared for paraffin sections, frozen sections and electron microscopy. The tissues for paraffin sections were fixed in 5"~ neutral formol-saline,

MITOCHONDRIAL MYOPATHY WITH MULTISYSTEM ABNORMALITIES

41

dehydrated in alcohol and embedded in paraffin wax. Five-pm sections were cut and were stained with haematoxylin and eosin (HE), and Gomori trichrome. Frozen sections were prepared by fixing the tissue to small plastic blocks with gum tragacanth and freezing with isopentane cooled to -160°C with liquid nitrogen. Sections cut to 10 #m in a cryostat were stained with HE, trichrome modified for frozen section (Engel and Cunningham 1963), reticulin counterstained with HE, periodic acid-Schiff (PAS), fettrot for fat, succinic dehydrogenase (Pearse 1961), myosin adenosine triphosphatase (myosin ATPase) by the method of Padykula and Herman (1965) and reversed myosin ATPase (Drews and Engel 1966). Fibre diameter curves were prepared by projecting sections stained with reversed ATPase at a magnification of x 400 and measuring the minimal diameter to the nearest 10 #m of the drawn outlines of the fibres. The fibre types were identified on the reversed ATPase sections at the same time. The "ragged-red" fibres were identified on the modified trichrome stain under the microscope and marked on the fibre diagram.

Electron microscopy Tissue for electron microscopy was sutured to a short length of swab stick before excision. It was fixed immediately in ice-cold 1~/o osmium tetroxide in Palade buffer, stained for 45 min in 4 ~ uranyl acetate in Palade buffer, dehydrated in alcohol and embedded in araldite. Sections were cut on an LKB ultramicrotome, stained with lead (Reynolds 1963) and examined on a Philips 300 electron microscope. RESULTS

Muscle Pathology Light microscopy The muscle showed no increase in fibrous tissue or interstitial fat. The most prominent feature in sections stained with the modified trichrome stain was the presence of scattered fibres with subsarcolemmal and intermyofibrillar collections of coarse, granular, red material ("ragged-red" fibres) (Engel 1971; Olson et al. 1972) (Fig. 1). Succinic dehydrogenase stained the same regions densely (Fig. 2). Nearly all the fibres which showed this change were Type I, and these "ragged-red" fibres represented 23 "~, of the total number of fibres in the muscle sections. In many fibres there was a considerable increase in the amount ofintracellular lipid material, which was present in abnormally large droplets. The fibres containing lipid droplets could be identified readily on the ATPase, modified trichrome, and in HE stains by the presence of small, sharplyoutlined round holes which were quite distinct from ice crystals. The large fat droplets were most prominent in Type I fibres, but were also observed in Type II fibres, they were only rarely seen in "ragged-red" fibres. Fibre diameters were measured on Type I, Type II, and "ragged-red'" fibres (Fig. 3). The diameter of Type I fibres and "ragged-red'" fibres were identical (range 15 #m 75/~m; mean 44.7/~m). The range of fibre diameters for Type II fibres was 5 /~m-75/tm (mean 36.1/~m). The figures are in the lower normal range (Brooke and Engel 1969).

42

J. G. MCLEOD, W. DE C, BAKER, C. D. SHOREY, (:. B. KERR

Fig. 1. Ragged-red fibre. There is a wide subsarcolemmal zone of granular red-staining material (arrow). Frozen section, Modified trichrome stain, × 800.

Electron microscopy The abnormalities consisted of excess lipid and groups of mitochondria containing empty spaces and paracrystalline inclusions (Figs. 4-7). These abnormalities were usually subsarcolemmal in distribution (Fig. 4) but were sometimes also intermyofibrillar (Fig. 7). The paracrystalline inclusions were made up of parallel bands of amorphous material surrounded by a single membrane. In some inclusions the surrounding membrane continued beyond the amorphous material as a double membrane (Fig. 5). A variant of this appearance was seen in some mitoch ondria where the peripheral double membrane was distended with amorphous material. The inner membrane was commonly serrated as though producing vestigeal cristac (Fig. 6). Moderate numbers of mitochondria contained spaces which were surrounded by a double membrane and appeared empty (Figs. 4, 5, 7). The nature of these spaces was not clear; they were less electron-dense than the lipid in the vicinity of the mitochondria and they did not appear to be invaginations.

MITOCHONDRIAL MYOPATHY WITH MULTISYSTEM ABNORMALITIES

43

Fig. 2. Mitochondrial accumulations staining densely with succinic dehydrogenase. Frozen section, × 800.

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44

J. (;. MCLEOI), W. I)E C. BAKER, ('. D. SHOREY, C. P;. KI!RP,

Fig. 4. Subsarcolemmal accumulations of mitochondria. Paracrystalline inclusions and cWar spaces are present in many mitochondria. ×, 27,000.

MITOCHONDRIAL MYOPATHY WITH MULTISYSTEM ABNORMALITIES

45

Fig. 5. A group of mitochondria, one of which contains paracrystalline inclusions from which the surrounding membrane continues as a double m e m b r a n e (arrow). Others contain apparently empty spaces surrounded by a double membrane. No normal cristae are visible, x 35,000.

DISCUSSION

The most striking histopathological feature of the muscle on light microscopy was the presence in 23 '); of fibres of subsarcolemmal and intermyofibrillar granular material which appeared red with the modified trichrome stain. Engel (1971) and Olson et al. (1972) used the term "ragged-red" fibres to describe fibres in which such abnormalities were present, and state that in normal muscle the proportion of "ragged-red" fibres is less than 0.1%. In the present case, as in the cases of Olson et al. (1972) and other cases of mitochondrial myopathy, the abnormalities were confined mainly to Type I fibres (Shy, Gonatas and Perez 1966; Hulsmann, Bethlem, Meijer, Fleury

46

J . G . MCLEOD, W. I)E ('. BAKER, C. D. SHOREY, C, 1~;, KERR

Fig. 6. A subsarcolemmal collection of elongated mitochondria containing paracrystal!ine inclusions which are apparently produced by an accumulation & m a t e r i a l between the peripheral membranes (arrow). The inner m e m b r a n e s appear serrated, x 47.000.

MITOCHONDRIAL MYOPATHY WITH MULTISYSTEM ABNORMALITIES

Fig. 7. A b n o r m a l mitochondria associated with an excess of lipid (L). x 27,000.

47

48

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M C L E O D , W . DE C. B A K E R , C. D. S H O R E Y , ( ' . B. K E R R

and Schellens 1967; Price, Gordon, Munsat and Pearson 1967; Van Wijngaarden, Bethlem, Meijer, Hulsmann and Feltkamp 1967: D'Agostino, Ziter, Rallison and Bray 1968; Bradley, Hudgson, Gardner-Medwin and Walton 1969: Fisher and Danowski 1969; Schellens and Ossentjuk 1969; Buscaino, De Giacomo and Mazzarella 1970; Castaigne, Laplane, Fardeau, Dordain, Autret and Hirt 1972 ; Jerusalem, Angelini, Engel and Groover 1973). The most notable ultrastructural abnormalities were seen in the mitochondria which tended to be aggregated in clusters in subsarcolemmal regions. Many were increased in size and were abnormal in shape. In some mitochondria empty spaces were seen between the cristae, and paracrystalline laminated inclusions were also present. These abnormalities are similar to those described in other reported cases of mitochondrial myopathy (Luft, Ikkos, Palmieri, Ernster and Afzelins 1962; Shy et al. 1966; Gonatas, Evangelista and Martin 1967: Hulsmann e t a / . 1967: Price et al. 1967; Shafiq, Milhorat and Gorycki 1967; Van Wijngaarden el al. 1967: D'Agostino et al. 1968; Bradley et al. 1969; Fisher and Danowski 1969; Schellens and Ossentjuk 1969; Buscaino et al. 1970; Sluga and Moser 1970 ; Spiro, Prineas and Moore 1970; Salmon, Esiri and Ruderman 1971; Lapresle, Fardeau and GodetGuillain 1972; Hudgson, Bradley and Jenkinson 1972; Afifi, Ibrahim, Bergman, Abu Haydar, Mire, Bahuth and Kaylami 1972; Castaigne et al. 1972; Olson et at. t972: Jerusalem et al. 1973 ; Morgan-Hughes and Mair 1973 ; Karpati et al. 1973 : Schneck, Adachi, Briet, Wolintz and Volk 1973). Mitochondrial abnormalities may be seen in a variety of neuromuscular disorders which include Duchenne muscular dystrophy (Mair and Tom6 1972), hypothyroid myopathy (Norris and Panner 1966), periodic paralysis (Schutta and Armitage 1969), polymyositis (Chou 1967; Shafiq et al. 1967 ; Mair and Tom6 1972), spinal muscular atrophy (De Recondo, Fardeau and Lapresle 1966; Shafiq et al. 1967), and steroid myopathy complicating McArdle's disease (Mastaglia, McCollum, Larson and Hudgson 1970). They have also been reported in two patients with hypermetabolism and muscle wasting (Ernster, Ikkos and Luft 1959; Afifi et al. 1972) and in an increasing number of patients with external ophthalmoplegia and ptosis (Zintz and Villiger 1967; Shy et al. 1967; Lessell, Kuwabara and Feldman 1969; Sluga and Moser 1970; Olson et al. 1972; Castaigne et al. 1972 ; Di Mauro, Schotland, Bonilia, Lee, Gambetti and Rowland 1973; Morgan-Hughes and Mair 1973; Karpati et al. 1973; Schneck et al. 1973). The other cases of mitochondrial myopathy are a heterogeneous group in which there is no clearly-defined pattern of clinical features. The age of onset is variable; in most cases the muscle weakness was evident at birth or in the first decade (Shy et al. 1966; Price et al. 1967 ; Hulsmann et al. 1967; Van Wijngaarden et at. t967 : D'Agostino et al. 1968; Schellens and Ossentjuk 1969; Buscaino et al. 1970; Spiro et al. 1970; Jerusalem et al. 1973) but in some cases the onset was in adult life (Bradley et al. 1969 ; Fisher and Danowski 1969). Muscle weakness and wasting are commonly proximal (Shy et al. 1966; Bradley et al. 1969; Spiro et al. 1970) but may have a facioscapulo-humeral (Hudgson et al. 1972) or distal (Lapresle et al. 1972) distribution or may be generalized (Jerusalem et al. 1973). Muscle cramps (Buscaino ~,~ a/. 1970), episodic weakness (Shy et al. 1966; Price et al. 1967; Schellens and Ossentjuk 1969), and salt craving (Shy et al. 1966: Sprio et al. 1970) have been additional features in some cases.

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MYOPATHY

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peripheral neuropathy epilepsy

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50

J. G. MCLEOD, W. 1)E C. BAKER. C. D. SHOREY, ('. B. KERR

Most of the reported cases of mitochondrial myopathy have been sporadic, like the present case, but in several the disorder was also present in siblings (Shy et al. 1966 ; Shafiq et al. 1967: D'Agostmo et al. 1968); 1 was the child of a consanguineous marriage (Bradley et al. 1969), and in 3 families there has been an autosomal dominant mode of inheritance (Buscaino et al. 1970; Hudgson et al. 1972; Lapresle ~,~al. 1972). In our patient, features additional to myopathy included short stature~ mental retardation, seizures, bilateral chorioretinitis, sensorineural deafness, ataxia, elevated CSF protein, abnormal carbohydrate metabolism, diffuse EEG abnormalities, and an abnormal ECG. These features have been observed in some patients with progressive external ophthalmoplegia associated with mitochondrial myopathy (Table 1). Short stature and cardiac abnormalities have been noted in some other patients with mitochondrial myopathy without external ophthalmoplegia (D'Agostino et al. 1968 : Fisher and Danowski 1969), and the occurrence of seizures and mental retardation has also been observed (Van Wijngaarden et al. 1967; D'Agostino c~, al. 1968). However, retinal degeneration, deafness and ataxia have not been reported previously in patients without external ophthalmoplegia. Elevated CSF protein is not an uncommon finding in progressive external ophthalmoplegia (Shy eta/. 1967 ; Olson e t a / . 1972 ; Karpati et al. 1973 ; Schneck et al. ! 973) but has not previously been noted in patients with mitochondrial myopathy and normal ocular movements. In ore; patient the IgA and IgM fractions were increased in the CSF but immunoglobulin levels were normal in the blood. In the only other patients in whom immunoglobulin levels were reported on blood and CSF, lgA, IgG and IgM fractions were increased in CSF and the IgA fraction was increased in the blood (Karpati et al. 1973). It seems probable that these abnormalities are non-specific. The possibility that our patient may develop ophthalmoplegia at a later stage in life cannot be excluded~ but it seems unlikely since ptosis and ocular paralysis are usually the earliest symptoms (Olson et al. 1972; Karpati et al. 1973). Mitochondrial abnormalities have been reported in liver (Gonatas ~,t al. t967), cerebellum (Schneck et al. 1973) and skin (Karpati et al. 1973) in addition to those present in muscle. In view of the frequent clinical and pathological involvement of tissues other than muscle in the mitochondrial myopathies, it seems likely that muscle disease is only one manifestation of a more widespread disturbance of tissue metabolism.

SUMMARY

A woman aged 27 years is described with mental retardation, short stature, epilepsy, muscle weakness, chorioretinitis, nerve deafness, ataxia, abnormalities of the electroencephalogram and electrocardiogram, elevated cerebrospinal fluid protein and abnormal carbohydrate metabolism. There was no ophthalmoplegia. Histopathological studies on quadriceps muscle biopsy demonstrated a high proportion of Type I fibres with subsarcolemmal collections of granular material (-ragged-red'" fibres). There was also an increase in intracellular lipid. On electron microscopy, abnormal mitochondria containing paracrystalline inclusions were seen predominantly in subsarcolemmal regions. The patient differs from other cases of mitochondrial

MITOCHONDRIAL MYOPATHY WITH MULTISYSTEM ABNORMALITIES

51

myopathy with this syndrome in having normal ocular movements. Muscle disease in such cases appears to be only one manifestation of a more widespread disorder of tissue metabolism. REFERENCES AHFI, A. K., M. Z. M. IBRAHIM,R. A. BERGMAN,N. ABU HAYDAR, J. MIRE, N. BAHUTH AND F. KAYLAMI (1972) Morphologic features of hypermetabolic mitochondrial disease, J. neurol. Sei., 15:271 290. BRADLEY, W. G., P. HUDGSON, D. GARDNER-MEDW1N AND J. N. WALTON (1969) Myopathy associated with abnormal lipid metabolism in skeletal muscle, Lancet, 1 : 495498. BROOKE, M. H. AND W. K. ENGEL (1969) The histographic analysis of human muscle biopsies with regard to fiber type, Part l (Adult male and female), Neurology (Minneap.), 79:221 233. BUSCAINO, G. A., P. DE GIACOMOAND L. MAZZARELLA(1970) TWO cases of so-called "mitochondrial myopathy". Preliminary report. In: N. CANAL,G. SCARLATOAND J. N. WALTON (Eds.), Muscle Diseases {Proceedings of an International Congress on Muscle Diseases, Milan, May 1969) (International Congress Series, No. 199), Excerpta Medica, Amsterdam, pp. 112-115. CASTAIGNE, P., D. LAPLANE, M. FARDEAU,G. DORDAIN, A. AUTRET AND L. HIRT (1972) Myopathies avec anomalies mitochondriales localisOes aux fibres de type I, Rev. neurol. 126:81 96. CHOU, S. M. (1969) "Megaconial" mitochondria observed in a case of chronic polymyositis, Acta neuropath. (Berl.), 12:68 89. D'AGOSTINO, A. N., F. A. ZITER,M. L. RALLISONAND P. F. BRAY(1968) Familial myopathy with abnormal muscle mitochondria, Arch. Neurol. (Chic.), 18:388 401. DE RECONDO,J., M. FARDEAUAND J. LAPRESLE(1966) Etude au microscope 61ectronique des 16sions musculaires d'atrophie neurog6ne par atteinte de la corne ant6rieure, Rev. neurol., 114: 169-192. DI MAURO, S., D. L. SCHOTLAND, E. BONIL1A,C.-P. LEE, P. GAMBETTIAND L. P. ROWLAND (1973) Progressive ophthalmoplegia, glycogen storage, and abnormal mitochondria, Arch. Neurol. (Chic.),29:170 179. DRACHMAN, D. A. (1968) Ophthalmoplegia plus. The neurodegenerative disorders associated with progressive external ophthalmoplegia, Arch. Neurol. (Chic.), 18: 654-674. DREWS, G. A. AND W. K. ENGEL (1966) Reversal of the ATP-ase reaction in muscle fibres by EDTA, Nature (Lond.), 212: 1551-1553. ENGEt., W. K. (1971) "Ragged-red" fibres in ophthalmoplegia syndromes and their differential diagnosis. In : B. A. KAKULAS(Ed.), Muscle Diseases and their differential diaynosis. (Abstracts of Papers presented at the 2nd International Congress on Muscle Diseases, Perth, 1971 ) (International Congress Series, No. 237), Excerpta Medica, Amsterdam, p. 28. ENGEL, W. K. AND G. G. CUNNINGHAM(1963) Rapid examination of muscle tissue. An improved trichrome method for fresh frozen biopsy sections, Neuroloyy (Minneap.), 13 : 919-923. ERNSTER, L., D. IKKOS AND R. LUFT (1959) Enzymatic activities of human skeletal muscle mitochondria: a tool in clinical metabolic research, Nature (Lond.), 184:1851 1854. FISHER, E. R. AND T. S. DANOWSKI (1969) Mitochondrial myopathy, Amer. J. clin. Path., 51 : 619-630. GONArAS, N. K., I. EVANGELISTAAND J. MARTIN (1967) A generalized disorder of nervous system, skeletal muscle, and heart resembling Refsum's disease and Hurler's syndrome, Part 2 (Ultrastructure), Amer. J. Med., 4 2 : 1 6 9 178. HUDGSON, P., W. G. BRADLEYAND M. JENKINSON(1972) Familial "'mitochondrial" myopathy. A myopathy associated with disordered oxidative metabolism in muscle fibres, Part 1 (Clinical, electrophysiological and pathological findings), J. neurol. Sci., 16: 343-370. HULSMANN, W. C., J. BETHLEM,A. E. F. H. MEIJER, P. FLEURYAND J. P. M. SCHELLENS(1967) Myopathy with abnormal structure and function of muscle mitochondria, J. Neurol. Neurosurg. Psychiat.. 30: 519 525. JERUSALEM,F., C. ANGELINI, A. G. ENGEL, AND R. V. GROOVER(1973) Mitochondria-lipid-glycogen (MLG) disease of muscle, Arch. Neurol. (Chic.), 29:162 169. KARPATI, G., S. CARPENTER, A. LARBRISSEAUAND R. LAFONTAINE(1973) The Kearns Shy syndrome. A multisystem disease with mitochondrial abnormality demonstrated in skeletal muscle and skin, J. neurol. Sci., 19:133 151. KEARNS, T. P. AND G. P. SAYRE(1958) Retinitis pigmentosa, external opthalmoplegia and complete heart block, Arch. Ophthal., 60:280 289. LAPRESLE, J., M. FARDEAUAND J. GODET-GU1LLAIN (1972) Myopathie distale et cong6nitale, avec hypertrophie des mollets, J. neuroL Sci., 17:87 102. LESSELL, S., T. KUWAaARAAND R. G. FELDMAN(1969) Myopathy and succinylcholine sensitivity, Amer. J. Ophthal., 68:789 796.

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J . G . MCLEOD, W. DE C, BAKER, C. D. SHOREY, (:. B. KERR

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