The Experts below are selected from a list of 10236 Experts worldwide ranked by ideXlab platform

Michael G. Hanna - One of the best experts on this subject based on the ideXlab platform.

  • Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms.
    The Journal of pediatrics, 2017
    Co-Authors: Emma Matthews, Michael G. Hanna, A. Silwal, Richa Sud, Adnan Y. Manzur, Francesco Muntoni, P. Munot
    Abstract:

    Objective To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment. Study design Retrospective case review of 38 children with a skeletal muscle Channelopathy attending the specialist pediatric neuromuscular service at Great Ormond Street Hospital over a 15-year period. Results Gait disorder and leg cramps are a frequent presentation of myotonic disorders (19 of 29). Strabismus or extraocular myotonia (9 of 19) and respiratory and/or bulbar symptoms (11 of 19) are common among those with sodium Channelopathy. Neonatal hypotonia was observed in periodic paralysis. Scoliosis and/or contractures were demonstrated in 6 of 38 children. School attendance or ability to engage fully in all activities was often limited (25 of 38). Conclusions Children with skeletal muscle channelopathies frequently display symptoms that are uncommon in adult disease. Any child presenting with abnormal gait, leg cramps, or strabismus, especially if intermittent, should prompt examination for myotonia. Those with sodium channel disease should be monitored for respiratory or bulbar complications. Neonatal hypotonia can herald periodic paralysis. Early diagnosis is essential for children to reach their full educational potential.

  • Muscle channelopathies: recent advances in genetics, pathophysiology and therapy.
    Current opinion in neurology, 2014
    Co-Authors: K. Suetterlin, Roope Männikkö, Michael G. Hanna
    Abstract:

    PURPOSE OF REVIEW This article reviews recent advances in clinical, genetic, diagnostic and pathophysiological aspects of the skeletal muscle channelopathies. RECENT FINDINGS Genetic advances include the use of the minigene assay to confirm pathogenicity of splice site mutations of CLC-1 chloride channels and a new gene association for Andersen-Tawil syndrome. Mutations causing a gating pore current have been established as a pathomechanism for hypokalaemic periodic paralysis. Mutations in nonchannel genes, including the mitochondrial mATP6/8 genes, have been linked to Channelopathy-like episodic weakness. Advances in diagnostic tools include the use of MRI and muscle velocity recovery cycles to evaluate myotonia congenita patients. Specific neonatal presentations of sodium channel myotonia are now well documented. An international multicentre placebo-controlled randomized clinical trial established that mexiletine is an effective therapy in the nondystrophic myotonias. This is the first evidence-based treatment for a skeletal muscle Channelopathy. Recent evidence in mouse models indicated that bumetanide can prevent attacks of hypokalaemic periodic paralysis, but this has not yet been tested in patient trials. SUMMARY Advances in genetic, clinical, diagnostic and pathomechanistic understanding of skeletal muscle channelopathies are being translated into improved therapies. Mexiletine is the first evidence-based treatment for nondystrophic myotonias. Bumetanide is effective in preventing attacks in mouse models of hypokalaemic periodic paralysis and now needs to be tested in patients.

  • Paroxysmal neuromyotonia: A new sporadic Channelopathy
    Neuromuscular disorders : NMD, 2012
    Co-Authors: Teeratorn Pulkes, Charungthai Dejthevaporn, Metha Apiwattanakul, Chutima Papsing, Michael G. Hanna
    Abstract:

    Neuromyotonia is a heterogeneous group of genetic and autoimmune channelopathies resulting in hyperexcitability of peripheral nerves. We report an unusual case of neuromyotonia, which to our knowledge has not been previously described. The patient developed intermittent attacks of severe painful muscle stiffness accompanied by sweating, myokymia and raised serum creatine kinase. Genetic analysis of KCNA1, KCNQ2 and SCN4A genes did not identify pathogenic mutation. Serum voltage-gated potassium channel antibody was also negative. He was successfully treated with acetazolamide and carbamazepine. This appears to be a new neuromuscular disease, "paroxysmal neuromyotonia", the etiology of which is still unknown.

  • Sodium and chloride channelopathies with myositis: coincidence or connection?
    Muscle & nerve, 2011
    Co-Authors: Emma Matthews, Richa Sud, James Miller, Malcolm R. Macleod, James W. Ironside, Gareth Ambler, Robin Labrum, Janice L. Holton, Michael G. Hanna
    Abstract:

    Introduction: A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown. Methods: We reviewed retrospectively all clinical and muscle biopsy findings of 3 patients with Channelopathy and additional myositis. Direct DNA sequencing was performed. Results: Pathogenic mutations were identified in each case. Biopsies demonstrated inflammatory infiltrates. Conclusions: Clinicians should consider muscle biopsy in Channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated creatine kinase. Chance association of myositis and Channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients. Muscle Nerve 44: 283-288, 2011

  • Episodic ataxia type 1: A neuronal potassium Channelopathy
    Neurotherapeutics, 2007
    Co-Authors: S Rajakulendran, Stephanie Schorge, Dimitri M Kullmann, Michael G. Hanna
    Abstract:

    Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A , the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.

Stephen G. Waxman - One of the best experts on this subject based on the ideXlab platform.

  • the cerebellar Channelopathy of multiple sclerosis
    Neurology, 2016
    Co-Authors: Stephen G. Waxman, Orhun H Kantarci
    Abstract:

    Clinical abnormalities in multiple sclerosis (MS) have traditionally been attributed to inflammation, demyelination, or degeneration of axons within the brain and spinal cord. Among those symptoms, clinical deficits due to cerebellar dysfunction, including loss of coordination, ataxia, tremor, and dysarthria, can reduce function substantially, are less likely to remit, and are more likely to be associated with progressive MS in the future.1 Interestingly, cerebellar signs and symptoms are sometimes seen in patients in whom structural lesions or inflammation of the cerebellum cannot be detected. These symptoms can be paroxysmal, similar to trigeminal neuralgia in patients with MS, which preferentially responds to sodium channel blockers. What is the basis for these clinical deficits?

  • Painful Na-channelopathies: an expanding universe
    Trends in molecular medicine, 2013
    Co-Authors: Stephen G. Waxman
    Abstract:

    The universe of painful Na-channelopathies – human disorders caused by mutations in voltage-gated sodium channels – has recently expanded in three dimensions. We now know that mutations of sodium channels cause not only rare genetic ‘model disorders' such as inherited erythromelalgia and Channelopathy-associated insensitivity to pain but also common painful neuropathies. We have learned that mutations of Na V 1.8, as well as mutations of Na V 1.7, can cause painful Na-channelopathies. Moreover, recent studies combining atomic level structural models and pharmacogenomics suggest that the goal of genomically guided pain therapy may not be unrealistic.

  • genetic aspects of sodium Channelopathy in small fiber neuropathy
    Clinical Genetics, 2012
    Co-Authors: Janneke G J Hoeijmakers, Stephen G. Waxman, Ingemar S J Merkies, Monique M Gerrits, Catharina G Faber
    Abstract:

    Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.

  • Acquired channelopathies in nerve injury and MS.
    Neurology, 2001
    Co-Authors: Stephen G. Waxman
    Abstract:

    Although neurophysiologic doctrine has traditionally referred to “the” voltage-gated sodium channel, it is now clear that there are at least nine genes that encode molecularly and physiologically distinct sodium channels. Mutations of sodium channel genes provide a basis for genetic channelopathies. Dysregulated expression of sodium channels due to alterations in activity of nonmutated channel genes, on the other hand, can produce acquired channelopathies. Two examples of acquired channelopathies are discussed in this article. Recent research has established that peripheral nerve injury can provoke an acquired Channelopathy in spinal sensory neurons; axonal transection triggers the turning-off of some previously active sodium channel genes and the turning-on of at least one previously silent sodium channel gene, a set of molecular changes that can result in hyperexcitability of these cells. Emerging evidence also suggests that an acquired Channelopathy, characterized by abnormal expression of sensory neuron specific sodium channels that can alter impulse trafficking within Purkinje cells, may contribute to the pathophysiology of MS. Subtype-specific drugs that selectively modulate various types of channels probably will soon be developed. The acquired channelopathies associated with nerve injury and MS may thus represent prototype disorders that present therapeutic opportunities.

  • Transcriptional channelopathies: an emerging class of disorders.
    Nature reviews. Neuroscience, 2001
    Co-Authors: Stephen G. Waxman
    Abstract:

    Two types of Channelopathy are now well recognized: genetic, in which ion channels function abnormally or fail to function as a result of mutations, and autoimmune, in which antibodies perturb channel function. Recent studies have provided growing evidence for the existence of a third type — transcriptional channelopathies — which result from changes in the expression of non-mutated channel genes. A well-studied example is peripheral nerve injury, which causes spinal sensory neurons to turn off some active sodium channel genes and turn on others that were previously silent, a set of changes that can result in hyperexcitability of these cells. Recent studies have also shown upregulated expression of sensory-neuron-specific sodium channels in Purkinje cells, indicating that a transcriptional Channelopathy might perturb cerebellar function in multiple sclerosis. It is probable that we will soon recognize further disorders that are characterized by dysregulation of channel gene expression in neurons. A better understanding of transcriptional channelopathies might provide us with new opportunities to treat these disorders.

Yaxun Sun - One of the best experts on this subject based on the ideXlab platform.

Michael J. Ackerman - One of the best experts on this subject based on the ideXlab platform.

Catharina G Faber - One of the best experts on this subject based on the ideXlab platform.

  • Myotonic discharges discriminate chloride from sodium muscle channelopathies.
    Neuromuscular Disorders, 2014
    Co-Authors: Gea Drost, Bas C. Stunnenberg, Jeroen Trip, Arendina W. Van Der Kooi, Ieke B Ginjaar, Kevin C. Mcgill, Baziel G M Van Engelen, George F. Borm, Machiel J Zwarts, Catharina G Faber
    Abstract:

    Abstract Non-dystrophic myotonic syndromes represent a heterogeneous group of clinically quite similar diseases sharing the feature of myotonia. These syndromes can be separated into chloride and sodium channelopathies, with gene-defects in chloride or sodium channel proteins of the sarcolemmal membrane. Myotonia has its basis in an electrical instability of the sarcolemmal membrane. In the present study we examine the discriminative power of the resulting myotonic discharges for these disorders. Needle electromyography was performed by an electromyographer blinded for genetic diagnosis in 66 non-dystrophic myotonia patients (32 chloride and 34 sodium Channelopathy). Five muscles in each patient were examined. Individual trains of myotonic discharges were extracted and analyzed with respect to firing characteristics. Myotonic discharge characteristics in the rectus femoris muscle almost perfectly discriminated chloride from sodium Channelopathy patients. The first interdischarge interval as a single variable was longer than 30 ms in all but one of the chloride Channelopathy patients and shorter than 30 ms in all of the sodium Channelopathy patients. This resulted in a detection rate of over 95%. Myotonic discharges of a single muscle can be used to better guide toward a molecular diagnosis in non-dystrophic myotonic syndromes.

  • genetic aspects of sodium Channelopathy in small fiber neuropathy
    Clinical Genetics, 2012
    Co-Authors: Janneke G J Hoeijmakers, Stephen G. Waxman, Ingemar S J Merkies, Monique M Gerrits, Catharina G Faber
    Abstract:

    Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.