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M-line is the narrow transverse band located in the center of the sarcomeric A-band that is mainly responsible for the stabilization of myosin thick filaments. A 27-year-old male patient with a positive medical history for ankylosing spondylitis presented with one month of proximal upper limb muscle weakness associated with pain on both acromioclavicular joints. A biopsy of deltoid muscle documented the disappearance of M-line, the misalignment of myofilaments, and the loss of the distinction between the A and I bands. Complete resolution of muscle weakness occurred after one year of treatment with antiTNFα agent Etanercept. Because of the acute onset of symptoms and the recovery after immunosuppressive treatment we hypothesized that an immune-mediated mechanism was responsible for the muscle disorder. The serum IgG-mediated autoreactivity to skeletal muscle antigens resolved by bidimensional electrophoresis was assessed in the described patient and compared with that of control subjects. The comparative analysis of the immunoreactive spots revealed that ATP synthase subunit α is specifically recognized by patient's serum, suggesting that the protein might represent a putative antigenic target in the disease. This study reports an acute reversible myopathy pathologically characterized by M-line involvement and associated with serological antibodies to the subunit α of ATP synthase.

Multiple myeloma (MM) accounts for ∼13% of all hematologic malignancies. Bortezomib treatment is effective in MM, but can be complicated with neurological side effects. We describe a patient with symptomatic MM who had a reversible metabolic myopathy associated with bortezomib administration and pathologically characterized by excessive storage of lipid droplets together with mitochondrial abnormalities. In a single-center prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, 7 developed muscular signs and/or symptoms. The myopathy was characterized by a proximal muscle weakness involving lower limbs and was an early complication. Complete resolution of muscle weakness occurred after treatment discontinuation. Conversely, none of the patients who received a treatment without bortezomib developed muscular symptoms. Experimental studies demonstrate that in primary human myoblasts bortezomib at low concentrations leads to excessive storage of lipid droplets together with structural mitochondrial abnormalities, recapitulating the pathologic findings observed in patient's muscle. Our data suggest that patients treated with bortezomib should be monitored for muscular signs and/or symptoms and muscle weakness should alert the clinician to the possibility of myopathy. Bortezomib-induced metabolic myopathy is a potentially reversible entity with important implications for management and treatment of patients with MM.

The gold standard to characterize idiopathic inflammatory myopathies is the morphological, immunohistochemical and immunopathological analysis of muscle biopsy. Mononuclear cell infiltrates and muscle fiber necrosis are commonly shared histopathological features. Inflammatory cells that surround, invade and destroy healthy muscle fibers expressing MHC class I antigen are the typical pathological finding of polymyositis. Perifascicular atrophy and microangiopathy strongly support a diagnosis of dermatomyositis. Randomly distributed necrotic muscle fibers without mononuclear cell infiltrates represent the histopathological hallmark of immune-mediated necrotizing myopathy; meanwhile, endomysial inflammation and muscle fiber degeneration are the two main pathological features in sporadic inclusion body myositis. A correct differential diagnosis requires immunopathological analysis of the muscle biopsy and has important clinical implications for therapeutic approach. In particular, unnecessary, potentially harmful, immune-suppressive therapy should be avoided alike in dystrophic myopathies with secondary inflammation.

Leukoencephalopathy is a hallmark of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) a devastating disorder characterized by ptosis, ophthalmoparesis, gastrointestinal dysfunction and polyneuropathy. To characterize MNGIE-associated leukoencephalopathy and to correlate it with clinical, biochemical and molecular data, four MNGIE patients with heterogeneous clinical phenotypes (enteropathic arthritis, exercise intolerance, CIDP-like phenotype and typical presentation) were studied by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps were also obtained. In two patients we also investigated the role of brain MRI in monitoring the evolution of leukoencephalopathy by performing follow-up imaging studies at an interval of one and two years. The extension and distribution of leukoencephalopathy were not clearly linked with age, phenotype or disease severity, and did not seem to be related to TYMP mutations, enzyme activity or pyrimidine levels. In the studied patients MRS revealed reduced N-acetyl-aspartate and increased choline signals. Although DWI appeared normal in all patients but one, ADC maps always showed moderate increased diffusivity. Leukoencephalopathy worsened over a two-year period in two patients, regardless of the clinical course, indicating a lack of correlation between clinical phenotype, size and progression of white matter abnormalities during this period. Brain MRI should be considered a very useful tool to diagnose both classical and atypical MNGIE. Serial MRIs in untreated and treated MNGIE patients will help to establish whether the leukoencephalopathy is a reversible condition or not.

To describe the incidence, major risk factors, and the clinical, electrophysiological, and histological features of critical illness myopathy (CIM). Major pathogenetic mechanisms and long-term consequences of CIM are also reviewed.

Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.

We describe four patients, from four different families, affected by a mild myopathy or asymptomatic elevated serum creatine kinase levels, in whom toluidine blue-stained semithin sections of muscle specimens revealed inclusions of different size and shape. The inclusions did not stain by routine histochemical studies. The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present in the terminal cisternae of sarcoplasmic reticulum. Our cases, both sporadic and familial, represent a new type of surplus protein myopathy.

Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin‐converting enzyme (ACE) could act as modulators of phenotype expression. Forty‐seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACEgene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p< 0.01) association between ACEgenotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACEinsertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease. Ann Neurol 2003

Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression. Forty-seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACE gene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p &lt; 0.01) association between ACE genotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACE insertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease. Ann Neurol 2003

The cellular isoform of the prion protein (PrPc) is a glycosylphosphatidylinositol‐anchored glycoprotein, normally expressed in neural and non‐neural tissues, including skeletal muscle. In transmissible spongiform encephalopathies, or prion diseases, PrPc, which is soluble in nondenaturing detergent and sensitive to proteinase K (PK)‐treatment, represents the molecular substrate for the production of a detergent‐insoluble and PK‐resistant isoform, termed PrPSc.

Abstract: Increased titers of circulating antisulfatide antibodies are consistently associated with a variety of chronic axonal and demyelinating polyneuropathy syndromes. Previous studies have shown that the pattern of antisulfatide binding to neural tissues correlates with the type of neuropathy. This suggests a possible role for antisulfatide antibodies in inducing peripheral nerve dysfunction, although their exact contribution to the pathogenesis of neuropathy is still unknown. We examined sural nerve biopsy specimens from two patients with sensorimotor and small fiber sensory neuropathy associated with high titers of IgM monoclonal antibodies to sulfatide. Electrophysiological and pathological findings were consistent with predominant demyelination in the patient with sensorimotor involvement, whereas evidence of demyelination was obtained only by teased fiber examination in the other patient. The ultrastructural study disclosed in both cases the presence of myelinated fibers with widely spaced myelin, due to a separation of leaflets of the intraperiod lines. Immunocytochemistry, performed on frozen sections, demonstrated the presence of IgM and complement product C3d bound to myelin sheaths of almost all fibers. Few fibers were immunoreactive for complement components C1q and C5. In addition, the terminal complement complex neoantigen C5b-C9, not associated with S protein, was detected on some myelinated fibers. The results suggest that, at the least in some forms of demyelinating neuropathy associated with antisulfatide antibodies, pathological changes are complement mediated. Our data further confirm previous clinical and experimental observations that complement activation initiates separation of myelin intraperiod lines.

Botulinum toxin is now widely used in the treatment of severla hyperkinetic movement disorders. To evaluate its efficacy in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign crampfasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection signifcantly lowered our patients' clinical cramp severity scores (mean ± SD: before, 3.80 ± 0.44; after, 1.40 ± 0.54), left muscle strength unchanged and significanlty increased their cramp threshold frequencies (before, 4.22 ± 2.26 Hz; after, 10.0 ± 3.74 Hz). The clinical beefit induced by botulinum toxin lasted about 3 months. Boutlinum toxin injections also significantly reduced fasciculation potentials in relaxed muscles (before, 0.86 ± 0.19 fasciculations/sec; after, 0.45 ± 0.11 fasciculations/sec). These findings show that local intramuscular injection of botulinum toxin provide effective, safe, and long‐lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and by impairing the input/output function of intrafusal and extrafusal motor end plates.

Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.

Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.

Brody disease is an inherited disorder of skeletal muscle function characterized by increasing impairment of relaxation during exercise. The autosomal recessive form can be caused by mutations in the ATP2A1 gene, which encodes for the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1) protein. We studied 2 siblings affected by Brody disease. The patients complained of exercise-induced delay of muscle relaxation and stiffness since childhood and had gene analysis of ATP2A1. Morphologic and biochemical studies were performed on a muscle biopsy from 1 patient. The biopsy showed fiber size variation and increased numbers of fibers with internal nuclei. Ultrastructural examination revealed dilatation of lateral cisternae and proliferation of tubular elements of the sarcoplasmic reticulum. By immunohistochemistry, SERCA1 was expressed in a normal pattern, but sarcoplasmic reticulum Ca2+-ATPase activity was significantly reduced. Immunoblotting after high-resolution 2-dimensional gel electrophoresis showed a significant difference in the amount of SERCA1 protein between the patient and controls. Both patients were found to have 2 previously unreported in-frame deletions in ATP2A1. Because SERCA1 protein has specific biochemical characteristics in our patient, these results underline the importance of a pathologic and biochemical analyses for the diagnosis. In addition, we describe 2 novel mutations in the ATP2A1 gene.