[Show abstract][Hide abstract] ABSTRACT: Statins intolerance is mainly due to their side effects on the neuromuscular system (primarily muscle). It has become an important issue because of the major cardiovascular risk reduction of this class of drugs. However, the facts related to these side effects are sometimes under-recognized or controversial. A literature review of the recent developments in the field is given. The clinical definition of statin myopathy and its presentation are not suitable for the myology field. Management and prevention are not validated. More genetic risk factors need to be established. Neurologists should become more involved in statin intolerance evaluation and management.
Preview · Article · Jan 2015 · European Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Increased survival of critically ill patients has focused the attention on secondary complications of intensive care unit (ICU) stay, mainly ICU-acquired weakness (ICUAW). ICUAW is relatively common with significant impact on recovery. Prolonging mechanical ventilation and overall hospitalization time, increased mortality, and persistent disability are the main problems associated with ICUAW. The chapter deals mainly with the differential diagnosis of neuromuscular generalized weakness that develops in the ICU, but focal ICUAW is reviewed too. The approach to the diagnosis and the yield of various techniques (mainly electrophysiological and histological) is discussed. Possible therapeutic interventions of this condition that modify the course of this deleterious situation and lead to better rehabilitation are discussed. The current postulated mechanisms associated with ICUAW (mainly the more frequent critical illness neuropathy and myopathy) are reviewed.
No preview · Article · Dec 2014 · Handbook of Clinical Neurology
[Show abstract][Hide abstract] ABSTRACT: The trip is not over yet as definite therapy for GNE myopathy is not yet available. Also the exact mechanisms by which GNE defects lead to isolated muscle disease in humans are not fully recognized. But in the Gaetano Conte lecture of 2013 I have tried to describe how much a progress was made in several research laboratories and clinical institutes in the investigation of this unique myopathy.
Preview · Article · Oct 2014 · Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases
[Show abstract][Hide abstract] ABSTRACT: The symptoms of acquired autoimmune ocular myasthenia are restricted to the extrinsic eye muscles, causing double vision and drooping eyelids. These guidelines are designed to provide advice about best clinical practice based on the current state of clinical and scientific knowledge and the consensus of an expert panel.
Evidence for these guidelines was collected by searches in the MEDLINE and Cochrane databases. The task force working group reviewed evidence from original articles and systematic reviews. The evidence was classified (I, II, III, IV) and consensus recommendation graded (A, B or C) according to the EFNS guidance. Where there was a lack of evidence but clear consensus, good practice points are provided.
The treatment of ocular myasthenia should initially be started with pyridostigmine (good practice point). If this is not successful in relieving symptoms, oral corticosteroids should be used on an alternate-day regimen (recommendation level C). If steroid treatment does not result in good control of the symptoms or if it is necessary to use high steroid doses, steroid-sparing treatment with azathioprine should be started (recommendation level C). If ocular myasthenia gravis is associated with thymoma, thymectomy is indicated. Otherwise, the role of thymectomy in ocular myasthenia is controversial. Steroids and thymectomy may modify the course of ocular myasthenia and prevent myasthenia gravis generalization (good practice point).
No preview · Article · Jan 2014 · European Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: GNE myopathy is a recessive adult onset, slowly progressive distal and proximal myopathy, caused by mutations in the GNE gene. The most frequent mutation in GNE myopathy patients is the Middle Eastern founder mutation M712T. We have generated Gne ( M712T/M712T ) knockin mice. A high mortality rate in the first generation due to renal failure was recorded (as previously described). However, the following Gne ( M712T/M712T ) offspring generations could be classified into 3 phenotypic categories: severe, mild and without apparent phenotype. By further crossing between mice with no apparent phenotype, we were able to establish a colony of Gne ( M712T/M712T ) knockin mice with a high- and long-term survival rate, lacking any renal phenotype. These mice did not present any muscle phenotype (clinical or pathological) for up to 18 months. No correlation was found between the expression of any of the two mRNA Gne isoforms in muscle and the mouse genotype or phenotype. However, the expression of isoform 2 mRNA was significantly higher in the kidney of Gne ( M712T/M712T ) kidney affected mice compared with control. In contrast, the expression of UPR markers Bip, Chop and of the spliced form of XBP1, was upregulated in muscle of Gne ( M712T/M712T ) mice compared with controls, but was unchanged in the affected kidney. Thus, Gne defects can affect both muscle and kidney in mouse, but probably through different mechanisms.
No preview · Article · Dec 2012 · Neuromolecular medicine
[Show abstract][Hide abstract] ABSTRACT: We present further developments in the study of the antisense oligonucleotide EN101. Ongoing in vitro and in vivo studies demonstrate that EN101 is a TLR9-specific ligand that can suppress pro-inflammatory functions and shift nuclear factor kappa B (NF-κB) from the pro-inflammatory canonical pathway to the anti-inflammatory alternative pathway, which results in decreases acetylcholinesterase (AChE) activity. Preliminary results of a double-blinded phase II cross-over study compared 10, 20, and 40 mg EN101 administered to patients with myasthenia gravis. Patients were randomly assigned to one of three treatment groups in weeks 1, 3, and 5 and received their pretreatment dose of pyridostigmine in weeks 2 and 4. Thus far, all doses show a decrease in QMG scores, with a greater response to higher doses.
No preview · Article · Dec 2012 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: GNE myopathy is an autosomal recessive adult onset disorder caused by mutations in the GNE gene. GNE encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase, the key enzyme in the biosynthesis pathway of sialic acid. Additional functions for GNE have been described recently, but the mechanism leading from GNE mutation to this myopathy is unclear. Therefore a gene therapy approach could address all potential defects caused by GNE mutations in muscle. We show that AAV8 viral vectors carrying wild type human GNE cDNA are able to transduce murine muscle cells and human GNE myopathy-derived muscle cells in culture and to express the transgene in these cells. Furthermore, the intravenous administration of this viral vector to healthy mice allows expression of the GNE transgene mRNA and of the coexpressed luciferase protein, for at least 6months in skeletal muscles, with no clinical or pathological signs of focal or general toxicity, neither from the virus particles nor from the wild type human GNE overexpression. Our results support the future use of an AAV8 based vector platform for a safe and efficient therapy of muscle in GNE myopathy.
No preview · Article · May 2012 · Neuromuscular Disorders
[Show abstract][Hide abstract] ABSTRACT: Thymoma is associated with multiple autoimmune disorders, most commonly myasthenia gravis (MG). However, symptomatic MG may first present following thymectomy. We report an unusual patient with paraneoplastic limbic encephalitis diagnosed a few months after total thymectomy for asymptomatic thymoma, followed 18 years later by the onset of symptomatic MG without evidence of tumor recurrence.
No preview · Article · Apr 2012 · Journal of the neurological sciences
[Show abstract][Hide abstract] ABSTRACT: Hereditary inclusion-body myopathy (h-IBM) and distal myopathy with rimmed vacuoles (DMRV) are the same condition, caused by mutations in the GNE gene (thus termed GNE-opathy). This is an adult-onset (usually in the third decade) myopathy initially affecting the distal leg muscles (mainly the tibialis anterior) and slowly progressing to proximal muscles, but sparing the quadriceps. The histological features are typical for rimmed vacuolar myopathy but electromyography and creatine kinase levels show no specific abnormality. This is a worldwide autosomal recessive disorder, recognized mainly in two clusters (Middle Eastern Jews and Japanese), but it has been reported on other continents too.
[Show abstract][Hide abstract] ABSTRACT: Acetylcholinesterase pre-mRNA is susceptible to alternative splicing. Myasthenia gravis has been shown to be associated with the expression of the readthrough transcript (AChE-R), which, unlike the normal "synaptic" transcript (AChE-S) is not tethered to the post-synaptic membrane, but is a soluble monomer in the synaptic cleft. In rats with experimental autoimmune myasthenia gravis (EAMG), inhibition of production of AChE-R using antisense is associated with a significant reduction in synaptic expression of AChE-R mRNA and protein, with improved muscle strength and stamina and increased survival. Synaptic AChE does not appear to be significantly affected by the induction of EAMG or treatment with antisense to AChE-R. Monarsen (EN101) is a synthetic 20-base antisense oligodeoxynucleotide directed against the human AChE gene. It is modified to achieve stability for oral administration. Sixteen patients with seropositive myasthenia gravis who were responsive to pyridostigmine were withdrawn from it and treated with Monarsen. Fourteen patients experienced a clinically significant response. In some, the improvement was dramatic. Although the dose of pyridostigmine was not optimized before the study, the majority of responders achieved better Quantitative Myasthenia Gravis scores than on pyridostigmine. The response of an individual muscle group to Monarsen was related to the degree of deterioration following the withdrawal of pyridostigmine. Cholinergic side effects were conspicuous by their absence. Monarsen is now being investigated in a phase II study.
No preview · Article · Jul 2008 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: Dysferlin encoding gene (DYS) is mutated in the autosomal recessive disorders Miyoshi myopathy, Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and distal anterior compartment myopathy, causing dysferlin deficiency in muscle biopsy. Three ethnic clusters have previously been described in Dysferlinopathy: the Libyan Jewish population originating in the area of Tripoli, Italian and Spanish populations. We report another cluster of this muscular dystrophy in Israel among Jews of the Caucasus region. A genomic analysis of the dysferlin coding sequence performed in patients from this ethnic group, who demonstrated an absence of dysferlin expression in muscle biopsy, revealed a homozygous frameshift mutation of G deletion at codon 927 (2779delG) predicting a truncated protein and a complete loss of functional protein. The possible existence of a founder effect is strengthened by our finding of a 4% carrier frequency in this community. These findings are important for genetic counseling and also enable a molecular diagnosis of LGMD2B in Jews of the Caucasus region.
No preview · Article · Jan 2008 · Neuromuscular Disorders
[Show abstract][Hide abstract] ABSTRACT: Mutations in GNE encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) cause hereditary inclusion body myopathy (HIBM). To define the role of GNE mutations in HIBM pathogenesis, GNE protein expression was analyzed. GNE protein is expressed at equal levels in HIBM patients and normal control subjects. Immunofluorescence detection of GNE did not reveal any mislocalization of GNE in skeletal muscle. We conclude that impaired GNE function, not lack of expression, may be the key pathogenic factor in HIBM. For diagnostic purposes, direct genetic analysis of the GNE gene in patients with IBM will remain the mainstay and is not aided by immunohistochemistry or immunoblotting using antibodies against the GNE protein.
[Show abstract][Hide abstract] ABSTRACT: Many drugs used in various branches of medicine, as well as alcohol and other substances of addiction, produce muscular symptoms, either through a direct effect on the skeletal muscles or by interfering with neuromuscular transmission or peripheral nerve function. A variety of chemicals, biological toxins, and venoms are also myotoxic. The mechanisms of action of drugs and toxins on muscle are diverse. Some have a direct toxic effect, either locally after intramuscular injection, or more widely after systemic administration or absorption of the agent. In case of drugs that are not inherently myotoxic, muscle damage may be secondary to an immunological process, to hypokalaemia, or to muscle compression and ischemia during periods of unconsciousness and immobility following a drug overdose. A change in ionic conductance and excitability of the plasma membrane is the basis for the myotonia induced by a number of drugs and chemicals, and for the muscular weakness and hypotonia that occurs in patients who become severely hypokalaemic or hyperkalaemic while taking diuretics or certain other drugs. Some drugs interfere with muscle protein synthesis and degradation. This occurs particularly with the natural and synthetic glucocorticoids that inhibit the synthesis of muscle specific proteins as well as increasing protein degradation. Chloroquine, amiodarone, and a number of other amphiphilic cationic compounds cause a myopathy characterized by autophagic degeneration and phospholipid accumulation in muscle. Various drug-induced disorders are discussed such as myalgia and muscle cramps, myotonia, necrotizing myopathies, acute rhabdomyolysis, mitochondrial myopathy, dyskalemic myopathy, dyskalemic myopathy, autophagic myopathies, and alcoholic myopathy.
No preview · Article · Feb 2007 · Handbook of Clinical Neurology