Congenital and metabolic myopathies

Congenital and Metabolic Myopathies Masao Kinoshita, MD Among various myopathies, two distinct groups are briefly summarized: congenital myopathies of which the disease concepts are based on the morphological findings of the structure of muscle fibers, and metabolic myopathies in which muscular involvement has been clarified or strongly suggested to be due to primary biochemical defects within the fibers. Also some interesting cases recently reported in Japan are briefly reviewed. Difficulty in evaluating the significance of pathologically determined myopathies and the connection between congenital and metabolic myopathies are discussed. It is postulated that some types of congenital myopathies may be due to incomplete, minimal, partial or restricted metabolic failures within the fibers. Kinoshita M. Congenital and metabolic myopathies. Brain Dev 1983;5:116-26

The number of papers describing various disorders that affect the skeletal muscle system have been increasing in recent years. There are two distinct groups of myopathies: one is a group in which the concepts of the diseases are based on the specific morphological changes of the muscle fibers, and the other is a group of diseases in which the pathogenesis of muscular involvement has been clarified or strongly suggested to be due to metabolic failures. In the present lecture, these two groups are briefly summarized together with a review of some interesting cases recently reported in Japan. Congenital Myopathies When the term "congenital" is strictly applied, all here do familial myopathies should be included in this group. However, muscular diseases listed in the upper half of Table 1 have many common features such as the relatively early onset of the illness, familial occurrence, nonprogressive course in the majority of cases, normal or slightly elevated serum CPK, myopathic EMG and specific pathological changes

From the Department of Medicine, Toho University, Tokyo.

Key words: Congenital myopathy, metabolic myopathy. Correspondence address: Dr. Masao Kinoshita, Department of Medicine, Toho University, Ohashi Hospital, 2-17-6, Ohashi, Meguro-ku, Tokyo 153, Japan.

116 Brain & Development, Vol 5, No 2,1983

of the ,fibers without any dystrophic degenerative changes or neurogenic group atrophy. In addition, type I fibers are more predominantly involved in most disorders. Here, in the narrow sense, these myopathies with various common features are called congenital myopathy. So-called floppy infants had been categorized as amyotonia congenita which later turned out to be a mixture of heterogenous conditions from Walton's benign congenital hypotonia to Werdnig-Hoffmann disease. The first to be isolated from other myopathies was central core disease reported by Shy et al in 1956 (1], and since then many attempts have been made to establish new disease entities by recognizing new morphological findings of the fibers . Nemaline myopathy [2], myotubular (centronuclear or pericentronuclear) myopathy [3], finger print body myopathy [4] , etc were isolated on the basis of characteristic changes of the contractile properties, and megaconial and pleoconial myopathies were identified by giant abnormal mitochondria [5] . However, one of the major problems in evaluating the significance of these morphologically determined myopathies is the fact that similar pathological changes have been reported to be present in various pathological conditions other than the original disorders. For example, targetoid fibers have a very close resemblance to central cores and are seen in denervated muscles, and nemaline bodies are observed in tenotomized muscles or in animals on prolonged

Table 1 Congenital myopathies

Table 2 Metabolic myopathies

Characterized by abnormal structures of contractile properties Central core disease (minicore or multicore disease) Nemaline myopathy Myotubular myopathy (centronuclear or pericentronuclear myopathy) Cytoplasmic body myopathy (atypical myopathy with myofibrillar aggregates) , Myopathy with tubular aggregates Finger-print body myopathy

Glycogenoses Glycogenosis II, III, IV, V, VII, etc

Characterized by mitochondrial abnormalities Megaconial myopathy Pleoconial myopathy Kearns-Shy (Kearns-Sayre) syndrome Characterized by fiber type abnormalities Congenital fiber type disproportion (familial type I fiber atrophy) Myositis ossificans Congenital muscular dystrophy

neostigmin treatment. Giant mitochondria are also seen in ischemic muscles or in intoxication with certain drugs. Therefore, not all disease concepts are fully accepted until their peculiar morphological changes are proven to be the result of single disease processes. Metabolic Myopathies Glycogenoses, lipid myopathies and mitochondrial abnormalities are the major groups of primary metabolic myopathies. Type II (acid maltase deficiency), III (debranching enzyme defect), IV (branching enzyme defect), V (phosphorylase deficiency) and VII (phosphofructokinase deficiency) are known to produce muscular symptoms, and disturbance of phosphohexoisomerase and of phosphoglucomutase levels are also known to involve the muscle. Painful cramp or contracture after exercise, myoglobinuria, lack of elevation of lactic acid in the blood after ischemic exercise and accumulation of glycogen in the muscle are the main symptoms, but not seen in all types. Myopathy probably due to a defect in utilization of fatty acids as an energy source was first reported by Bradley et al in 1966 [6]. Later, carnitine deficiency and carnitine palmityltransferase (CPT) deficiency were proven to be causes of disturbance of intramuscular

Lipid myopathies Carnitine deficiency Carnitine palmityltransferase deficiency Systemic triglyceride storage disease Other obscure lipid storage diseases Mitochondrial myopathies Luft's hypermetabolic myopathy Cytochrome b deficiency Cytochrome c oxidase deficiency NADH-Co Q reductase deficiency Pyruvate carboxylase deficiency Pyruvate decarboxylase deficiency etc Other metabolic myopathies Myopathy in Fabry disease Myopathy in a-beta-lipoproteinemia Myopathy in low-alpha-lipoproteinemia etc Possibly metabolic myopathies Malignant hyperpyrexia Familial paroxysmal myoglobinuria Periodic paralysis etc

lipid metabolism. Carnitine deficiency is either limited to muscle [7] or generalized [8] , and shows intramuscular lipid storage, but CPT deficiency does not always show the storage [9]. Episodic attacks of cramp-like pain and myoglobinuria after exercise are usual features of the disease, and between attacks no muscular symptoms are present. Intramuscular lipid storage is also observed in generalized triglyceride storage disease and in other obscure lipid disorders. Some types of glycogenoses and most mitochondrial myopathies also have intramuscular accumulation of neutral lipids. In addition to the already mentioned structurally determined mitochondrial myopathies, several myopathies have been determined to be due to mitochondrial abnormalities by biochemical procedures. Historically, hypermetabolic myopathy reported by Luft et al [10] was the first case, and recently direct or indirect evidence for defects of mitochondrial enzymes have been reported for several disorders [11-15]. The already mentioned CPT deficiency was also one of such examples.

Kinoshita: Congenital and metabolic myopathies 117

Fig 1 Atypical myopathy with myofibrillar aggregates. Muscle fibers are segmentally involved with large inclusions (Masson trichrome, x 100).

These disorders are grossly classified into three subgroups: 1) those due to defects in utilization of substrates, 2) those with deficiencies of some properties of the mitochondrial respiratory chain, and 3) known or obscure disturbances of energy conservation. These disorders usually have various neurological or generalized symptoms other than muscular manifestations as well. Ataxia, mental retardation, seizures, febrile episodes, vomiting, lactic and pyruvic acidemia, and hyperalaninemia are common features. There are some other metabolic disorders that may cause myopathy. They have no defects of intracellular energy metabolism, and the true mechanism of muscular involvement is obscure. Some of them are also listed in Table 2. Cases Recently Reported in Japan It was not long after the original cases had been

recognized that cases with congenital myo118 Brain & Development, Vol 5, No 2,1983

pathieswere first reported in Japan. Nemaline myopathy and myotubular myopathy were reported in 1968 [16], and myopathy with abundant cytoplasmic bodies was observed in 1971 [17]. Myopathy with giant mitochondria was recognized in 1976 [18]. However, central core disease has been very rare, and only a few cases have been observed since 1978. Familial type I fiber atrophy was reported in 1975 [19]. Histochemical characteristics were almost identical to those of congenital fiber type disproportion [20], but selective atrophy of type I fibers was more strongly stressed. Recently myopathy with tubulomembraneous bodies was reported by Fukuhara et al [21]. Some of the morphological changes seen in these Japanese cases are illustrated in Figs 1-6. As for glycogenoses, at least Japan has three original types. Phosphofructokinase deficiency was reported by Tarui et al in 1965 [22], and disturbance at the phosphohexoisomerase level by Satoyoshi et al in 1967 [23]. Recently Nishimura et al found LDH-M subunit deficien-

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Kinoshita: Congenital and metabolic myopathies 121

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Kinoshita : Congenital and metabolic myopathies 123

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124 Brain & Development, Vol 5, No 2,1983

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Fig 11 Schematic illustration of the connection between morphologically determined myopathies and three types of metabolic myopathies.

cy in which only the M subunit is deficient in the blood and muscle (Fig 7) [24] . Lipid storage myopathy has been seen in familial hyperlipoproteinemia [25], but the mechanism of lipid storage is obscure. Neither carnitine deficiency nor CPT deficiency have been recognized. As for myopathies due to mitochondrial enzyme defects, only those with disturbance of pyruvate metabolism have been reported to have massive mitochondrial accumulation within the fibers (Fig 8) [26]. Hypermetabolic myopathy or abnormalities of the mitochondrial respiratory chain have not been observed in Japan. Apart from abnormal energy metabolism, Hashimoto has reported a very rare case with Fabry disease in which the clinical picture was predominantly of myopathy and no usual symptoms of the disease were present. Osmiophilic inclusions were observed in the endothelial cells of intramuscular blood vessels as well as within the fibers (Fig 9) [27]. Severe lipid storage myopathy was observed in a patient with von Gierke disease [28] despite that the disease has been believed not to involve the striated muscle. Comment As already mentioned, it is still obscure whether or not every peculiar morphological change

of the muscle fibers represents a single disease process. Accordingly, some of the congenital myopathies have been doubted to be true disease entities. Even questions were raised against their myopathic nature, for some authors considered selective atrophy of type I fibers in some congenital myopathies to be the result of the neurogenic process. However, no evidence of lesions in the spinal anterior horn cells or the peripheral nerves has been obtained at autopsy of a few fatal cases. It is likely that not a true denervation but certain neuronal factors may influence. Type I predominance, another feature of the diseases, may be the result of continuous reconversion of type II to I due to dominant slow type innervation. It may be possible that partial, minimal or restricted metabolic failures cause morphological changes of selected components. As shown in Fig 5, familial type I fiber atrophy has a close resemblance to the ".orphology of M-L-G myopathy [29]. These facts might suggest that some congenital myopathies are caused by metabolic failures. Degenerative breakdown of the whole structures of individual fibers, as is the usual picture of metabolic myopathies, is absent in congenital myopathies. Maybe this is due to a difference in severity, in the extent or in the nature of metabolic failures . Selective involvement of type I fibers is a common feature of morphologically determined myopathies, and is also common in metabolic myopathies. It is natural that type I fibers are more frequently affected in lipid and mitochondrial myopathies because energy metabolism of type I fibers largely depends on mitochondrial activities and beta-oxidation of fatty acids. But morphologically, type I fibers are also selectively involved in glycogenoses [3~, 31], though defective anerobic glycolysis is expected to damage type II fibers more predominantly in these disorders. From the morphological point of view, the relationship between various myopathies is schematically illustrated in Fig 11. References 1. Shy GM, Magee KR. A new congenital nonprogressive myopathy. Brain 1956;79:610-2l. 2. Shy GM, Engel WK, Somers IE, Wanko T. Nemaline myopathy: A new congenital myopathy. Brain 1963 ;86 :793-810. 3. Spiro AI, Shy GM, Gonatas NK. Myotubular

Kinoshita: Congenital and metabolic myopathies 125

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