On a dominantly inherited myopathy with tubular aggregates

Neuromuscular Disorders 7 (1997) 512–520

On a dominantly inherited myopathy with tubular aggregates Jean-Jacques Martin*, Chantal Ceuterick, Gert Van Goethem Born-Bunge Foundation and University of Antwerp, Gebouw T-Rm 5-18, Universiteitsplein 1, B-2610 Wilrijk, Belgium Received 12 June 1997; revised version received 22 August 1997; accepted 11 September 1997

Abstract A 19-year-old patient presented with exercise-related myalgia, fatigue and elevated creatine kinase levels. Histology of a muscle biopsy was characterized by the presence of very large amounts of tubular aggregates. Both his father and paternal grandfather had elevated creatine kinase and large amounts of tubular aggregates in their muscle biopsies. The aggregates consisted of closely packed vesicles and tubules filled with electron-dense material or with one to several smaller tubules. Disorders with tubular aggregates in the muscle fibres such as hyperornithinaemia with gyrate atrophy of the retina, hypokalaemic periodic paralysis, hyperkalaemic periodic paralysis, myotonia congenita, alcoholism, osteomalacic myopathy etc. have been excluded. Tubular aggregates can be found in muscle disorders characterized by exercise-induced cramps, pain and stiffness. They also represent the predominant histological feature of some familial myopathies due to a yet unidentified genetic defect. In our family, there was male-to-male transmission, confirming dominant inheritance.  1997 Elsevier Science B.V. Keywords: Tubular aggregates; Dominant inheritance; Exercise-related myalgia; Creatine kinase

1. Introduction

2. Case reports

Tubular aggregates are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They are thought to represent an adaptive mechanism aiming at regulating an increased intracellular level of calcium in order to prevent the muscle fibres from hypercontraction and necrosis. They are derived from the sarcoplasmic reticulum as shown by electron microscopy and by the use of anti-Ca2+ sarcoplasmic reticulum ATPase antibodies [1,2]. They may occur in a wide variety of circumstances. They constitute a minor feature in many different conditions but may also represent a major phenomenon in the muscles of patients with exercise-induced cramps, pain and stiffness or in sporadic or inherited familial myopathies with muscle weakness. Some authors [3] have questioned the existence of a correlation between muscle weakness and the presence of tubular aggregates, e.g. in hyperornithinaemia. We report a dominantly inherited myopathy with tubular aggregates and male-to-male transmission as shown in Fig. 1.

2.1. Patient 1, born on 16 October 1976 (III-1)

* Corresponding author.

0960-8966/97/$17.00  1997 Elsevier Science B.V. All rights reserved PII S0960-8966 (97 )0 0119-3

2.1.1. Present illness The propositus was a male patient born in 1976. He was doing every day heavy physical work in his father’s garage and was racing cars as a hobby. His chief complaints were easy fatigability, exertional myalgia and muscle cramps. The cramps occurred in the morning or in the evening, when the patient was lying in bed or sitting in a chair and disappeared when he stretched his muscles. He had never noted myoglobinuria. Neither diplopia nor difficulties to chew or to swallow were noted. There were no cardiac complaints. He was treated for acne by a dermatologist who discovered an increased creatine kinase level and referred the patient to us. Family history was found afterwards to be contributory since patient 2 was the propositus’ father and patient 3 his paternal grandfather. Nothing was known concerning the other grandparents except that the maternal grandmother had sarcoidosis. Clinical examination showed a strongly-built young male patient. The strength was 5 in all proximal and distal muscle groups according to the Medical Research Council Memorandum Scale. The only exception was a strength of 4+ for

J.-J. Martin et al. / Neuromuscular Disorders 7 (1997) 512–520

the interossei muscles in the hands. There was no amyotrophy. There were neither myotonia nor myokymias. No pain could be elicited by palpation of the muscles. The deep tendon reflexes were present and symmetrical. There was neither cerebellar dysfunction nor pyramidal signs. The cranial nerves were normal. The perception of pain, touch, temperature and proprioception was also normal. 2.1.2. Laboratory work-up Creatine kinase constantly elevated at 554, 568, 680 and 857 U/l (normal up to 70). Aldolase was at 11.9 U/l (normal up to 7). Basal levels of lactic acid were normal. In an ischaemic forearm test, a normal increase of lactic acid and a mild increase of ammonia was found. There was a normal increase and decrease of lactic acid during cycloergometry. Results of routine blood tests were normal but for slightly elevated transaminases (SGOT: 30 U/l with normal values from 2 to 17 U/l; SGPT: 32 U/l with normal values from 5 to 22), slightly increased LDH (258 U/l, normal values from 124 to 241 U/l), negative syphilis serology, normal immunological screening without antinuclear, antismooth muscle cells and anti-mitochondrial antibodies. Thyroid functions and vitamin levels were normal. A normal pattern of amino-acids in serum and urine was found. There was no indication of hyperornithinaemia. Echocardiogram indicated a minimal degree of mitral and tricuspid valve insufficiency; and an early stage of dilated cardiomyopathy. A control, 3 years later, did not show any changes. Electrocardiogram (ECG) during cycloergometry was normal. Electromyogram (EMG) showed normal motor and sensory conduction velocities. There were no fibrillations or no positive sharp waves. There were myogenic features in the tibialis anterior muscle and neurogenic action potentials in the quadriceps muscle. There were less severe abnormalities in the gastrocnemius, gluteus maximus, paraspinal muscles and in the upper extremities. For results of muscle biopsy of the left vastus lateralis muscle, see Section 4. CT-scans of the muscles showed normal volume and density of the muscles. Scoliosis and slightly increased kyphosis of thoracic spine, increased lordosis and mild retrolisthesis of L5 were found.

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Clinical examination at age 42 years showed an obese patient with an essentially normal neurological examination. The strength of upper and lower extremities was normal. There was no amyotrophy but for the sequels of the fracture of the left femoral bone with scarring of the thigh. No myotonia could be elicited. Creatine kinase level was 2488 U/l (normal up to 170 for that laboratory). ECG was abnormal with intraventricular conduction disturbances. Echocardiogram suggested a dilatation of the left ventricle with an unimpaired ejection fraction but the examination was suboptimal because of the obesity. EMG gave normal motor and sensory conduction velocities and showed mild chronic neurogenic involvement in the lower extremities with slightly polyphasic potentials in the quadriceps muscle (not examined on the side of the fracture). A muscle biopsy was done in the right vastus lateralis muscle. Fibrillations were seen when the muscle was exposed for biopsy. The muscle showed similar but more severe lesions than in the son, associating neurogenic and myogenic features. 2.3. Patient 3, born on 22 December 1922 (I-1) He was the father of patient 2 and the grandfather of patient 1. Past history was characterized by two operations for herniated lumbar disks, respectively at age 56 and 59 years. There were severe postoperative sequelae with bilateral foot drop and hypesthesia in both feet. At that time creatine kinase was elevated at 900 U/l (normal up to 70). Clinical examination at age 71 years showed normal cranial nerves and normal upper extremities. There was a bilateral

2.2. Patient 2, born on 22 July 1953 (II-1) He was the father of patient 1 and was examined because of the muscle pathology of his son. Past history was characterized by different motorcycle injuries with a fracture of the left femoral bone. The patient had no complaints. His strength was normal. He did heavy work without any other problems than a tiredness at the end of the day. The day after he usually felt normal again. There was no exertional myalgia. He weighed 108 kg for a height of 1 m 73 cm. Transaminases had been elevated for years although the patient did not drink alcoholic beverages.

Fig. 1. Family tree showing the dominant type of inheritance with a maleto-male transmission of the disease. The black symbols represent the patients.

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Table 1 Histology and histoenzymology (Fig. 2) Techniques

Patient 1 (H 126–94)

Patient 2 (H 78–96)

Patient 3 (H 77–96)

Gomori trichrome and HE

Variations in the diameters of the muscle fibres; centralisation of nuclei; necrotic fibres; myophagias; large amounts of sarcoplasmic or subsarcolemmal basophilic masses corresponding to tubular aggregates (TAs) Normal TAs are PAS + TAs are ± TAs are strongly + Normal inversion of the pattern Present Checkerboard pattern. TAs are mainly present in type IIa and IIb fibres Present

Variations in the diameters of the muscle fibres; small fields of atrophic angular fibres; myophagias, necrotic fibres; very large amounts of sarcoplasmic or subsarcolemmal basophilic masses corresponding to TAs; endomysial fibrosis Some fatty replacement TAs are PAS + TAs are ± TAs are strongly + Normal inversion of the pattern Present Checkerboard pattern. TAs are mainly present in type IIa and IIb fibres Present

Variations in the diameters of the muscle fibres; centralisation of nuclei; presence of basophilic strands in the sarcoplasma or beneath the sarcolemma corresponding to TAs

Oil red O PAS SDH NADH-TR Menadione a-GDH Phosphorylase Myofibrillar ATPase AMP-DA

Fatty replacement TAs are PAS + TAs are ± TAs are strongly Normal inversion of the pattern Present Checkerboard pattern. TAs are mainly present in type IIa and IIb fibres Present

TAs, tubular aggregates.

steppage, a decreased sensation in the dermatome S1 on the left side. Both ankle jerks were absent. Creatine kinase was 917 U/l (normal up to 170 because of a change in the assay).

EMG showed normal motor and sensory conduction velocities and old neurogenic changes in the left quadriceps muscle.

Table 2 Immunohistochemistry (Fig. 2) Antibodies against

Patient 1

Patient 2

Patient 3

Dystrophin 1-2-3 Spectrin Utrophin Merosin Laminin 50 kDa SGL 43 kDa DAG Myosin

NL NL NL NL NL NL Not done Increased staining of atrophic or necrotic fibres Many + fibres TAs are strongly + Focal granular positivity in affected muscle fibres Positive granules in a few fibres

NL NL NL NL NL NL NL Increased staining of atrophic fibres Many + fibres TAs are strongly + Focal increase around centralised nuclei Positive granules in a few fibres Diffuse faint or strong positivity in some fibres Not done

Ubiquitin Vimentin C5b-9 (complement)

Uniform strong positivity in a few fibres Faint + around lesions in muscle fibres No staining + fibres are present Not done

NL NL NL NL NL NL NL Pattern of type I and type II fibres A few + fibres TAs are strongly + Focal increase around centralised nuclei Presence at the level of TAs in some fibres TAs are −

CD45RO (activated T cells)

Not done

CD68 (macrophages)

Not done

HLA-DR (MHC class II)

Not done

HLA-ABC (MHC class I)

Not done

MHC-d SERCA2-ATPase Desmin AT 120 Tubulin bA4 amyloid

No staining Many + fibres Macrophages in necrotic fibres are + A few + endomysial cells + cells in necrotic fibres Strong + of the macrophages in the necrotic fibres Strong + of the macrophages in the necrotic fibres; + in endomysial cells Same as HLA-DR

Not done No staining A few + fibres Normal distribution A few + endomysial cells A few + endomysial cells Walls of blood vessels are + Walls of blood vessels are +

NL, normal immunoreactivity; TAs, tubular aggregates; SGL, sarcoglycan; DGL, dystroglycan; MHC-d, myosin heavy chain-developmental; MHC, major histocompatibility complex; SERCA2-ATPase, sarcoplasmic reticulum Ca2+ ATPase.

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Because of the neurogenic pathology in the lower extremities, the muscle biopsy was performed in the right deltoid muscle. Moderate myogenic features were observed but large amounts of tubular aggregates were found both by light and electron microscopy. 2.4. Methods Muscle biopsies were examined by light and electron

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microscopy using classical histological, histo-enzymological and immunohistochemical light- and electron microscopic techniques. Muscle specimens were snap frozen in liquid-nitrogen-cooled isopentane. Serial cryostat sections (8 mm) were cut and stained using conventional histochemical methods [4] for light microscopy. For immunohistochemistry, sections were fixed (+) for 10 min in acetone or left unfixed (−), incubated with a whole panel of antibodies directed against membrane and cytoske-

Fig. 2. (A) Muscle biopsy of patient 2 (the father of patient 1). Large amounts of intermyofibrillar and subsarcolemmal tubular aggregates in type II muscle fibres and small group of atrophic angular fibres. Frozen section, NADH-tetrazolium reductase, magnification ×280. (B) Muscle biopsy of patient 1. The tubular aggregates are immunodecorated by the antibody against sarcoplasmic reticulum Ca2+-ATPase (SERCA2-ATPase) in type II fibres (arrows). Frozen section, SERCA2-ATPase, avidin-biotin complex technique, magnification ×310.

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letal muscle proteins and processed routinely, as previously reported [5]. Antibodies were also used to immunolocalise inflammatory cells. Primary antibodies used in this study included the following antibodies: mouse anti-dystrophin 1 [1:5, Novocastra; (-)], mouse anti-dystrophin 2 (1:5, Novocastra; (−)), mouse anti-dystrophin 3 (1:100, Novocastra; (−)), mouse anti-spectrin (1:500, Novocastra; (−)), mouse anti-43 kDa b-dystroglycan (1:200, Novocastra; (−)), mouse anti-utrophin (1: 100, Dr. G.E. Morris; (+)), mouse anti-50 kDa sarcoglycan, (1:200, Dr. K. Campbell; (+)), mouse anti-human laminin (1:100, Dakopatts; (+)), mouse anti-human merosin (1:2000, Chemicon; (+)), rabbit anti-myosin (1:50, Sigma; (+)), mouse anti- desmin (1:200, Dakopatts; (+)), mouse anti-vimentin (1:200, Dakopatts; (+)), mouse anti-a-tubulin (1:1000, Sigma; (+)), mouse anti-myosin heavy chain (developmental) MHC-d (1:50, Novocastra; (−)); mouse sarcoplasmic reticulum Ca2+-ATPase or SERCA2-ATPase (1:500, Novocastra; (+)); mouse anti-tau AT120 (1:5000, Innogenetics; (−)), rabbit anti-ubiquitin (1:500, Dakopatts; (+)); rabbit anti-b-amyloid protein sequence 2–43, A4, (1:500, Dr. K. Beyreuther; (+)), mouse anti-human T cell, CD45RO (1:500, Dakopatts; (+)), mouse anti-human macrophage, CD 68 (1:300, Dakopatts; (+)), anti-human leucocyte common antigen (1:100, Dakopatts; (+)), mouse anti-human C5b-9 (1:100, Dakopatts; (+)), anti-human HLA-DR (1:50, Dakopatts; (+)), anti-human HLA-ABC (1:200, Dakopatts; (+)).

Sections were incubated overnight at room temperature and immunostained with the peroxidase-antiperoxidase (PAP) technique for the polyclonal antibodies and with the avidin-biotin complex (ABC) technique for the monoclonal antibodies, using Dakopatts and Amersham reagents, respectively. Colour was developed with 3,3-diaminobenzidine (DAB) tetrahydrochloride. Sections were counterstained with Harris hematoxylin, dehydrated and coverslipped with Eukitt. Standard classical electron microscopy techniques were performed [6].

3. Results For results of light microscopy, see Tables 1 and 2 and Fig. 2. For results of electron microscopy, see Table 3 and Fig. 3.

4. Discussion There was autosomal dominant male-to-male transmission in the family reported in the present study. The most striking feature was the discordance between the rather mild complaints of exertional myalgia, fatigability and muscle cramps in the propositus, the absence of relevant clinical symptoms in the two affected ascendants on one hand, the

Table 3 Electron microscopy (Fig. 3) Structures

Patient 1

TAs

Large subsarcolemmal and intermyofibrillar amounts (1–14 mm in diameter) Numerous closely packed parallel spherical type I tubules (20–70 nm in diameter) containing a smaller inner tubule and few type II tubules filled with electron-dense flocculent material. No type III tubules T-system Rarely dilated SR Dilated vesicles adjacent to TAs Triads Scattered throughout TAs; sometimes in continuity with TAs Glycogen Surrounding TAs Lipid droplets + Residual bodies 0 Filamentous bodies 0 Internal nuclei + Mitochondria Increased in number and in size Necrotic fibres Numerous dilated type II tubules

Atrophic fibres Endomysial capillaries

+ NL

Patient 2

Patient 3

Very large subsarcolemmal and intermyo fibrillar amounts (0.5–20 mm in diameter) Presence of type I and type III tubules (100–200 nm in diameter) with several inner microtubule-like structures. Less numerous type II tubules

Focal subsarcolemmal and intermyofibrillar clusters (0.7–8 mm in diameter) Presence of type I and type II tubules (10–160 nm in diameter). No type III tubules

Rarely dilated Dilated vesicles adjacent to TAs Scattered throughout TAs; sometimes in continuity with TAs Surrounding TAs + + 0 + Increased in number and in size Type I and type II tubules close to non-specific vacuolar structures. No type III tubules ++ Increased in number

Honeycombs Dilated vesicles adjacent to TAs Scattered throughout TAs; sometimes in continuity with TAs Surrounding TAs ++ 0 + ++ Increased in number and in size Tubules were not observed

+ NL

TAs, tubular aggregates, classified in type I, II and III according to Cameron et al. [7]; SR, sarcoplasmic reticulum; +, present; 0, absent; NL, normal.

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increased creatine kinase levels and the severity of the accumulation of tubular aggregates in nearly all type II fibers, in association with necroses and myophagias of muscle fibres on the other hand. The lesions were less severe in the grandfather who underwent a biopsy of the deltoid muscle instead of the vastus lateralis because of the neurogenic signs in the lower extremities due to previous intervertebral disk pathology and surgery. It was therefore impossible to determine whether these milder lesions were due to a different expres-

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sion of the disorder or to a less severe involvement of the upper extremities. Tubular aggregates represented probably an adaptive response to the unknown primary genetic defect and they did not prevent normal physical activities as a whole in the propositus and his father. The grandfather was older and incapacitated by a lumbar spine pathology. Immunohistochemistry confirmed the strong positivity of the tubular aggregates with the antibody directed against the SERCA2-ATPase. It ruled out dystrophinopathies and some

Fig. 3. (A) Muscle biopsy of patient 1. The ultrastructural examination reveals a subsarcolemmal cluster of tubular aggregates in a muscle fibre. Glutaraldehyde fixation, araldite embedding, staining with uranyl acetate and lead citrate. (B) Muscle biopsy of patient 3 (the grandfather of patient 1). Cross- and longitudinal sectioned tubular aggregates displaying type I tubules (arrow) with a small inner tubule and type II tubules (arrowheads) filled with electrondense floccular material. Glutaraldehyde fixation, araldite embedding, staining with uranyl acetate and lead citrate. Scale bar, (A,B) 1 mm.

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Table 4 Conditions in which TAs have been observed as a minor or a prevalent feature Presence of tubular aggregates

Reference

Adults with non-specific complaints of muscle pains and cramps and structures resembling cylindrical spirals Exercise-induced muscle cramps and myopathy, sometimes associated with increased sensitivity to caffeine Exercise-induced muscle cramps without progressive myopathy Myasthenic syndrome with cardiomyopathy Familial vacuolar myopathy and thrombocytopenia Autosomal dominant neuromuscular disease with cylindrical spirals and occasionally tubular aggregates Chronic progressive external ophthalmoplegia and myalgia Progressive myopathy with proximal progressing to distal muscle wasting Fukuyama type of congenital muscular dystrophy Various forms of periodic paralysis with hyokalaemia or hyperkalaemia Various conditions such as hyperthyroidism, myopathy in an adrenalectomized patient with attacks of muscle weakness, osteomalacic myopathy due to anticonvulsant drugs, zidovudine therapy for AIDS, porphyria cutanea tarda, steroid responsive myopathy, neoplastic disease, postviral infections Myasthenia gravis Alcoholism Whipple’s disease Hyperornithinaemia-gyrate atrophy of the choroid and retina

[15] [16–18] [9,19–22] [23] [24] [25] [26] [27] [28] [29–31] [32–36]

sarcoglycanopathies. It showed an accumulation of desmin in muscle fibers containing centralised nuclei and the existence of a few regenerating fibers. The cells present in fibers undergoing necrosis were immunostained by antibodies directed against macrophages and activated T cells. Electron microscopy showed large amounts of spherical type I tubules containing a smaller inner tubule. Less numerous type II tubules filled with electron-dense material and type III tubules showing several inner microtubule-like structures were also seen. The overall myofibrillar structure was normal but in the necrotic fibers. Tubular aggregates have special histochemical and immunohistochemical features [8]. They are generally found in type II fibres; they are strongly positive for NADH-tetrazolium reductase and myoadenylate deaminase (AMP-DA) but negative for succinate dehydrogenase. They contain heat shock protein (HSP) epitopes [9]. They are immunoreactive to anti-Ca2+ sarcoplasmic reticulumATPase antibodies and also to antibodies to calsequestrin [1]. Ultrastructural examination reveals that the subsarcolemmal and intermyofibrillar clusters of tubular aggregates consist of different types of closely packed type I, type II and type III tubules [7]. The presence of tubular aggregates potentiates the loading ability of the muscle fibres; their origin from junctional sarcoplasmic reticulum represents a function equivalent to hypertrophy of the terminal cisterns. Tubular aggregates are thought to represent an adaptive, compensatory response to an increased intracellular level of calcium, preventing the irreversible contracture of the muscle fibres and other deleterious effects. The fact that epitopes of HSP are expressed could be significant since these proteins undergo an increased synthesis following a wide range of cellular insults including physical trauma, chemical injury and irradiation. The HSPs could produce conformational changes in the structure of the constituent proteins of the sarcoplasmic reticulum resulting in the for-

[37] [38] [39] [40]

mation of tubular aggregates. This process could be reversible. The question to determine how often tubular aggregates are encountered in muscle biopsies has been addressed by different authors: Rosenberg et al. [10] have found tubular aggregates in 15 out of 1500 consecutive biopsies (1%) among whom two patients with hypokalaemic paralysis, one with hyperkalaemic paralysis, one with myotonia congenita, three with inflammatory myopathies and eight patients with muscle pains and cramps, not necessarily precipitated by pain or exercise. Niakan et al. [11] reported tubular aggregates in 19 out of 3000 consecutive muscle biopsies (0.6%): 12 with severe myalgia among which seven with myalgia only, two with ALS and three with neuropathy. The seven remaining patients without myalgia had neuropathy (two), ALS (one), systemic lupus erythematosus (one), congenital myopathy (one) or muscle weakness of undetermined etiology (two). By electron microscopy of 210 consecutive biopsies, Kalyan-Raman et al. [12] found that 16 specimens showed tubular aggregates (7.6%) and of these only one had detectable subsarcolemmal aggregates on oxidative enzyme staining in histochemical studies. Ten out of the 16 patients had chronic muscle pain with variable exertional muscle stiffness and cramps; two of the 10 had type II predominance and one had AMP-DA deficiency. Of the remaining six patients with tubular aggregates, three had myotonic muscular dystrophy, one uremic neuromyopathy and one carcinomatous neuromyopathy. The last biopsy was from a healthy control subject from an ongoing fibromyalgia study. Another routine study of 136 muscle biopsies by electron microscopy [13] has shown that tubular aggregates were observed in 18 cases (13%) and that tubular aggregates were predictably associated with chronic muscle pain syndrome (100%). The fact that tubular aggregates are more frequently found by electron than by light microscopy indicates that they are not very abundant in most of the cases, in

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Table 5 Progressive myopathies with accumulation of tubular aggregates Reference

Patients

Description

[46]

Two siblings

Slowly progressive limb-girdle weakness without accessory features such as myasthenia, cramps or periodic weakness. Slowly progressive weakness without atrophy, myalgia, cramps or episodic weakness Mild weakness and muscle aching or cramps, with two patients having winging of the scapula Slowly progressive limb-girdle weakness; one with a cardiopathy. Muscle aching after exercise Slowly progressive proximal weakness, limitation of eye movement and Achilles tendon contractures. CK was 5–10 times normal Muscle stiffness and swelling after prolonged exercise in a 39 year-old man. Forearm ischemic test with normal rise of serum lactate. Graded exercise testing on a bicycle ergometer; slightly reduced oxygen uptake. 31-P MR spectroscopy; large glycogenolysis-induced pH decrease Fatigability, exertional myalgia, muscle cramps in the propositus, no specific complaints in the two other patients; nearly normal neurological examination; CK elevated to 5–12 times the upper normal values

[3] [47]

Seven patients in three generations Five patients in three generations

[2]

Three young patients, sporadic

[7]

Father and daughter

[48]

Patient and two male first cousins and the daughter of one of them

Present family

Male-to-male transmission in three generations

contradistinction to what has been observed in our three patients. Tubular aggregates are indeed encountered in a variety of circumstances, some being physiological such as in the muscles of apparently normal male children in which low numbers of tubular aggregates can sometimes be found. They have rarely been observed in females but have been observed in patients with hyperornithinaemia with gyrate atrophy. They can be produced by anoxia in isolated skeletal muscle [14]. Tubular aggregates are also found in many different pathological conditions, some of them are listed in Table 4 [15–24] [25–34] [35–40]. A few are muscle disorders characterized by exercise-induced muscle cramps or represent well identified conditions such as myotonic dystrophy, myasthenia gravis, polymyositis or hyperthyroidism; others are related to metabolic diseases. It is, for example well known that hyperornithinaemia-gyrate atrophy, due to a deficiency of ornithine-d-aminotransferase, is associated with tubular aggregates [40]. Tubular aggregates have been reported in normal animals such as in normal pigeon latissimus dorsi muscle [41] or in pathological conditions such as in vitamin E deficient rats [42], in murine dystrophy heterozygotes [43] or in strains of MRL+/+ male mice with tubular aggregates in which the tubular aggregates were abolished by castration [44]. Testosterone may indeed affect the formation of tubular aggregates in normal mouse skeletal muscles [45].Taking these facts into account, tubular aggregates do not appear to represent a specific feature of any muscular disorder. They are often found in discrete amounts by using electron microscopy. They constitute however the prevalent histological feature in some inherited myopathies. Table 5 summarises the scarce data available in the literature, including the family reported in the present study. A sporadic occurrence is described in the patients reported by Figarella-Branger et al. [2]. Autosomal dominant inheritance is observed in the

families described by Rohkamm et al. [3], Cameron et al. [7], Pierobon-Bormioli et al. [47] and ourselves. An autosomal recessive inheritance is noted in the patients reported by de Groot and Arts [46] and in the family mentioned by Bendahan et al. [48]. It is interesting to note that in the patient reported by Bendahan et al. [48], magnetic resonance spectroscopy has shown a pronounced hyperacidosis at the end of the exercise. The authors propose two hypotheses to explain this hyperacidosis: (1) the activation of the Ca2+ dependent phosphorylase kinase, increase the activation of anaerobic ATP supply, producing an abnormally high accumulation of blood lactate during ischaemic exercise; (2) due to fibre II predominance in their patient, ATP production is, at least for the major part, under the control of glycogenolysis and this could result in a dramatic pH decrease.

Acknowledgements We gratefully acknowledge the help of Mrs I. Bats, L. DeWit, U. Lu¨bke, E. Peeters and G. Seeldraeyers for expert morphological techniques and photographic illustrations. This work was supported by the Fonds voor Geneeskundig Wetenschappelijk Onderzoek (Grant numbers 3.0020.90 and 3.009.94) and by the Born-Bunge Foundation and by the Sheid-van Bogaert legacy for Neurological Sciences.

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