Journa! of

J. Neurol. 22 l, 25--37 (1979)

tq ro y © by Springer-Verlag 1979

Progressive Extrinsic Ophthalmoplegia with Peripheral Neuropathy and Storage of Muscle Glycogen M. Moggio, G. Valli, C. Cerri, G. Scarlato, and G. Pellegrini Department of Neurology, Medical School of the University of Milan, Milan, Italy

Summary. A case of progressive extrinsic ophthalmoplegia associated with peripheral neuropathy and hypertriglyceridemia type IV is described. Motor and sensory conduction velocities of the spinal nerves were severely decreased, while the EMG of the facial muscles was more suggestive of a myopathic disorder. Electron microscopic study of biopsies of biceps and peroneus brevis muscles disclosed many ragged red fibers, mainly type I, which contained typical abnormal mitochondria. Other fibers, all type II, contained increased amounts of glycogen between myofibrils or beneath the sarcolemmal membrane, but the mitochondria were normal. These fibers were more abundant in the peroneus brevis than in the biceps muscle. Nerve biopsy revealed marked loss of myelinated fibers, but neither mitochondrial changes nor glycogen storages were evident in Schwann's ceils. Biochemical investigations confirmed the increased amount of glycogen in both muscle biopsies and revealed a decrease of guanilcyclase. Phosphorylase, phosphorylase b kinase, adenilcyclase, and carnitine concentrations were all normal. The pathogenesis of this syndrome is discussed and the relationship between mitochondrial abnormalities and glycogen accumulation in muscle tissue are considered.

Key words: Ophthalmoplegia plus - Peripheral neuropathy - Glycogen storage, ophthalmoplegia plus - Polyneuropathy, ophthalmoplegia plus Mitochondria, abnormal. Zusammenfassung. Beschreibung eines Falles von Ophthalmoplegia externa mit Polyneuropathie und einer Hypertriglyzerid~imie vom Typ IV. Hochgradige Verlangsamung der motorischen und sensiblen Erregungsleitung im peripheren Nerven. Im Gesicht war das Ergebnis der Nadelmyographie eher auf Myopathie verd/ichtig. Address for offprint requests: Dr. G. Pellegrini, Clinic of nervous disease, Via F. Sforza No. 35, I-Milan, Italy

0340-5354/79/0221/0025/$ 02.60

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M. Moggio et al. In der Biopsie des Muscutus biceps und Musculus peronaeus brevis zeigten sich zahlreiche ,,ragged red fibers", vorwiegend vom Typ I, die im elektronenmikroskopischen Bild abnorme Mitochondrien enthielten. Andere Fasern, s/~mtliche vom Typ II, wiesen einen erh6hten Glykogengehalt zwischen den Myofibrillen oder Subsarkolemmal auf, w/~hrend die Mitochondrien normal erschienen. Diese letztgenannten Fasern waren zahlreicher im Musculus peronaeus brevis. Die Nervenbiopsie zeigte einen ausgesprochenen Verlust an myelinisierten Fasern, jedoch waren in den Schwannschen Zellen weder Anomalie der Mitochondrien noch Glykogenspeicherung sichtbar. Biochemische Untersuchungen best/itigten den vermehrten Glykogengehalt in beiden Muskelbiopsien und zeigten eine Verminderung der Guanilzyklase. Hingegen waren Phosphorylase, Phosphorylase-b-Kinase, Adenilzyklase und Karnitin in normaler Konzentration vorhanden. Es wird die Pathogenese des Syndromes diskutiert und die Beziehung zwischen den mitochondrialen Anomalien und der Vermehrung des Glykogens im Muskelgewebe besprochen.

Introduction

"Ophthalmoplegia plus" (Drachman, 1968) or "oculo-cranio-somatic neuromuscular disease" (Olson et al., 1972) is a complex syndrome that includes a great variety of clinical and pathological manifestations (Kearns and Sayre, 1958; Daroff et al., 1966; Drachman, 1968; Gonatas et al., 1967; Schneck et al., 1973; Karpati et al., 1973). Nosological limits of this entity are rather uncertain (Berenberg et al., 1977). Familial cases are very few. In "the family studied by Tamura et al. (1974), the disease seems to have been transmitted as an autosomal recessive trait, but in the familial cases described by Lashner et al. (1978), the pattern of inheritance is an autosomal dominant. The wide spectrum of the disease in the last family is particularly evident and is in favor of the hypothesis that the various clinical associations must be considered as different expression of a single genetic defect. Electron microscopic study of the muscle biopsy revealed ragged red fibres and mitochondriat abnormalities. A similar mitochondrial pathology may be present in liver cells (Gonatas et al., 1967), in sweat gland (Karpati et al., 1973) and cerebellar tissue (Schneck et al., 1973). In four patients with an ophthalmoplegic type of muscular dystrophy, Sluga and Moser (1970) observed storage of glycogen in muscle tissue associated with mitochondrial abnormalities. A similar observation has been made by Di Mauro et al. (1973). Whether these mitochondrial alterations are primitive or secondary to an unknown metabolic defect is still an open question. Undoubtedly they are nonspecific since they can be encountered in a great variety of neuromuscular diseases. Nevertheless, Morgan-Hughes et al. (1977) reported a case ofmyopathy with similar mitochondrial abnormalities in which a primitive deficiency of mitochondrial cytochrome b was demonstrated. This is the report of a case of progressive extrinsic ophthalmoplegia with peripheral neuropathy, hypoacusis and type IV hypertriglyceridemia (Fredrickson, 1967). In addition to the ragged red

Progressive Extrinsic Ophthalmoplegia

27

fibers the muscle biopsy revealed large amounts of glycogen, especially in subsarcolemmal spaces, and in muscle fibres without mitochondrial alterations.

Case History A man of 43 years had progressive bilateral ptosis and limitation of lateral eye movements for 15 years. On some occasions he noted diplopia. He never complained of dysphagia. At the age of 36 years he complained painful cramps of brief duration in the sural, abdominal, trapezius and lateral muscles of the neck, especially after muscular effort, muscular strength was preserved. At the age of 40 years he noted bilateral paracusis without hearing loss.

Physical Examination The patient was a slender man, height: 167 cm, weight: 45 kg. Cardiac rhythm and frequency were normal. The liver was slightly enlarged. There was bilateral ptosis and weakness of opening and closing the lids. Ocular movements were severely limited in all directions. The pupils were equal with normal reflex to light. The facial muscle were slightly weak. There was neither dysphagia nor dysphonia and movements of the soft palate appeared normal. Flexion of the neck was moderately weak; there was generalized muscular wasting with winged scapulae and mild weakness of the shoulder muscles. All other muscle groups had normal strength. Deep tendon reflexes were absent in all four limbs. There was slight impairment of superficial sensation in the distal part of the limbs. There were no pathological reflexes.

Laboratory Results The following investigations were within normal limits: hemogram, erythrocyte sedimentation rate, blood urea, fasting blood sugar, glucose tolerance test, serum electrolytes, protein electrophoresis, platelet counts, thyroid function, phytanic acid, uric acid, serum creatine phosphokinase and aldolase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase, cholesterol F.F.A., glucagone, and adrenaline gave rise to a normal increase of blood glucose. CSF was also normal. The following tests were abnormal: total lipids, in various determination, were between 1120 and 1280mg% (n.v. 400-1000mg%), triglycerides were between 262 and 700mg% (n.v. 7 4 - 1 7 2 m g % ) , plasma lipoprotein electrophoresis: VLDL: 52.4mg% (n.v. 1 2 - 2 9 m g % ) ; LDL: 73.6mg% (n.v. 76-145 mg%); H D L : 3 4 m g % (n.v. 2 2 - 7 0 m g % ) ; serum bilirubin: 120mg%; lactic acid: 29.7mg% (n.v. 9 - 1 6 m g % ) . X-rays of the cranium and of the thorax were normal. The E E G showed brief bursts of theta activity in the extraoccipital regions. The vector cardiogram was normal. Audiometric examination revealed bilateral perceptive pantonal hypoacusis. The retinas contained no abnormal pigment and the E R G was normal.

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M. Moggio et al.

Electrophysiological Studies The nerve conduction study showed marked slowing of the common peroneal nerve motor conduction velocity (25 m/s); the compound action potential of the extensor digitorum brevis muscle was 4.2 mV stimulating the nerve at the ankle, and 3.2mV stimulating the nerve at the knee, with a decrement of 24%. The latencies of the sensory action potential (SAP) of the median and ulnar nerves were also prolonged (4.3 ms in both nerves), while their amplitude was near the normal limits (7 and 9 taV, respectively). Repetitive supramaximal stimulation of the ulnar nerve at 2 and 5 Hz, did not show significant decrement of the compound action potential, recorded from the abductor digiti minimi, and this potential had normal amplitude (12mV). Needle electromyography, carried out in I interosseus, tibialis anterior and vastus medialis muscles at rest, revealed rare fibrillation and fasciculation potentials; the motor unit potentials (MUP), voluntarily recruited, were moderately diminished in number and showed an evident increase of amplitude and duration. The EMG findings were completely different in the facial muscles; there were no fibrillation potentials and the MUPs were mostly short and polyphasic, recruited in an early interference pattern during submaximal voluntary contraction. In conclusion the neurophysiological studies were indicative of a demyelinating motor and sensory polyneuropathy in the spinal nerves, while in the facial muscles the findings were more suggestive of myopathic disease.

Morphological Studies Muscle Biopsies. Two biopsies were obtained from the left biceps and from the left peroneus brevis muscles, both under local anesthesia. Cryostat sections were prepared and a battery of histological and histochemical reactions were performed (hematoxylin and eosin, modified trichrome, nicotinamide adenine nucleotide dehydrogenase (NADH), succinic dehydrogenase (SDH), ATPase pH 9.4--4.6--4.3, PAS, phosphorylase, acid phosphatase and oil red 0). Samples of both muscles were fixed in 2.5% glutaraldehyde buffered at pH 7.4 with cacodylate buffer and post-fixed in 2% buffered osmium tetroxide. The material was embedded in Spurr. Thin sections for electron microscopy were stained with uranyl acetate and lead citrate.

Histology and Histochemistry. With a modified Gomori trichrome method many muscle fibres had the appearance of ragged red fibers (Fig. 1). These fibers were much more numerous in the biceps muscle than in the peroneus brevis and gave intense reactions with succinic dehydrogenase (Fig. 2), NADH-tetrazoliumreductase, PAS and oil red 0; ATPase reactions demonstrated that these ragged red fibers were type I (Fig. 3). Beside these fibers there were others, particularly abundant in the peroneus brevis, which had large subsarcolemmal areas filled with PAS-positive material (Fig. 4). These areas were devoided of granular red material by modified trichrome stain and gave no reaction with ATPase (Fig. 5), SDH (Fig. 6), N A D H , menadione linked a-glycerophosphate dehydrogenase

Progressive Extrinsic Ophthalmoplegia

29

Fig. 1. Collection of red material in subsarcolemmal area of muscle fiber (ragged red fiber). Biceps muscle. Trichrome Gomori, x 450 Fig. 2. Serial section. Increase of SDH activity in ragged red fibers. Biceps muscle, x 450 Fig. 3, Serial section. The ragged red fibers are all type I. Biceps muscle, ATPase pH 9.4, × 450 Fig. 4. Accumulation of PAS-positive material in two nonragged red fibers, both type II. Peroneus brevis muscle. PAS, × 450

(Fig. 7) and oil red 0. These fibers were all type II. In both biopsies there was evident type grouping and a predominance of type I fibers (Fig. 8).

Electron Microscopy. Ultrastructural examination revealed severe mitochondrial changes in the ragged red fibers. Mitochondria abnormal in number and shape were present between the myofibrils and under the subsarcolemmal space, often containing single or multiple crystalloid inclusions (Fig. 9). Sometimes the cristae were proliferated and concentrically placed (Fig. 10). Pathological aggregates of glycogen granules and lipid droplets, were present among the mitochondria.

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M. Moggio et al.

Fig. 5. Serial section. Absence of ATPase reaction inside PAS-positive areas. Peroneus brevis muscle. ATPase pH 9.4, x 450 Fig. a. Serial section. Absence of SDH reaction areas. Peroneus brevis muscle. SDH, x 450 Fig. 7. Serial section. Menadione linked a-glycerophosphate dehydrogenase gave no reaction inside same areas. Peroneus brevis muscle, x 450 Fig. 8. Grouping and predominance of type I fibers in biceps muscle. ATPase pH 9.4, x 250

O t h e r muscle fibers, w i t h o u t m i t o c h o n d r i a l alterations, c o n t a i n e d large a m o u n t s o f glycogen b o t h in s u b s a r c o l e m m a l a n d i n t e r m y o f i b r i l l a r spaces (Fig. 11). These a c c u m u l a t i o n s o f glycogen often caused a r e d u c t i o n o f the n u m b e r a n d size o f myofibrils. T h e r e were t u b u l a r aggregates inside the stored glycogen in a few fibers (Fig. 12).

Nerve Biopsy. A nerve b i o p s y was t a k e n f r o m the left superficial p e r o n e a l nerve; the s a m p l e was fixed a n d included for electron m i c r o s c o p y as previously described.

Histology and Electron Microscopy. The histological e x a m i n a t i o n revealed considerable loss o f m y e l i n a t e d fibers (Fig. 13). U l t r a s t r u c t u r a l investigation d i d not

Fig. 9. Accumulations of abnormal mitochondria with crystal-like inclusions and glycogen granules beneath sarcolemmal membrane of ragged red fibers, × 25,000

Fig. 10. Clusters of mitochondria with abnormal cristae in ragged red fiber, × 25,000

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M. Moggio et al.

Fig. 11. Glycogen storage between myofibrils in muscle fiber without mitochondrial changes, x 25,000

reveal any abnormality of the axons; Schwann's cells did not contain either mitochondrial abnormalities or glycogen accumulations.

Biochemical Studies

The following determinations were performed on both muscle samples: glycogen (Hammermeister et al., 1965); myophosphorilase (Lyon and Porter, 1969); phosphorylase b kinase (Krebs et al., 1959); adenylcyclase (Canal et al., 1975); guanylcyclase (Cerri et al., 1978); acid maltase (Hudgson et al., 1968); carnitine (Parvine et al., 1977).

Results

Glycogen: I biopsy II biopsy

1.35g% 1.91g%

(n.v. 0.5ml.0) (n.v. 0.5--1.0)

Fig. 12. Tubular aggregates inside large subsarcolemmal collection of glycogen granules. Note absence of mitochondria, x 32,000

Fig. 13. Semithin section of superficial peroneal nerve exhibiting severe diminution ofmyelinated fibers. Toluidine blue, x 250

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M. Moggio et al.

Phosphorylase total: I biopsy II biopsy

1.77 ~tM of Pi/mg NCP/20' 2.55 ~tM of Pi/mg NCP/20'

(n.v. (n.v.

1.3 + 0.5) 1.3 +0.5)

Phosphorylase a: I biopsy II biopsy

0.8 ~tM of Pi/mg NCP/20' 1.0 ~tM of Pi/mg NCP/20'

(n.v. 0.7 +0.1) (n.v. 0.7+0.1)

Phosphorylase B kinase: I biopsy 32.0 laM of Pi/mg NCP/10' II biopsy 14.9 laM of Pi/mg NCP/10'

(n.v. 20-2-_4) (n.v. 20+4)

Guanylcyclase: I biopsy II biopsy

0 (supernatant and particulate) pM/mg/20' 0 (supernatant and particulate) pM/mg/20'

(n.v. 82.5 + 6.3) (n.v. 82.5 + 6.3)

0.40pM/mg NCP/5' (basal) 1.1 pM/mg NCP/5' (NaF activated)

(n.v. 0.66+0.05) (n.v. 1.46+0.2)

19 n M / m g NCP

(n.v. 20--50)

Adenylcyclase: I biopsy

Carnitine: I biopsy

Discussion

The clinical features of our case are similar to those commonly found with ophthalmoplegia plus (Drachman, 1968), though there was no degeneration of the pigment of the retina, no cardiac conduction defects, and no CSF abnormality. It is well known that the clinical features of this syndrome are varied and that not all are present in the same patient, and that clinical symptoms can occur later at different ages. On the other hand in our patient there were associations rarely observed with ophthalmoplegia plus such as peripheral neuropathy, and hyperlipoproteinemia type IV, according to Fredrickson's classification. Polyneuropathy has been described in only ten cases of progressive extrinsic ophthalmoplegia (PEO) (Stephens et al., 1958; Gonatas et al., 1967; Drachman, 1970; Croft et al., 1977). In the four familial cases described by Stephens et al. (1958), heredoataxia was also present and the polyneuropathy was of the Charcot-Marie-Tooth type. In the case published by Gonatas et al. (1967) zebra bodies in the cytoplasm of Schwann's cells were found at the ultrastructural examination. Hyperlipoproteinemia type IV is a common dyslipidemia. We do not know whether this finding is casual in our patient, or due to reduced breakdown of the triglycerides because of the abnormal mitochondria. In this syndrome, in fact, mitochondrial alterations have been found also in liver cells (Gonatas et al., 1967; Okamura et al., 1976; Scarlato et al., 1978), cerebellum neurons (Adachi et al., 1973) and sweat gland (Karpati et al., 1973). The histology, histochemistry and

Progressive Extrinsic Ophthalmoplegia

35

electron microscopy revealed the characteristic features observed in ophthalmoplegia plus, such as ragged red fibers and mitochondrial abnormalities (Engel, 1971; Olson et al., 1972). In our case an unusual finding was the increased concentration of glycogen, not only in the ragged red fibers, but also in many type II muscle fibers without mitochondrial abnormalities. These accumulations were particularly abundant in the fibers of the peroneus brevis muscle. Increased amounts of glycogen were observed first by Sluga and Moser (1976) in four patients affected by progressive muscular dystrophy, ophthalmoplegia and abnormal mitochondria. The only biochemical alteration they found was the failure to increase the blood lactate and pyruvate after the adrenalin stimulation test. For this reason they postulated that an elective disturbance of the activation mechanism of adrenalin in glycolysis was responsible of the glycogen accumulation. Di Mauro et al. (1973) also found glycogen storage in a patient with progressive ophthalmoplegia and similar mitochondrial changes in the muscle fibers, but they considered the glycogen storage due to the mitochondrial abnormalities. The study of respiratory and oxidative capacities of isolated mitochondria demonstrated a lack of respiratory control with a-glycerophosphate and a low respiratory rate with pyruvate plus malate as substrates. Tricopoliodystrophy is another rare disease with an excess of muscular glycogen attributed to a primitive deficiency of mitochondrial content of cytochrome al + a3 (French et al., 1972). Ultrastructural features of muscular mitochondria in this disease are quite similar to those observed in our case (Ghatak et al., 1972). The mitochondrial myopathy described by Morgan-Hughes et al. (1977), also contained alterations of number and structure of muscle mitochondria associated with abnormal increase of glycogen. The content of cytochrome b in isolated mitochondria was markedly reduced; respiratory rate and respiratory control were impaired with pyruvate, glutamate, succinate and a-glycerophosphate as substrates. These findings support a relationship between the mitochondrial derangement and glycogen storage. Nevertheless in our patient an excess of glycogen was also present in muscle fibers without morphological mitochondrial abnormalities. The role played by these organelles in the mechanism of glycogen accumulation is difficult to explain in this case, considering that the activity of the primary enzymes of glycogen breakdown was normal. In both biopsies we found only a decreased activity of guanylcyclase which stimulates glycogen synthetase; we think that this depressed activity is probable compensatory to the increased content of glycogen in muscle tissue. If the synthesis of glycogen is not stimulated, it seems reasonable to assume a lack of utilization. The high level of lactic acid in the blood strengthens this hypothesis. Finally we would like to point out the demyelinating nature of the peripheral neuropathy, as shown by the reduced conduction velocity and the severe loss of myelinated fibers in the peripheral nerve, without abnormalities of the axis cylinders at the electron microscopy. The pathogenesis of this syndrome is still unclear; we have found no morphological abnormalities of mitochondria and no glycogen accumulation in Schwann's cells. These data do not support the hypothesis of a primitive mitochondrial defect in our case. We rather think that the mitochondrial alterations are a consequence of an unknown cause which damages both muscle and peripheral nerve.

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Olson, W., Engel, W. K., Walsh, G. O., Einegler, R.: Oculocraniosomatic neuromuscular disease with "ragged red fibers." Histochemical and ultrastructual changes in limb muscles of a group of patients with,idiopathic progressive external ophthalmoplegia. Arch. Neurol. 26, 193--211 (1972) Okamura, K., Santa, T., Nogae, K., Omae, T.: Congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. J. Neurol. Sci. 27, 79 (1975) Parvin, R., Pande, S.: Microdetermination of carnitine and carnitine acetyltransferase activity. Anal. Biochem. 79, 190--201 (1977) Scarlato, G., Peltegrini, G., Veicsteinas, A.: Morphologic and metabolic studies in a case of oculo-cranio-somatic neuromuscular disease. J. Neuropathol. Exp. Neurol. 37, 1-- 12 (1978) Schneck, L., Adachi, M., Briet, M., Wolintz, A., Volk, B. W.: Ophthalmoplegia plus with morphological and chemical studies of cerebellar and muscle tissue. J. Neurok Sci. 19, 37--44 (I973) Sluga, E., Moser, K.: Myopathy with glycogen storage and giant mitochondria (ultrastructural and biochemical findings). Proc. Int. Cong. Muscle Dis. Amsterdam: Excerpta Medica 1970 Stephens, J., Hoover, M. L., Denst, J.: On familial ataxia, neural amyotrophy and their association with progressive external ophthalmoplegia. Brain 81, 556--566 (1958) Tamura, K , Santa, T., Kuroiwa, Y.: Familial oculocranioskeletal neuromuscular disease with abnormal mitochondria. Brain 97, 665--672 (1974) Received October 23, 1978