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Michael G Hanna - One of the best experts on this subject based on the ideXlab platform.
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Novel Insights into the Pathomechanisms of Skeletal Muscle Channelopathies
2014Co-Authors: James A Burge, Michael G HannaAbstract:The non‐dystrophic myotonias and primary periodic paralyses are an important group of genetic muscle diseases characterised by dysfunction of ion channels that regulate membrane excitability. Clinical manifestations vary and include myotonia, hyperkalaemic and hypokalaemic periodic Paralysis, progressive myopathy and cardiac arrhythmias. The severity of myotonia ranges from severe neonatal presentation causing respiratory compromise through to mild later onset disease. It remains unclear why the frequency of attacks of Paralysis varies greatly or why many patients develop a severe permanent fixed myopathy. Recent detailed characterisation of human genetic mutations in voltage gated muscle sodium (gene: SCN4A), chloride (gene: CLCN1), calcium (gene: CACNA1S) and inward rectifier potassium (genes: KCNJ2, KCNJ18) channels has resulted in new insights into disease mechanisms, clinical phenotypic variation and therapeutic options
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Novel Insights into the Pathomechanisms of Skeletal Muscle Channelopathies
Current Neurology and Neuroscience Reports, 2012Co-Authors: James A Burge, Michael G HannaAbstract:The nondystrophic myotonias and primary periodic paralyses are an important group of genetic muscle diseases characterized by dysfunction of ion channels that regulate membrane excitability. Clinical manifestations vary and include myotonia, hyperkalemic and hypokalemic periodic Paralysis, progressive myopathy, and cardiac arrhythmias. The severity of myotonia ranges from severe neonatal presentation causing respiratory compromise through to mild later-onset disease. It remains unclear why the frequency of attacks of Paralysis varies greatly or why many patients develop a severe permanent fixed myopathy. Recent detailed characterizations of human genetic mutations in voltage-gated muscle sodium (gene: SCN4A ), chloride (gene: CLCN1 ), calcium (gene: CACNA1S ), and inward rectifier potassium (genes: KCNJ2, KCNJ18 ) channels have resulted in new insights into disease mechanisms, clinical phenotypic variation, and therapeutic options
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Skeletal muscle channelopathies: nondystrophic myotonias and periodic Paralysis.
Current opinion in neurology, 2010Co-Authors: Dipa L. Raja Rayan, Michael G HannaAbstract:Purpose of reviewThe aim is to review the recent findings in relation to the genetics, pathophysiology, clinical phenotypes, investigation and treatment of the nondystrophic myotonias (NDMs) and periodic paralyses.Recent findingsThe number of pathogenic mutations causing NDMs and periodic paralyses in known genes continues to expand. In addition, a mutation has been identified in the ryanodine receptor gene manifesting as an atypical periodic Paralysis phenotype. Another recent study indicated that thyrotoxic hypokalaemic periodic Paralysis is determined by mutations in a novel gene encoding an inwardly rectifying potassium channel, Kir2.6. Work studying molecular mechanisms indicates that 90% of the known mutations causing hypokalaemic periodic Paralysis (HypoPP) result in loss of positively charged arginine residues in the S4 segments of either SCN4A or CACNA1S, possibly creating a gating-pore current that may be important in the pathogenesis of HypoPP. Recent studies evaluating clinical features and health status in NDM patients have provided more detailed insights into the significant morbidity associated with these diseases. Ultrasound has been successfully used to demonstrate muscle abnormalities in NDM patients and magnetic resonance spectroscopy studies applied to HypoPP patients suggest that this technique can demonstrate both disease-related and treatment-related changes.SummaryRecent discoveries in the skeletal muscle channelopathies have increased our understanding of the genetics and pathophysiology of these diseases. Studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials. Randomized controlled trials to establish an evidence base upon which to recommend standard treatments are required.
Robert C. Griggs - One of the best experts on this subject based on the ideXlab platform.
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Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias.
Current opinion in neurology, 2009Co-Authors: Daniel Platt, Robert C. GriggsAbstract:Purpose of reviewTo summarize advances in our understanding of the clinical phenotypes, genetics, and molecular pathophysiology of the periodic paralyses, the nondystrophic myotonias, and other muscle channelopathies.Recent findingsThe number of pathogenic mutations causing periodic Paralysis, nondy
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Treatment of neuromuscular channelopathies: Current concepts and future prospects
Neurotherapeutics, 2008Co-Authors: James C. Cleland, Robert C. GriggsAbstract:Our understanding of the molecular pathogenesis of the neuromuscular ion channelopathies has increased rapidly over the past two decades due to the identification of many of the genes whose mutation causes these diseases. These molecular discoveries have facilitated identification and classification of the hereditary periodic paralyses and the myotonias, and are likely to shed light on acquired ion channelopathies as well. Despite our better understanding of the pathogenesis of these disorders, current treatments are largely empirical and the evidence in favor of specific therapy largely anecdotal. For periodic Paralysis, dichlorphenamide—a carbonic anhydrase inhibitor — has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic Paralysis. A second trial, comparing dichlorphenamide with acetazolamide versus placebo, is currently in progress. For myotonia, there is only anecdotal evidence for treatment, but a controlled trial of mexiletine versus placebo is currently being funded by a Food and Drug Administration—orphan products grant and is scheduled to begin in late 2008. In the future, mechanism-based approaches are likely to be developed. For example, exciting advances have already been made in one disorder, myotonic dystrophy-1 (DM-1). In a mouse model of DM-1, a morpholino antisense oligonucleuotide targeting the 3′ splice site of CLCN1 exon 7a repaired the RNA splicing defect by promoting the production of full-length chloride channel transcripts. Abnormal chloride conductance was restored, and myotonia was abolished. Similar strategies hold potential for DM-2. The era of molecularly-based treatments is about to begin.
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Familial Periodic Paralysis
Molecular Biology of Membrane Transport Disorders, 1996Co-Authors: Louis J. Ptáček, Robert C. GriggsAbstract:The periodic paralyses have traditionally been divided into hypokalemic, hyperkalemic, normokalemic, and paramyo-tonic forms.1 Over the past decade, a combination of electrophysiologic and molecular biologic studies have clarified the classification of the disease (Table 31.1). It has become apparent that there are two broad categories of disease: hypokalemic periodic Paralysis and hyperkalemic periodic Paralysis. All forms of periodic Paralysis are either autosomal dominantly inherited or occur as sporadic cases that are probably the result of new mutations. Hyperkalemic periodic Paralysis usually results from a disorder of the skeletal muscle, voltage-gated sodium channel. The molecular alterations have been defined for most cases.2,3 It is becoming clear that a number of disorders once considered separate entities are in fact allelic to hyperkalemic periodic Paralysis including: paramyotonia congenita4,5 and most recently, a form of myotonia without periodic Paralysis that is potassium-sensitive.6,7 There are, however, a small proportion of patients with hyperkalemic periodic analysis that is not allelic.8
Neil N Chheda - One of the best experts on this subject based on the ideXlab platform.
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incidence of vocal cord Paralysis with and without recurrent laryngeal nerve monitoring during thyroidectomy
Archives of Otolaryngology-head & Neck Surgery, 2007Co-Authors: Maisie L Shindo, Neil N ChhedaAbstract:Objective To compare the incidence of postoperative vocal cord paresis or Paralysis in a cohort of patients who underwent thyroidectomy with and without continuous recurrent laryngeal nerve (RLN) monitoring by a single senior surgeon. We hypothesize that continuous RLN monitoring reduces the rate of nerve injury during thyroidectomy Design Retrospective medical chart review. Setting Academic tertiary care medical center. Patients A total of 684 patients (1043 nerves at risk) who underwent thyroid surgery under general anesthesia. Main Outcome Measure Incidence of vocal cord paresis or Paralysis in patients who underwent thyroid surgery with continuous RLN monitoring vs those undergoing surgery without continuous RLN monitoring. Results The incidence of unexpected unilateral vocal cord paresis based on RLNs at risk was 2.09% (n = 14) in the monitored group and 2.96% (n = 11) in the unmonitored group. This difference was not statistically significant. The incidence of unexpected complete unilateral vocal cord Paralysis was 1.6% in each group. Two of the 5 paralyses in the unmonitored group and 7 of the 11 paralyses in the monitored group had complete resolution. Conclusions Monitoring of the RLN does not appear to reduce the incidence of postoperative temporary or permanent complete vocal cord Paralysis. There appeared to be a slightly lower rate of postoperative paresis with RLN monitoring, but this difference was not statistically significant.
Dipa L. Raja Rayan - One of the best experts on this subject based on the ideXlab platform.
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Skeletal muscle channelopathies: nondystrophic myotonias and periodic Paralysis.
Current opinion in neurology, 2010Co-Authors: Dipa L. Raja Rayan, Michael G HannaAbstract:Purpose of reviewThe aim is to review the recent findings in relation to the genetics, pathophysiology, clinical phenotypes, investigation and treatment of the nondystrophic myotonias (NDMs) and periodic paralyses.Recent findingsThe number of pathogenic mutations causing NDMs and periodic paralyses in known genes continues to expand. In addition, a mutation has been identified in the ryanodine receptor gene manifesting as an atypical periodic Paralysis phenotype. Another recent study indicated that thyrotoxic hypokalaemic periodic Paralysis is determined by mutations in a novel gene encoding an inwardly rectifying potassium channel, Kir2.6. Work studying molecular mechanisms indicates that 90% of the known mutations causing hypokalaemic periodic Paralysis (HypoPP) result in loss of positively charged arginine residues in the S4 segments of either SCN4A or CACNA1S, possibly creating a gating-pore current that may be important in the pathogenesis of HypoPP. Recent studies evaluating clinical features and health status in NDM patients have provided more detailed insights into the significant morbidity associated with these diseases. Ultrasound has been successfully used to demonstrate muscle abnormalities in NDM patients and magnetic resonance spectroscopy studies applied to HypoPP patients suggest that this technique can demonstrate both disease-related and treatment-related changes.SummaryRecent discoveries in the skeletal muscle channelopathies have increased our understanding of the genetics and pathophysiology of these diseases. Studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials. Randomized controlled trials to establish an evidence base upon which to recommend standard treatments are required.
Karin Jurkat-rott - One of the best experts on this subject based on the ideXlab platform.
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MRI in Muscle Channelopathies
Magnetic Resonance Imaging of the Skeletal Musculature, 2013Co-Authors: Karin Jurkat-rott, Marc-andré Weber, Frank Lehmann-hornAbstract:Myotonia is an involuntary-slowed relaxation after a forceful voluntary muscle contraction which is experienced by the patient as muscle stiffness. Electrical hyperexcitability of the muscle fiber membrane is the basis of myotonia. The stiffness recedes with repeated contractions, a phenomenon called warm-up. Patients in whom muscle stiffness worsens with repetition or with cooling suffer from paradoxical myotonia or so-called paramyotonia. This type of myotonia is associated with episodes of flaccid limb muscle weakness similar to periodic Paralysis. Patients with periodic Paralysis experience episodic weakness spells with varying intervals of normal muscle function. Electrical inexcitability of the muscle fiber membrane is the basis of periodic Paralysis. Two dominant episodic types of weakness with or without myotonia are distinguished by the serum K+ level during the attacks of tetraplegia: hyper- and hypokalemic periodic Paralysis. Independently of the severity and frequency of the paralytic episodes, many patients develop a chronic progressive myopathy in the forties, an age at which the attacks of weakness decrease. Although channelopathies such as myotonias and periodic paralyses are known for episodic symptoms, in most cases progressive focal or general muscular weakness is present. Routine protocols of proton (1H) magnetic resonance imaging (MRI) show normal muscle morphology or may demonstrate edematous or lipomatous changes, atrophy or hypertrophy; however, these morphologic changes are not very disease-specific. The following chapter introduces examples of conventional and modern functional imaging methods like 23Na MRI for evaluation of muscular channelopathies, in which an autosomal-dominant bequeathed defect of muscular Na+ channels leads to a pathologic Na+ influx that causes intermittent or permanent muscular paresis as well as muscular stiffness. 23Na MRI by which aspects of muscular pathogenesis such as muscular Na+ homeostasis can be visualized and monitored has effectively achieved value in the radiologic management of muscular Na+ channel diseases, since 23Na MRI is able to depict an intracellular muscular sodium accumulation simultaneous to development of muscular paresis. This sodium accumulation correlates well with the grade of paresis and is reproducible.
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Hereditary Muscle Channelopathies
Emery and Rimoin's Principles and Practice of Medical Genetics, 2013Co-Authors: Frank Lehmann-horn, Reinhardt Rüdel, Karin Jurkat-rottAbstract:A combination of electrophysiological and molecular genetic studies has resulted in the discovery of certain skeletal muscle disorders caused by pathologically functioning ion channels. The group of thus defined hereditary “muscle channelopathies” comprises congenital myasthenic syndromes, nondystrophic myotonias, dyskalemic periodic paralyses, central core myopathy and multiminicore myopathy, as well as malignant hyperthermia. Many muscle channelopathies are benign disorders, but muscle hypermetabolism resulting in muscle stiffness and hyperthermia as in an event of malignant hyperthermia can be life-threatening. In addition, forms of familial periodic Paralysis can be severe when they produce serious dyskalemia that disturbs cardiac excitation conduction. The hypokalemia is most pronounced in thyrotoxic periodic Paralysis. Some of the periodic paralyses are associated with a progressive permanent weakness. The weakness is explained by strongly depolarized, inexcitable muscle fibers that accumulate sodium and water. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression. Expression studies of putative mutations have become standard in supporting the disease-causing nature of mutations. Not all variants detected by genetic analysis may be causative for a clinical dysfunction; they may be just a functional polymorphism. These problems are addressed and a more critical evaluation of the underlying genetic data is proposed.
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Muskuläre Kanalopathien : Myotonien und periodische Paralysen (CME Weiterbildung · Zertifizierte Fortbildung)
Der Nervenarzt, 2011Co-Authors: Karin Jurkat-rott, Holger Lerche, Frank Lehmann-hornAbstract:The myotonias and familial periodic paralyses are muscle channelopathies. They have in common an impaired muscle excitation that is caused by mutations in voltage-gated Na + , K + , Ca 2+ , and Cl − channels. Membrane hyperexcitability usually results in myotonic stiffness; with increasing membrane depolarization hyperexcitability can be transiently turned into hypoexcitability causing transient weakness as in severe myotonia. Hypoexcitability due to long-lasting depolarization that inhibits action potential generation is the common mechanism for the periodic paralyses. Interictally, the ion channel malfunction may be compensated, so that specific exogenous or endogenous provocative factors are required to produce symptoms in the patients. An especially obvious triggering agent is the level of serum potassium, the ion decisive for resting membrane potential and degree of excitability. Periodic Paralysis mutations for which the ion channel malfunction is not fully compensated interictally cause progressive myopathy.
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Genetic heterogeneity in hypokalemic periodic Paralysis (hypoPP)
Human Genetics, 1994Co-Authors: Emmanuelle Plassart, Karin Jurkat-rott, Alexis Elbaz, Jose Vale Santos, Jocelyne Reboul, Pascale Lapie, Dominique Chauveau, Joao Guimaraes, Jean-marie Saudubray, Jean WeissenbachAbstract:Hypokalemic periodic Paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases known to involve an abnormal function of ion channels. The latter includes hypokalemic and hyperkalemic periodic paralyses, and non-dystrophic myotonias. We recently showed genetic linkage of hypoPP to loci on chromosome 1q31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3. We propose to term this locus hypoPP-1. Using extended haplotypes with new markers located on chromosome 1q31-32, we now report the detailed mapping of hypoPP-1 within a 7 cM interval. Two recombinants between hypoPP-1 and the flanking markers D1S413 and D1S510 should help to reduce further the hypoPP-1 interval. We used this new information to demonstrate that a large family of French origin displaying hypoPP is not genetically linked to hypoPP-1. We excluded genetic linkage over the entire hypoPP-1 interval showing for the first time genetic heterogeneity in hypoPP.
