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Juvenile dermatomyositis (JDM), adult dermatomyositis, and polymyositis (PM) are idiopathic inflammatory myopathies (IIMs) characterized by muscle infiltration and specific muscle fiber alterations. They are thought to have an autoimmune etiology, but triggering factors, and how immunologic attack induces muscle weakness, remain unknown. Recent evidence suggests a key role for type I interferon (IFN)-mediated innate immunity in dermatomyositis, which we explored in JDM, dermatomyositis, and PM by gene expression profiling, and other methods.

Congenital muscular dystrophies (CMD) with reduced glycosylation of alpha-dystroglycan (-DG) are a heterogeneous group of conditions associated with mutations in six genes encoding proven or putative glycosyltransferases.

The diagnosis of glycogenosis type II is often complicated by the rarity of the condition and the heterogeneity of the clinical manifestations of the disease. It is a progressive, debilitating, and often fatal neuromuscular disorder that manifests as a continuum of clinical phenotypes, which vary with respect to organ involvement, age at onset, and severity. Early diagnosis requires both increased awareness among physicians regarding the clinical characteristics of the disease and fast and reliable acid alpha-glucosidase (GAA) enzyme activity assays to confirm the GAA deficiency. The clinical diagnosis of glycogenosis type II is confirmed by virtual absence (found in infants) and marked reduced activity (found in juveniles and adults) of GAA enzyme in blood samples, cultured fibroblasts, and muscle biopsies. This article specifically highlights the need for early recognition of the clinical manifestation of the disease in infants, juveniles, and adults. Descriptions of the main clinical features of the condition, as well as differential diagnosis are included. In addition, the tests required for a confirmed diagnosis are described, and use of muscle imaging to evaluate muscle pathology is reviewed.

Glycogenosis type II is a multisystem disorder that requires management by a multidisciplinary team. The team should include several specialists, such as a metabolic disease specialist or biochemical geneticist, cardiologist, pulmonologist, neurologist, neuromuscular specialist, intensivist, orthopedist, respiratory therapist, physical therapist, occupational therapist, otolaryngologist speech therapist, audiologist, genetic counselor, and a metabolic dietician, who, as a team, will be capable of addressing the different manifestations of the condition. Aspects of functional assessment, rehabilitation, nutritional management, care coordination, nursing, genetic counseling, prenatal diagnosis, and screening are discussed in this article. In addition, treatment of glycogenosis type II is reviewed with attention to emerging therapeutic options.

Mutations in the LMNAgene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype correlation could be established to date.

To assess the efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy in a randomized, double-blind, placebo-controlled trial involving 10 Italian centers.

Glycogen storage disease type IV (GSD-IV) is a clinically heterogeneous autosomal recessive disorder due to glycogen branching enzyme (GBE) deficiency and resulting in the accumulation of an amylopectin-like polysaccharide. The typical presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular form of GSD-IV varies in onset (perinatal, congenital, juvenile, or adult) and severity.

The term myofibrillar myopathy refers to a rare and clinically heterogeneous group of muscle disorders. The pathogenesis of this myopathy is not well understood. The morphologic hallmark is myofibrillar destruction with abnormal expression of numerous proteins, most consistently of desmin.

Nonsense mutations outside the splicing consensus sequence have been reported to cause skipping of the nonsense-containing exon in several human diseases. We describe, for the first time, nonsense-mediated exon skipping in the laminin alpha2 (LAMA2) gene. Two siblings from a consanguineous family had altered expression of the laminin alpha2 chain and moderate clinical manifestations. In both we identified the new nonsense mutation Arg744Stop, which we expected to result in a totally non-functional polypeptide. However, analysis of the transcript revealed skipping of exon 15, containing the mutation, even though the consensus sequences for splicing at both ends of the exon and the beginning of intron 15 were unaltered. Exon skipping restored the open reading frame of the mutant transcript and resulted in a truncated protein. In cases where the genetic findings do not elucidate the phenotype, mRNA analysis is necessary to clarify the primary effect of mutations. Our findings also point to the necessity of immunochemical screening for expression of laminin alpha2 chain in atypical dystrophic adults as well as children.

Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the β sarcoglycan gene. One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaffected father carries the 8 bp duplication, was not found. In patient 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of α and γ sarcoglycans in heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. Differing expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy can result from mutations in α and γ sarcoglycans, we show for the first time that the condition can also be caused by mutations in the β sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.

Abstract: We present the MRI findings in five patients with congenital muscular dystrophy (CMD) and merosin (laminin α 2) deficiency, which was total in one and partial in four. In one patient with partial merosin deficiency, MRI was normal. The other four patients had supratentorial white matter abnormalities. In three, T2-weighted images revealed subcortical, deep lobar and periventricular high signal in white matter, while in the other there were only small peritrigonal areas of increased signal. On T1-weighted images, there was slightly low signal. Cortical abnormalities were absent. None of these changes were accompanied by symptoms or signs of central nervous system involvement. White matter abnormalities in a patient with CMD should prompt investigation of merosin.

We report our experience on myoblast transplantation in three Duchenne muscular dystrophy patients. Pure myoblasts (55 × 10 6per patient) from HLA-matched donors, were injected into a tibialis anterior and the controlateral muscle was sham injected. Three months after transplantation, biopsies from the injected muscles were negative for dystrophin expression by immunocytochemistry. Reverse transcriptase-PCR (RT-PCR) failed to amplify any fragments of the deleted regions. This result confirms that myoblast transplantation is feasible, although the efficacy of this therapeutic approach is poor.

We report our experience of needle biopsy over the past two and a half, viz. 395 cases. We find that the technique meets the needs of diagnosis and research very satisfactorily. We describes its advantages over open biopsy and recommend it in preference to the latter, provided that the necessary technical skill for processing the sample is available.

A protocol for the evaluation of functional activities in subjects with Duchenne muscular dystrophy (DMD) was designed. The aim of our study was to define objective clinical criteria for the evaluation both of the clinical status of the patient and of the natural history of the illness itself. A protocol with such criteria is particularly necessary when testing the efficacy of treatment. 43 still-ambulant children with DMD between the ages of 3.10 yr and 10.4 yr were examined. Of this number 19 children were evaluated every 4 months over a period of 12 months; of these 14 formed part of a randomized double blind trial with L-carnitine (1.2–1.8 g/day) versus placebo.

The case of a 69-year-old woman who developed muscle weakness on chronic amiodarone treatment is reported. Muscle biopsy showed vacuolar alterations and a marked accumulation of amiodarone and of its metabolite desethylamiodarone was found in the muscle sample despite normal blood levels. Amiodarone-induced morphological alterations of the muscle may be related to the actual tissue concentration rather than to the blood level.

Muscle hypertrophy is rare in denervating diseases. A patient with calf enlargement associated with L5–S1 radiculopathy and another with thenar, hypothenar, forearm and calf muscle hypertrophy in the course of chronic relapsing inflammatory demyelinating polyneuropathy are described. Gastrocnemius muscle biopsy revealed both type I and type II fibre hypertrophy in the former case and predominant type I fibre hypertrophy in the latter. Passive stretching and abnormal spontaneous muscular activity might have played a role in the origin of hypertrophy in both patients, but a satisfactory explanation for denervation hypertrophy has yet to be provided.

Over the last 14 years we have thymectomized 106 myasthenic patients, 62 by transcervical and 44 by transsternal approach. At the end of the follow-up 49 patients (46,2%) had improved, 12 of these (11,2%) being in remission. Our data supply no guidance regarding the prognosis of individual patients at the time of thymectomy.

We studied the effect of riboflavin treatment on the clinical status and on the activities of β-oxidation and respiratory chain enzymes in a 69-year-old patient with late-onset myopathy. Before treatment, she was very weak and wasted in the limbs and trunk muscles; also, she could not walk or attend to daily activities. Marked lipid storage was present in the muscle biopsy. The activities of short-chain acyl coenzyme A (acyl-CoA) dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) in isolated muscle mitochondria were reduced to less than 10 of control values. This defect in fatty acid oxidation was associated with a marked deficiency of two flavin-dependent respiratory chain complexes: complex I activity was 20 and complex II activity was 25 of control values. By contrast, the activities of the nonflavin-dependent complex III and complex IV were normal. Western blot analysis of the patient's muscle mitochondrial extracts with antibodies raised against purified SCAD, MCAD, and the α-and β-subunits of the electron transfer flavoprotein (ETF) showed absence of SCAD cross-reacting material (CRM), markedly decreased MCAD-CRM, and normal amounts of both α- and β-ETF-CRM. After riboflavin treatment, the patient's clinical status dramatically improved and morphologic changes in muscle disappeared. SCAD activity increased to 55 of control values, whereas MCAD, LCAD, and complex I and complex II activities normalized. SCAD and MCAD immunoreactivity was restored to normal. On the basis of our experience and the data in the literature, we concluded that some lipid storage myopathies can show dramatic response to riboflavin.

Abstract: We have investigated the expression, using immunohistochemistry, of β- and γ-sarcoglycans in the muscles of 20 patients in whom previous screening had revealed a deficiency of α-sarcoglycan. α-, β- and γ-sarcoglycans were absent in 7 patients and variably reduced in 8 patients, in 2 of whom β-sarcoglycan was more reduced than the α- and γ-proteins. In 5 other patients with variably reduced α- and β-sarcoglycans, γ-sarcoglycan was completely absent. In all patients the distribution of hyposthenia at disease onset was similar, and predominantly involved pelvic girdle muscles; however, the age at onset and rate of disease progression were highly variable. In severely compromised patients, the onset of disease was before 10 years of age and γ-sarcoglycan or all three sarcoglycans were absent from muscles. Immunohistochemical analysis of sarcoglycans should be part of routine screening for muscle dystrophies to identify patients with sarcoglycanopathy. Gene analysis is necessary to identify the primary defect; however, sarcoglycan immunohistochemistry may be useful for indicating which gene to investigate. Further biochemical characterization of the interactions between these proteins is required to fully elucidate their roles in causing severe, moderate or mild muscular dystrophy.

Abstract: The absence of dystrophin in muscle fibers is associated with a major reduction in dystrophin-associated proteins (DAPs) and disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. We investigated the expression of the DAPs β-dystroglycan, α-sarcoglycan, γ-sarcoglycan and syntrophin as well as utrophin in the muscles of 13 Duchenne muscular dystrophy (DMD) carriers (with variable percentages of dystrophin-deficient fibers and with a range of clinical symptoms), 2 Becker muscular dystrophy (BMD) carriers (expressing a highly truncated protein in some fibers), 2 girls with a DMD-like phenotype, and 11 BMD carriers with almost normal dystrophin expression (reduced or patchy distribution in a few fibers only and rare dystrophin-deficient fibers). DAPs were highly reduced in all fibers lacking dystrophin in the DMD carriers, but were almost normal in the dystrophin-deficient fibers of the 2 BMD carriers with highly truncated dystrophin. In the 11 BMD carriers with nearly normal dystrophin, the few fibers with reduced or patchy dystrophin immunostaining also showed reduced DAP expression in correlation with dystrophin expression. Immunoblot for β-dystroglycan and α-sarcoglycan confirmed the immunohistochemical findings. Utrophin expression was slightly increased in a proportion of fibers in the DMD and BMD carriers with dystrophin mosaicism. We found no correlation between utrophin expression and DAP expression. We conclude that absence or reduction of dystrophin in muscle fibers of DMD and BMD carriers causes a reduction of DAPs in the same fibers, as observed in DMD and BMD patients, while utrophin does not seem to play a role in DAP expression in adult muscle.

We have raised an anti‐emerin polyclonal antibody against a fusion protein encompassing most of the hydrophilic portion of emerin. Using this antibody, we have analyzed emerin expression in Emery‐Dreifuss muscular dystrophy (EDMD) patients and controls, by immunocytochemistry, in peripheral blood mononuclear cells and lymphoblasts. Emerin was localized on the surfaces of nuclei in control skeletal muscle and skin but was absent or reduced in patient skeletal muscle, was absent from the skin of patients, and was expressed only in a few nuclei in a patient's mother. Immunoblot of peripheral blood cells from EDMD patients showed absence of the emerin band, altered‐size emerin, or a protein of normal molecular mass but slightly reduced quantity. The diagnosis of X‐linked EDMD is normally confirmed by genegic analysis of the STA gene coding for emerin. We propose immunocytochemical evaluation of emerin expression in skin biopsies as a sensitive and more convenient tool for diagnosing X‐linked EDMD and, in particular, for distinguishing it from the autosomal dominant form. This technique may be applied to suspected EDMD patients, especially sporadic cases or those with incomplete clinical phenotype, and also suspected carriers. Immunoblot of peripheral blood cells is also useful, but it may not unequivocally identify carriers and some patients.

This paper deals with basic problems of glucocorticoid eosinopenia and of regulations within the eosinophile cell system. The effects of glucocorticoids on single regulatory factors of this system, such as eosinotactic stimuli, eosinopoiesis, life span and rate of removal of eosinophils, are discussed in detail. Eosinophilopoiesis is not influenced by glucocorticoids. This finding, added to the observation that blocking the reticuloendothelial system suppresses the glucocorticoid eosinopenia and that these compounds have no eosinolytic properties in vitro, speaks against the contention that the eosinopenic effect of the glucocorticoids is actually due to a direct lytic effect on the eosinophils. A distributional shift of eosinophils in vascular sectors functioning as blood depots, or a migration into tissues can be abandoned as explanations of glucocorticoid eosinopenia. The hypothesis of a fixation at sites of physiologic demand is certainly not a valid explanation of glucocorticoid eosinopenia, since glucocorticoids suppress the eosinotactic stimuli. Blocking experiments of the RES show that the rate of disappearance of the eosinophils is a resultant of the functional condition of the RES and of the sum of the eosinopenic stimuli. On the basis of our investigations we arrive at the conclusion that glucocorticoid eosinopenia depends upon an inhibition of the release of mature eosinophils from the bone marrow and upon an increased destruction of eosinophils in the reticuloendothelial system. The level of the original eosinophilia, that is to say, the percentage of young forms with a long life expectancy, determines the degree of eosinopenia attained by a single application of glucocorticoid and the time lapse before aneosinophilia develops under continuous glucocorticoid administration.

Zusammenfassung DieCharcot - Leydenschen Kristalle bilden sich unter bestimmten Bedingungen allmählich im Laufe der Autolyse menschlicher cosinophiler Granulocyten. Durch mechanische Läsion der Eosinophilen können im Objektträgerpräparat bereits innerhalb von Minuten Kristalle erzeugt und in ihrem Wachstum mikroskopisch verfolgt werden. Es handelt sich um unbeständige Gebilde, die in wäßriger, eiweißfreier Lösung oft nur wenige Stunden haltbar sind. Die In-vitro-Produktion vonCharcot-Leydenschen Kristallen und ihre Isolierung ermöglicht zahlreiche physikalische und chemische Untersuchungen.

Zusammenfassung Unter Berücksichtigung der erwähnten klinischen und experimentellen Tatsachen lassen sich über den Mechanismus der Insulineosinopenie folgende Rückschlüsse ziehen:1.Das Insulin wirkt an sich nicht eosinopenisch. Die Eosinopenie ist die Folge der durch das Insulin hervorgerufenen Hypoglykämie.2.Die Insulin-Hypoglykämie kann zur Eosinopenie führena)durch eine reaktive Adrenalinausschüttung, die die eosinopenische Wirkung der im Blut kreisenden Glucocorticoide potenziert,b)durch eine stressbedingte Vermehrung der ACTH-Glucocorticoid-Sekretion. Dieser Mechanismus ist aber nur dann im Spiel, wenn die Hypoglykämie einen Stress auslöst und wenn das HVL-NNR-System funktionstüchtig ist. In solchen Fällen ist der eosinopenischen Effekt die Resultante einer gesteigerten Sekretion von Glucocorticoiden und deren Potenzierung durch gegenregulatorisch ausgeschüttetes Adrenalin.

A 23-year-old man with X-linked Becker type muscular dystrophy underwent cardiac transplantation because of dilated cardiomyopathy which was complicated by terminal heart failure. Impairment of muscle function was mild and slowly progressive, whereas the cardiac disease was severe and rapidly progressive. All four chambers of the removed heart were grossly dilated; microscopically, the myocardial fibres were hypertrophic and pale; the nuclei exhibited pleomorphism with variability in nuclear size, shape, and depth of staining.

Zusammenfassung An Hand von 268 Fällen wird gezeigt, daß akute Kohlenoxyd- und Schlafmittelvergiftungen zu Veränderungen des Blutbildes führen, die der Stressreaktion nachSelye entsprechen. Im Mechanismus dieser Reaktion bestehen zwischen Schweregrad des Stress und Grad der Reaktion der neuralen und hormonalen Komponenten direkte gleichsinnige quantitative Beziehungen.