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X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

A novel myopathy characterized by hexagonally cross-linked tubular arrays has been reported in five patients. We studied the clinical and histopathological features of five additional unrelated patients with this myopathy. Patients experienced exercise intolerance with exercise-induced myalgia and weakness, without rhabdomyolysis. One patient additionally presented mild permanent pelvic girdle muscle weakness. Age at onset varied between 13 and 56 years. The inclusions were eosinophilic on H and E, bright red with modified Gomori's trichrome stains, present in type 2 fibers, and revealed immunoreactivity selectively for a caveolin-3-antibody. Ultrastructurally, the inclusions showed a highly organized, hexagonally cross-linked crystalloid structure. Mutations in the caveolin-3 encoding gene were excluded. Biochemical assessment of glycogenolysis in muscle was normal. Inherited or sporadic myopathy with hexagonally cross-linked tubular arrays is associated with a homogeneous clinical and histopathological phenotype. This myopathy should be included in the differential diagnosis of patients with exercise intolerance and myalgia., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Cap disease is a rare congenital myopathy associated with skeletal malformations and respiratory involvement. Abnormally arranged myofibrils taking the appearance of a "cap" are the morphological hallmark of this entity. We report a case of cap disease concerning a 42-year-old man, without any family history and presenting a p.Arg168His mutation on the TPM3 gene. His first biopsy at 7years had only shown selective type I hypotrophy. Mutations of TPM3 gene have been found in nemaline myopathy, congenital fiber type disproportion, but never before in cap disease.

X-linked myopathy with excessive autophagy (XMEA) is a childhood-onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p it is an essential assembly chaperone of the V-ATPase, the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, which upregulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell. Our results uncover macroautophagic overcompensation leading to cell vacuolation and tissue atrophy as a mechanism of disease.

Myosin Storage Myopathies (MSM) have emerged as a new group of inherited myopathies with heterogenous clinical severity and age of onset. We have identified in a woman and her daughter, a pLeu1793Pro mutation in MYH7. This mutation has already been reported to be associated with MSM presenting as neonatal hypotony. Our index case complained of proximal muscle weakness at age 30. Her daughter presented at birth with a cardiomyopathy without any skeletal muscle involvement. This report underlines the clinical variability of MSM even with a given mutation or in a same family.

We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

Unlabelled: Early and severe cardiomyopathy may be related to myofibrillar myopathy., Case Report: We report a one-year-old child with early and severe restrictive cardiomyopathy. The diagnosis of myofibrillar myopathy was obtained on skeletal muscle and endomyocardial biopsies. The patient died despite inotropic support and mechanical ventilation., Conclusion: Myofibrillar myopathy must be considered when exploring the etiology of a restrictive cardiomyopathy in children. The diagnosis relies on examination of endomyocardial or skeletal muscle biopsy samples.

Granulomatous inflammation is infrequently observed in muscle biopsy. We report a series of 7 patents presenting with granulomas in muscle. Two of them had a history of sarcoidosis In 4 other cases, muscle Involvement revealed systemic sarcoidosis. Among the 6 cases of sarcoidosis, we observed 2 with acute myositis and 4 chronic forms. The last patient presented with polymyositis in association with melanoma. In sarcoidosis, muscle biopsy showed a granulomatous inflammation of varying intensity, which was generally associated with mononuclear inflammatory cells. Most of granulomas were located in the perimysium and the endomysium and necrosis was absent. Inflammatory cells were predominantly macrophages and CD4 positive lymphocytes. On the contrary, in the case of paraneoplastic polymyositis,granulomas were rare, most of inflammatory cells were CD8 positive lymphocytes and numerous areas of necrosis were observed. Class I MHC molecules were expressed on the membrane of muscle fibers. As a general rule, requisite examinations must be performed to search for sarcoidosis in patients exhibiting granulomas on muscle biopsy.

Colchicine, a microtubule polymerization inhibitor, can very occasionally induce myopathy. We report two cases of colchicine myopathy. Both patients presented with myalgia and proximal muscle weakness. The first patient, an 80-year-old woman, had chronic renal failure related to renal amyloidosis. She had been treated by colchicine for 4 months. The second, a 75-year-old man with normal renal function, suffering from gout, was treated by colchicine for 3 weeks. Muscle biopsies displayed the same alterations, but the degree of severity was different. Conventional histology revealed vacuolar changes characterized by acid phosphatase-positive vacuoles and myofibrillar disarray foci. The lesions were selective for type I fibers. Ultrastructural study demonstrated autophagic vacuoles. Most of the vacuoles expressed dystrophin but not merosin. Several fibers reacted with anti-MHC class I antibody and granular deposits of membrane attack complex were observed on the surface of numerous myofibers. Anti-alphaB-crystallin antibody strongly reacted with vacuolar content. Physiopathologically, microtubules are primordial for vesicle movements and colchicine induces autophagic vacuole accumulation by preventing their fusion with lysosomes. The selective type I involvement is probably due to the higher tubulin amount in type I fibers. AlphaB-crystallin overexpression is related to its microtubule protection properties. Moreover, we suggest that vacuoles randomly floating in sarcoplasm might occasionally meet the plasma membrane and open in the extracellular space, leading to complement activation. Accurate diagnosis of colchicine myopathy is relevant because the treatment is based on colchicine interruption.

In 1988, Kalimo et al. (Ann Neurol 23 (1988) 258)described a new type of X-linked myopathy in a Finnish family. The clinical course was characterized by slow progression of muscle weakness without loss of ambulation in childhood and no evidence of cardiac, respiratory, or central nervous system involvement. Muscle fibers were not necrotic and showed excessive autophagic activity and exocytosis of the phagocytosed material. These authors proposed the name X-linked myopathy with excessive autophagy. Subsequently, only one French family has been reported with similar clinical and histopathological data. We report here five new families with a total of eight affected boys with the same clinical and histopathological features as reported in the original families. Histopathological findings of an asymptomatic mother are also reported. Vacuolar changes in muscle fibers result both from invaginations of the sarcolemma along with a variable component of basal lamina and from an autophagic process. The complement C5b-9 membrane attack complex associated with MHC class 1 antigen and calcium deposits is involved in muscle fiber damage. Among the X-linked myopathies, the identification of this new type is of great interest because of its favorable prognosis and unique morphological findings.

Purpose: Acute myopathy of intensive care has been described infrequently in children and never after organ transplantation. We report a case of acute myopathy of intensive care in a child after heart transplantation., Clinical Features: An 11-yr-old girl, with no previous medical history, developed acute cardiomyopathy leading to cardiac shock. Family history revealed four cases of unidentified myopathy and/or cardiomyopathy. Preoperatively, while muscle biopsy was near normal, myocardial biopsy revealed non specific mitochondrial disorders. A few days after heart transplantation, she developed acute hypotonia and flaccid quadriplegia, consistent with the diagnosis of acute myopathy of intensive care. Nerve conduction studies were normal, electromyography showed myopathic changes and a new muscle biopsy from quadriceps femoris showed severe loss of myosin filaments and ATPase activity in type 2 fibres. A large laboratory screening failed to demonstrate a metabolic disease or a known myopathy. Muscle strength recovered progressively in three weeks allowing home discharge. A few months later, she was free of symptoms and muscle biopsy showed full histopathological recovery., Conclusion: Acute myopathy of intensive care can occur in children after heart transplantation. It should be suspected in the presence of muscle weakness and difficulty in weaning from ventilatory support. Electromyography confirmed a myogenic process and muscle biopsy allowed diagnosis. Full clinical and histopathological recovery usually occur within three weeks.

Unlabelled: MACROPHAGIC MYOFASCIITIS: A most unusual inflammatory myopathy, first described by Germmad had been reported with increasing frequency since 1993 in the leading French myopathology centers. We present our experience with this new disease: macrophagic myofasciitis., Clinical Features: By November 1999, 70 cases of macrophagic myofasciitis had been recorded since our first description. The first 22 patients (sex ratio M/F = 1:3) referred with the presumptive diagnosis of polymyositis (n = 11), polymyalgia rheumatica (n = 5), mitochondrial cytopathy (n = 4), and congenital myopathy or muscle dystrophy (n = 1 each). Symptoms included myalgia (91%), anthralgia (68%), marked asthenia (55%), muscle weakness (45%), and fever (32%)., Laboratory Findings: Abnormal laboratory findings included elevated CK levels (50%), markedly increased erythrocyte sedimentation rate (37%), and myopathic EMG (35%). Muscle biopsy showed a unique myopathological pattern characterized by: i) centripetal infiltration of epimysium, perimysium and perifascicular endomysium by sheets of large cells of the monocyte/macrophage lineage (CD68+, CD1a-, S100-, with a PAS-positive content; ii) absence of necrosis, of both epithelioid and giant cells, and of mitotic figures; iii) presence of occasional CD8+ T-cells; iv) inconspicuous muscle fiber damage. The picture was easily distinguishable from sarcoid myopathy and fasciitis-panniculitis syndromes. The infectious diseases know to be associated with reactive histiocytes, including Whippleís disease, Mycobacterium avium intracellulare infection and malakoplakia, could not be documented. Patients improved under corticosteroid therapy and/or immunomodulatory therapeutic, Conclusion: A new inflammatory muscle disorder, characterized by a distinctive pathological pattern of macrophagic myofasciitis is emerging in France.

X-linked myopathy with excessive autophagy (XMEA, MIM 310440) is a rare inherited mild myopathy. We have used 32 polymorphic markers spanning the entire X chromosome to exclude most of the chromosome except the Xq28 region in a large XMEA family. Using three additional families for linkage analysis, we have obtained a significant two-point lod score with marker DXS1183 (Z = 2.69 at theta = 0). Multipoint linkage analysis confirmed the assignment of the disease locus with a maximal lod score of 2.74 obtained at recombination fraction zero. Linkage of XMEA to the Xq28 region is thus firmly established. In addition, we have ruled out the Emery-Dreifuss muscular dystrophy to be allelic with XMEA by direct sequencing of the emerin gene in three of our families.

We report the case of a 28 year-old woman with left scapuloperoneal syndrome since the age of 24. The course was slowly progressive and diffuse weakness was observed 4 years later. Serum creatine kinase levels were moderately elevated (x3 normal value) and EMG showed mixed neurogenic and myogenic patterns. Muscle biopsy showed type I predominance and numerous reducing bodies in muscle fibers. Reducing bodies were strongly immunoreactive with antibodies to dystrophin, alpha-sarcoglycan, vimentin and ubiquitin. Desmin immunoreactivity was increased at the periphery of some reducing bodies but alphaB crystallin, alpha actinin, titin and nebulin were negative. Western blot analysis showed an increase in dystrophin, vimentin and desmin expression. Ultrastructurally, reducing bodies were composed of tubulofilamentous material, 17 nm in diameter, and immunoreactive with anti-Dys 2 antibody. Granulofilamentous material, immunoreactive with anti-desmin antibody was observed at the periphery of some reducing bodies. This report further highlights the proteinic composition of reducing bodies and shows that late onset reducing body myopathy may occur.

Muscle biopsy is a simple procedure of great diagnostic interest when correct processing is obtained. Specimens for molecular genetics are very important. Paraffin embedded material is not sufficient in most of the cases except in some inflammatory processes. Histochemical techniques on frozen material are of major interest. Immunohistochemistry and electron microscopy can also be used. The aim of this paper is to describe the procedure of the muscle biopsy, the various techniques and the possible artefacts.

Clinicopathological, immunohistochemical and biochemical studies were performed on seven patients from five families showing an abnormal accumulation of desmin in the muscle fibers. Late onset myopathy was observed in all the cases studied. The clinical features were heterogeneous and usually nonspecific. However, some patients presented with dysphonia, dysphagia or cardiomyopathy. These features are highly suggestive of desmin myopathy. Using electron microscopy, desmin myopathy is characterized by an accumulation of granulofilamentous material. Depending on the distribution of the material, however, three different patterns of desmin accumulation can be observed: (1) large circumscribed inclusions, (2) intermyofibrillar areas of diffusely distributed material, and (3) deposits around large spheroid bodies. The second pattern is characterized by a rubbed-out appearance using oxidative enzyme reactions. For all the patients studied here, the immunohistochemical data showed that the desmin accumulation fitted these three patterns of distribution. For six patients, immunoblot analysis confirmed the desmin accumulation patterns and showed that an increase in the expression of the 53-kDa protein had occurred. The third pattern of desmin accumulation confirms the pathological heterogeneity of cytoplasmic and spheroid bodies. Desmin does not accumulate in all cytoplasmic and spheroid body myopathies, as observed in two other familial cases presented here.

31-P MR spectroscopy has been used to investigate metabolic events surrounding muscular contraction in a patient with an unusual myopathy characterized by clinical signs of muscle stiffness and swelling after prolonged exercise. Histological assays demonstrated a predominance of type II fibers with tubular aggregates. These structures had low calcium content although calcium-ATPase protein was present. Metabolic measurements were normal at rest except for the presence of a marked signal in the phosphodiester region which could reflect membrane abnormalities. Exercise-induced PCr consumption was in the normal range but the extent of the related intracellular acidosis was abnormally large. Kinetics of PCr and PCr/Pi ratio post-exercise recovery were delayed, but were likely to reflect the effect of the very low end-of-exercise pH rather than an aerobic deficiency. Finally, proton efflux from muscle to bloodstream, measured during the initial recovery period, was delayed, indicating altered mechanisms of proton handling. The most prominent metabolic abnormality recorded is the large glycogenolysis-induced pH decrease which might be linked to either abnormal activation of glycogenolysis and/or impaired proton and lactate handling within the muscle. The association between tubular aggregates and hyperacidosis is of interest but the exact causal relationship remains to be elucidated.

Acute myopathy occurred in a 49-year-old woman hospitalized in the intensive care unit for status asthmaticus. She was given high-dose intravenous steroid therapy and intubated. Pancuronium bromide was used for prolonged curarization. Flaccid quadriplegia developed with preservation of the deep tendon reflexes. Muscle biopsy showed a myogenic process with disorganized myofibrils and selective loss of thick myosin filaments. This mainly myogenic process would result from the toxic effect of corticosteroids favored by prolonged curarization although the effect of other factors still remains unknown.

The pathological findings in 165 patients explored for malignant hyperthermia (MH) susceptibility are reported. The first group of 120 subjects were patients investigated for MH. These patients had suffered an attack of MH under anaesthetic or were members of families in which a subject had died of MH. In vitro contracture tests revealed 25 malignant hyperthermia susceptible (MHS) subjects, with positive contracture tests for halothane and caffeine, 5 malignant hyperthermia subjects with reaction to caffeine only (MHC), 3 malignant hyperthermia subjects with reaction to halothane only (MHH) and 87 malignant hyperthermia negative (MHN) subjects with normal contracture tests. The second group of 45 subjects had exertional heat stroke. In vitro contracture tests performed at least 3 months after the exertional heat stroke revealed 11 MHS, 6 MHC, 2 MHH subjects and 26 MHN. In both groups, whatever the in vitro contracture test results, pathological findings were heterogeneous and revealed various changes: rhabdomyolysis, mitochondrial myopathy, denervation, type II atrophy, AMPase deficiency, non-specific findings or normal features. Central core myopathy was only observed in the first subgroup and was the only disease significantly associated with MH. In contrast to previous reports, this study demonstrates the absence of a specific malignant hyperthermia or exertional heat stroke myopathy. Furthermore, the discovery of MHS subjects among the EHS group of patients highlights the need for systematic exploration of all these patients.

Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/P(i)) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/P(i) ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the improvement, showing a significant increase in the PCr/P(i) ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/P(i) ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment.

In order to evaluate the developmental status of myofibers in 3 cases of adult centronuclear myopathies (CNM) with type I predominance, we searched for the expression of (a) developmentally regulated cytoskeleton proteins (myosin heavy chains (MHC), vimentin, desmin), and (b) cell surface molecules (neural cell adhesion molecules isoforms, NCAM). Desmin intermediate filaments were overexpressed in some fibers with centrally located nuclei and radially organized. Muscle fibers do not express vimentin. These findings were not observed in muscle biopsies from disease controls with numerous central nuclei. Few myofibers (less than 5%) expressed developmental MHC together with either embryonic NCAM or adult NCAM and rare fibers only expressed adult NCAM. Most of the remaining fibers neither expressed NCAM nor developmental MHC but were slow MHC positive. These features do not favor the hypothesis of a general arrest of muscle fiber maturation in adult CNM. It is more likely that fibers undergo a very slow developmental process with a long delay of innervation as shown by some fibers with NCAM expression. Nevertheless, innervation appears to be successful, as suggested by the large number of NCAM negative fibers. Moreover, the abnormal myofiber distribution could be related to this functional disturbance of innervation.

Purpose: The coexistence of mitochondrial myopathy and polymyalgia rheumatica without giant cell arteritis is an interesting association. The frequency of this association was assessed in a prospective study., Patients and Methods: Muscle biopsy specimens were obtained from 15 patients with polymyalgia rheumatica. When ragged red fibers (RRF) were observed, histochemical, ultrastructural, and biochemical studies were performed., Results: In five cases, we found the typical appearance of mitochondrial myopathy, with the presence of numerous RRF. Histochemical and biochemical results confirmed these mitochondrial myopathies, showing miscellaneous deficiencies of mitochondrial respiratory chain enzymes., Conclusion: Persistence of histologic and biochemical abnormalities after steroid treatment in two patients seems to indicate that a subclinical mitochondrial myopathy preceded polymyalgia rheumatica. How a mitochondrial myopathy could induce or facilitate the emergence of a polymyalgia rheumatica remains unknown.

We report a late onset form of polysaccharide myopathy with progressive limb girdle muscles weakness, without cardiomyopathy. Muscle biopsy showed a vacuolar myopathy in type 1 fibres. The PAS positive diastase resistant deposits were made of filamentous material at electron microscopy similar to long chain glycogen. Muscle glycogen levels and glycogen metabolism enzymes were normal. Numerous abnormal mitochondrial with paracrystalline inclusions were observed around the storage material. Twelve patients with polysaccharide amylopectin-like storage myopathy have previously been reported. This disease must be distinguished from other diseases with polysaccharide accumulation such as branching enzyme deficiency and some cases of phosphofructokinase deficiency. In other disorders, no deficient enzymes in the glycogen pathway was found. Some of them show systemic storage (Lafora disease, adult polyglucosan body disease). Corpora amylacea, Bielchowsky bodies and basophilic degeneration of the myocardium represent localised depositions. A few inclusions can also be observed in hypothyroid myopathy. In polysaccharide myopathy allosteric inactivation of phosphofructokinase by a mitochondrial dysfunction is considered by analogy with cases of polysaccharide storage related to phosphofructokinase deficiency.

A 55 year-old male experienced a dystonia of the right upper limb followed by a ptosis with complete ophthalmoplegia and cataract. He developed a sensory neuropathy and personality changes. Ragged-red fibers were found on muscle biopsy. There was a major defect in complex III and IV activity.

The case of a 41 year old woman with amyloid myopathy is reported. Clinical involvement consisted of limb girdle muscle weakness, mild scapular muscle atrophy and dysphagia. In contrast with the published cases, abnormal firmness, pseudohypertrophy of the musculature and macroglossia were absent. Muscle biopsy showed endo- and perimysial amyloid deposits but also inflammatory infiltrates. Inflammatory cells typing was studied by immunocytochemical methods and revealed a predominant T-helper cell infiltration. Free kappa light chains were present in serum and urine. Serum immunoglobulin levels were reduced. Bone marrow examination revealed mild plasmocytosis without abnormal cells. Immunofluorescence and immunoperoxidase techniques for identification of the type of amyloid fibrils showed positivity with antisera to kappa light chains. A 4-year follow-up revealed a progressive worsening of muscle weakness despite immunosuppressive treatment. No malignant plasmocytosis occurred. The unusual inflammatory muscle infiltration observed in this case may suggest an associated polymyositis.

Muscular glycogenosis is a disease resulting from genetic abnormalities altering an enzyme which is involved in glycogen metabolism. In addition to disorders of glycogenolysis and glycolysis, there are other pathological processes such as acid maltase (alpha-glucosidase) deficiency and diseases associated with abnormal glycogen structure. Glycolysis is the only metabolic pathway that can produce ATP in the absence of oxygen. It is then easy to understand that any disturbance in this energy pathway can result in dysfunction of the muscle machine and in a number of symptoms which are common to these abnormalities. An overall review of the various diseases know to exist on the glycogenolytic and glycolytic pathway will enable the reader to acquire a better knowledge of their particular features.

Slowly progressive myopathy with tubular aggregates is rare and dominantly or recessively inherited. Three sporadic cases are reported in the present study occurring in 2 men and 1 young woman. All patients had proximal limb weakness without severe atrophy. They also complained of exercise-induced stiffening and cramps of their leg muscles. In 1 case severe cardiomyopathy caused unfavorable clinical course and death. Serum creatine kinase activity was normal and electromyogram showed only slight myopathic changes. Tubular aggregates were found to be the sale morphological abnormality. They were present in type II fibres in 1 case and in type I and type II fibres in the others. An immunocytological study with a polyclonal antibody against Ca2+ SR-ATPase showed positivity of the tubular aggregates with this antibody. A quantitative analysis (SAMBA 2000 alcatel TITN) was carried out on frozen sections stained for calcium. It showed a lower calcium content in tubular aggregates than in other part of the fibre. Slowly progressive myopathy with tubular aggregates may be distinguished from other diseases where tubular aggregates are the sale structural change, such as myopathies with myasthenic features and some neuromuscular diseases with exercise intolerance without progressive course. Usually, tubular aggregates are not a specific finding; they have been described in various disorders in association with other structural changes.

Antibodies directed against neural cell adhesive molecules (NCAM) and in particular a monoclonal antibody recognizing polysialylated isoforms, were used to characterize the expression of these molecules in normal and diseased human muscles. Normal subjects as well as patients with inflammatory, dystrophic and denervating diseases were examined. By immunohistochemistry the main observations were (1) satellite cells expressed the non-sialylated form of NCAMs; (2) regenerative fibers strikingly expressed NCAMs and their sialylated isoforms both on membranes and in the cytoplasm; (3) in denervated muscles, fibers in atrophic groups and some fibers in acute denervation expressed NCAMs on their membrane but not the highly sialylated form; (4) finally, some fibers in myotonic dystrophy and fibers with rimmed vacuoles also expressed NCAMs. Biochemical approaches, using enzymes such as endoglycosidase N and phosphatidylinositol phospholipase C combined with immunoblot analysis allowed visualization of the nature of the expressed isoforms. We have shown that non activated cells, i.e. satellite cells and denervated fibers do not express polysialylated NCAMs. This post-translational modification may be only observed in activated or regenerating fibers. This would parallel the sequence of NCAM expression occurring in normal myogenic pathways.

The authors report 5 cases of stress myalgias associated with tubular aggregates seen in muscle biopsy specimens. A few similar cases are reported in the literature and a close relationship is established by some authors between the morphologic anomaly present in type II fibers and the lack of tolerance to stress. However, tubular aggregates are not specific and found in other disorders, especially the hyperkaliemic periodic paralysis where all types of fibers are affected. The origin of the aggregates is unknown. They could come from the endoplasmic reticulum containing an excess of calcium and form aggregates in order to prevent a muscle contraction.

In ten patients with inclusion body myositis (IBM) five muscular biopsies showed profuse inflammatory exudates and three showed a few scattered inflammatory cells with partial invasion in some muscle fibers. No inflammatory cells were seen in two cases. In all patients, histopathological, histomorphometric and immunocytochemical studies were performed. Immunocytochemistry for the class I and class II major histocompatibility complex gene product (MHC) was performed in all cases and in ten control muscles including: normal muscles [3], dermatomyositis [3], polymyositis [3], scleroderma [1]. In the five cases of IBM with inflammatory exudates, subsets of lymphocytes were analyzed with a panel of monoclonal antibodies against B cells, T4 cells, T8 cells, K and natural killer cells and macrophages. Some muscle fibers expressed class I MHC antigens in the inflammatory cases of IBM. These fibers were near the inflammatory exudates and occasionally showed a partial invasion. No expression of class I MHC was found in normal muscles and in non-inflammatory cases of IBM. The antigen which triggers the mononuclear cells in the inflammatory forms of IBM is probably not the filamentous inclusions in rimmed vacuoles. In other inflammatory myopathies, expression of class I MHC was present on all fibers in polymyositis, only in the perifascicular area in dermatomyositis and in scleroderma. It could be suggested that the term "inclusion body muscle disease" be applied to cases with rimmed vacuoles and "IBM-like" filaments without inflammatory cells.

Exercise intolerance with slight myalgia worsened by a cold environment resulted in the diagnosis of CPT deficiency in a young boy with no family history. Recurrent myoglobinuria is not the hallmark of such a deficit. Biochemical examination of muscle biopsy in suggestive situations is the way to diagnosis. Concomitant myoadenylate deficiency in this patient could represent a precipitating factor. Partial CPT deficiency in all the patients reported was first explained through the mechanism of intra mitochondrial fatty acid transport but raises questions about the regulation of CPT synthesis.

The muscle biopsy performed in a 58-year-old woman with a myopathy involving pelvic girdle and lower limbs displayed unusual intermediate filament aggregates by light and electron microscopy. No cardiac involvement was detected. The filamentous aggregates selective for type 1 fibers were found in subsarcolemmal and intermyofibrillar areas closely related to Z bands. Immunohistochemical study by light and electron microscopy using polyclonal and monoclonal antibodies and avidin-biotin peroxidase method revealed that aggregates consisted of desmin filaments. Desmin positive material was unstained with vimentine antibodies.

A predominance and/or an atrophy of type I fibers and a loss of deep tendon reflexes are often observed in different types of congenital myopathy. Various data indicate that both findings can be linked: dysfunction of the myotatic reflex can induce predominant involvement of type I fibers. In order to specify the mechanism of the loss of tendon reflex, an investigation of the Hoffmann reflex (H reflex) was performed in one case of centronuclear myopathy and in one case of congenital type fiber disproportion with type I hypertrophy. The Achilles tendon reflex was absent but the H reflex showed normal recruitment amplitude and latency. The Jendrassik maneuver reinforced the H reflex. These results indicate the involvement of muscle spindles or impairment of the fusimotor system. Nuclear bag intrafusal fibers have common characteristics with type I extrafusal fibers. Both types of fibers could be involved simultaneously in congenital myopathies, thus explaining the loss of tendon reflex.

A 34 year-old man had complained since childhood of weakness of the right lower limb. His mother had a myopathy. Examination showed weakness and amyotrophy of the antero-external regions of the legs, mainly on the left, moderate weakness of the right scapular girdle and slight facial weakness. Serum creatine kinase was increased. Electromyogram and CT scan images were of the myogenic type. Biopsy showed a centronuclear myopathy. The course was slowly progressive. Centronuclear myopathy is rare in adults. The facio-scapulo-humeral localization has been described in numerous other pathologic types of myopathy.

Two recent publications have shown the advantage of understanding the deficit in AMP desaminase in rheumatology. On this subject, the authors report 4 cases of deficit in AMP desaminase. The first one includes a semiology made of pain, and stiffening, the second case is discovered in the course of a primary muscular disease. The third case is present during the first stage of a spinal cord compression. The fourth case is a muscular deficit accompanied with a histological picture of inflammation, considered initially as a chronic polymyositis, but explained secondarily as a pseudo-polymyositis form of facio-scapulo-humeral dystrophy. In this respect, the cases from the literature are divided into three groups: asymptomatic, infraclinical forms, forms occurring in the course of specific diseases (muscular diseases, spinal cord diseases, inflammations of the connective tissues, metabolic diseases), apparently isolated forms. In the latter, emerges a semiology made of pain, cramps, stiffening of the lower extremities occurring on exertion. However, the specificity of the symptoms remains to be discussed.

Concentric laminated bodies are described in five cases (one case previously reported and four new ones) of various muscle diseases. A general review of previous reports on these structures is made. They appear to be unspecific bodies generally noticed in abnormal skeletal muscle in various disorders; nevertheless they were found in normal muscle fibres of the mothers of children affected by myopathy. They have a complex filamentous structure. According to the authors, their myofilamentous nature is uncertain but seems more probable than a mitochondrial or lipidic one.

Osteomalacic myopathies are rare. They can prevail, however, and occur before bone abnormalities. The diagnosis must rest on clinical observation since the histopathologic images are not specific. On the other hand the demonstration of muscular weakness is very frequent during osteomalacia. In fact two types of manifestations correspond to the same anatomopathologic lesions. These are myopathic changes observed also during light microscopy, histoenzymologic and ultrastructural examination in the 10 patients examined. On the basis of these morphologic changes, muscular involvement can be considered to be part of the osteomalacia syndrome. The contribution of various factors including secondary hyperparathyroidism, vitamin D metabolism disorders, and phosphorus depletion is discussed. It is probable that many of them act together, causing reversible changes in muscular fibers. The intimate mechanisms of these changes are unknown.

The case of 65 year old woman with progressive enlargement and "wooden" induration of the pelvic girdle and thigh muscles due to an amyloid infiltration is reported. Muscle changes appeared two years after a diagnosis of myeloma with free lambda light chains. The patient complained of muscle pain, lassitude and weakness. Macroglossia was present. Skeletal muscle (vastus lateralis) contained large amounts of amyloid substance and showed type 2B atrophy. There was no fiber type grouping. Some amyloid deposits abutted on the muscle fiber, destroyed the basal lamina and sarcolemma, but never infiltrated it. Besides the amyloid phagocytosis by macrophages, a relationship between amyloid filaments and fibroblasts was present. Another non-congophilic substance was revealed using the Avidin-Biotin peroxidase complex to localize lambda light chains by light microscopy and corresponded to a granular substance in electron microscopy. Clinicopathological results are discussed with a review of thirteen similar cases previously reported.

The authors describe a case of myopathy characterized physically by limb weakness, eyelid ptosis, voluntary and reflex paralysis of vertical movements of gaze, and loss of deep tendon reflexes; and morphologically by the abnormal presence of centrally located nuclei in muscle fibers and type 1 fiber hypotrophy. The establishment in this case study of two particular findings--the probably nuclear or supranuclear ophthalmoplegia and the apparently impaired nuclear migration from the center of the muscle fiber toward its periphery--supports the hypothesis of a neuromuscular disorder whose level of severity depends on the degree of difficulty in the nuclear migration itself. This would be linked to a reduction in central nervous system influence.

210 cases of diffuse myalgias are analysed. Among them two groups of very near frequency can be distinguished. The first group (100 cases) concerns mainly inflammatory myalgias. In the second group (110 cases) no organic aetiology is found. They appear as purely "functional", frequent manifestations of an anxious and/or depressive condition. Their evolution is often chronic and refractory to therapeutics; the diagnosis is frequently misappreciated.

A case of centronuclear myopathy is presented, showing a rapid course in a 47-year-old male. Clinical and muscular findings were consistent with the diagnosis of centronuclear myopathy. On nerve biopsy, there was evidence of a regenerative process. Electron microscopy showed proliferation of Schwann cells with numerous Büngner's bands and other anomalies. This rare case with peripheral nerve changes may provide evidence to support the hypothesis of peripheral nerve involvement in centronuclear myopathy.

The inflammatory forms of facioscapulohumeral myopathies are rare. In a series of 52 cases, six patients had these types. Only four cases could be investigated with immunochemical staining (immunoperoxidase). Monoclonal antibodies reactive for B cells, T4 cells, T8 cells, natural killer cells were used for cell typing. Macrophages were identified by the acid phosphatase reaction. Nine muscles have been used as controls: 3 normal muscles, 3 polymyositis and 3 dermatomyositis. In all these inflammatory myopathies T cells were the most abundant cells. NK cells were rare. In inflammatory FSH-D and in polymyositis the infiltrates were principally endomysial, whereas T8 lymphocytes were more abundant than T4 lymphocytes; it was the contrary in the perivascular and perimysial sites of accumulation. In dermatomyositis the infiltrates were especially perivascular. In this site of accumulation T4 was twice abundant than T8, B cells and macrophages were also very abundant. In the endomysium the T8 cells were more numerous than T4 cells. It seems that the inflammatory forms of FSH-D should be considered as an inflammatory myopathy. In these forms a polymyositis should be associated with the dystrophy. These forms could be considered as an association of a polymyositis and a muscular dystrophy, but the circumstances of their appearance and their non-response to corticosteroid administration remain to be determined.

The authors review the literautre and then proceed to analyse a series of 16 cases of Gougerot Sjögren Syndrome. The electromyogram (EMG) was abnormal on only 2 occasions. Histologically inflammatory aspects could be seen on 4 occasions with perifascicular atrophy in one case. Atrophy of II fibres was present in 7 cases together with signs of disorganization of the mitochondrial reticulum and images of mitochondrial aggregates. Under the electron microscope minor anomalies were particularly visiole and the internal structure was normal as often as not. Overall it is possible to distinguish forms of a subacute polymyositis type (4 cases), and a pauci-inflammatory myalgic type proximal to the scappular predominance (4 cases), in which the mitochondrial anomalies are commonest. Another "infraclinical" group shows no other frankly pathological changes. Finally in 3 cases the "dry" syndrome is strictly free of any muscular attack.