The Experts below are selected from a list of 429 Experts worldwide ranked by ideXlab platform
Michael G. Hanna - One of the best experts on this subject based on the ideXlab platform.
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Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms.
The Journal of pediatrics, 2017Co-Authors: Emma Matthews, Michael G. Hanna, A. Silwal, Richa Sud, Adnan Y. Manzur, Francesco Muntoni, P. MunotAbstract: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.
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Muscle channelopathies: recent advances in genetics, pathophysiology and therapy.
Current opinion in neurology, 2014Co-Authors: K. Suetterlin, Roope Männikkö, Michael G. HannaAbstract: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.
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Ca v 1.1 Channel and Hypokalemic Periodic Paralysis
Pathologies of Calcium Channels, 2013Co-Authors: Emma Matthews, Michael G. HannaAbstract:Hypokalaemic periodic paralysis is a rare inherited autosomal dominant neuromuscular disorder due predominantly to dysfunction of the alpha subunit of the Cav1.1 ion channel, although a significant minority of cases are due to dysfunction of another sarcolemmal ion channel, Nav1.4. Hypokalaemic periodic paralysis has been phenotypically described for several centuries but it was not until 1994 that the first causative gene CACNA1S was identified, followed later by a second gene, SCN4A. Electrophysiologic studies attempted to understand how mutations in these genes affected channel function to account for the described phenotype, but early studies were frustratingly inconclusive. Not least because, a satisfactory explanation eluded researchers as to how two ion channels with very different roles could cause the same disease. In 2007, however, an aberrant gating pore current was identified in several Nav1.4 mutations that revolutionised the hypothesis of the pathogenesis of hypokalemic periodic paralysis. In this chapter we review the evolution of our current understanding of this important skeletal Muscle Channelopathy.
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Muscle channelopathies: does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis?
The Journal of Physiology, 2010Co-Authors: Emma Matthews, Michael G. HannaAbstract:Hypokalaemic periodic paralysis (hypoPP) is the archetypal skeletal Muscle Channelopathy caused by dysfunction of one of two sarcolemmal ion channels, either the sodium channel Nav1.4 or the calcium channel Cav1.1. Clinically, hypoPP is characterised by episodes of often severe flaccid Muscle paralysis, in which the Muscle fibre membrane becomes electrically inexcitable, and which may be precipitated by low serum potassium levels. Initial functional characterisation of hypoPP mutations failed to adequately explain the pathomechanism of the disease. Recently, as more pathogenic mutations involving loss of positive charge have been identified in the S4 segments of either channel, the hypothesis that an abnormal gating pore current may be important has emerged. Such an aberrant gating pore current has been identified in mutant Nav1.4 channels and has prompted potentially significant advances in this area. The carbonic anhydrase inhibitor acetazolamide has been used as a treatment for hypokalaemic periodic paralysis for over 40 years but its precise therapeutic mechanism of action is unclear. In this review we summarise the recent advances in the understanding of the molecular pathophysiology of hypoPP and consider how these may relate to the reported beneficial effects of acetazolamide. We also consider potential areas for future therapeutic development.
Magnus R. Dias-da-silva - One of the best experts on this subject based on the ideXlab platform.
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Whole genome and exome sequencing realignment supports the assignment of KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic paralysis locus: functional characterization of two polymorphic Kir2.6 isoforms
Molecular Genetics and Genomics, 2016Co-Authors: Rolf M. Paninka, Diego R. Mazzotti, Marina M. L. Kizys, Angela C. Vidi, Hélio Rodrigues, Silas P. Silva, Ilda S. Kunii, Gilberto K. Furuzawa, Manoel Arcisio-miranda, Magnus R. Dias-da-silvaAbstract:Next-generation sequencing (NGS) has enriched the understanding of the human genome. However, homologous or repetitive sequences shared among genes frequently produce dubious alignments and can puzzle NGS mutation analysis, especially for paralogous potassium channels. Potassium inward rectifier (Kir) channels are important to establish the resting membrane potential and regulating the Muscle excitability. Mutations in Kir channels cause disorders affecting the heart and skeletal Muscle, such as arrhythmia and periodic paralysis. Recently, a susceptibility Muscle Channelopathy—thyrotoxic periodic paralysis (TPP)—has been related to Kir2.6 channel ( KCNJ18 gene). Due to their high nucleotide sequence homology, variants found in the potassium channels Kir2.6 and Kir2.5 have been mistakenly attributable to Kir2.2 polymorphisms or mutations. We aimed at elucidating nucleotide misalignments by performing realignment of whole exome sequencing (WES) and whole genome sequencing (WGS) reads to specific Kir2.2, Kir2.5, and Kir2.6 cDNA sequences using BWA-MEM/GATK pipeline. WES/WGS reads correctly aligned 26.9/43.2, 37.6/31.0, and 35.4/25.8 % to Kir2.2, Kir2.5, and Kir2.6, respectively. Realignment was able to reduce over 94 % of misalignments. No putative mutations of Kir2.6 were identified for the three TPP patients included in the cohort of 36 healthy controls using either WES or WGS. We also distinguished sequences for a single Kir2.2, a single Kir2.5 sequence, and two Kir2.6 isoforms, which haplotypes were named RRAI and QHEV, based on changes at 39, 40, 56, and 249 residues. Electrophysiology records on both Kir2.6_RRAI and _QHEV showed typical rectifying currents. In our study, the reduction of misalignments allowed the elucidation of paralogous gene sequences and two distinct Kir2.6 haplotypes, and pointed the need for checking the frequency of these polymorphisms in other populations with different genetic background.
D.g. Avode - One of the best experts on this subject based on the ideXlab platform.
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Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family
Neuromuscular disorders : NMD, 2007Co-Authors: Dismand Houinato, Anatole Laleye, Constant Adjien, Marius Adjagba, Damien Sternberg, Pascale Hilbert, Jean-michel Vallat, Raphael Darboux, Benoît Funalot, D.g. AvodeAbstract:Abstract Hypokalaemic periodic paralysis (HypoKPP) is a skeletal Muscle Channelopathy caused by mutations in calcium (CACNA1S) and sodium (SCN4A) channel subunits. A small number of causative mutations have been found in European and Asian patients, but not in African patients yet. We have identified a large Beninese family in which HypoKPP segregated over five generations and was caused by the CACNA1S R1239H mutation. We report on the clinical and histopathological spectrum of the disorder in this family. A later age at onset (15.8 ± 8.8 years), and particular triggering factors due to specific African life conditions seem to be characteristic of our observation.
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Case report Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family
2007Co-Authors: Dismand Houinato, Anatole Laleye, Constant Adjien, Marius Adjagba, Damien Sternberg, Pascale Hilbert, Jean-michel Vallat, D.g. AvodeAbstract:Hypokalaemic periodic paralysis (HypoKPP) is a skeletal Muscle Channelopathy caused by mutations in calcium (CACNA1S) and sodium (SCN4A) channel subunits. A small number of causative mutations have been found in European and Asian patients, but not in African patients yet. We have identified a large Beninese family in which HypoKPP segregated over five generations and was caused by the CACNA1S R1239H mutation. We report on the clinical and histopathological spectrum of the disorder in this family. A later age at onset (15.8 ± 8.8 years), and particular triggering factors due to specific African life conditions seem to be characteristic of our observation. � 2007 Elsevier B.V. All rights reserved.
Emma Matthews - One of the best experts on this subject based on the ideXlab platform.
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Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms.
The Journal of pediatrics, 2017Co-Authors: Emma Matthews, Michael G. Hanna, A. Silwal, Richa Sud, Adnan Y. Manzur, Francesco Muntoni, P. MunotAbstract: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.
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Ca v 1.1 Channel and Hypokalemic Periodic Paralysis
Pathologies of Calcium Channels, 2013Co-Authors: Emma Matthews, Michael G. HannaAbstract:Hypokalaemic periodic paralysis is a rare inherited autosomal dominant neuromuscular disorder due predominantly to dysfunction of the alpha subunit of the Cav1.1 ion channel, although a significant minority of cases are due to dysfunction of another sarcolemmal ion channel, Nav1.4. Hypokalaemic periodic paralysis has been phenotypically described for several centuries but it was not until 1994 that the first causative gene CACNA1S was identified, followed later by a second gene, SCN4A. Electrophysiologic studies attempted to understand how mutations in these genes affected channel function to account for the described phenotype, but early studies were frustratingly inconclusive. Not least because, a satisfactory explanation eluded researchers as to how two ion channels with very different roles could cause the same disease. In 2007, however, an aberrant gating pore current was identified in several Nav1.4 mutations that revolutionised the hypothesis of the pathogenesis of hypokalemic periodic paralysis. In this chapter we review the evolution of our current understanding of this important skeletal Muscle Channelopathy.
-
Muscle channelopathies: does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis?
The Journal of Physiology, 2010Co-Authors: Emma Matthews, Michael G. HannaAbstract:Hypokalaemic periodic paralysis (hypoPP) is the archetypal skeletal Muscle Channelopathy caused by dysfunction of one of two sarcolemmal ion channels, either the sodium channel Nav1.4 or the calcium channel Cav1.1. Clinically, hypoPP is characterised by episodes of often severe flaccid Muscle paralysis, in which the Muscle fibre membrane becomes electrically inexcitable, and which may be precipitated by low serum potassium levels. Initial functional characterisation of hypoPP mutations failed to adequately explain the pathomechanism of the disease. Recently, as more pathogenic mutations involving loss of positive charge have been identified in the S4 segments of either channel, the hypothesis that an abnormal gating pore current may be important has emerged. Such an aberrant gating pore current has been identified in mutant Nav1.4 channels and has prompted potentially significant advances in this area. The carbonic anhydrase inhibitor acetazolamide has been used as a treatment for hypokalaemic periodic paralysis for over 40 years but its precise therapeutic mechanism of action is unclear. In this review we summarise the recent advances in the understanding of the molecular pathophysiology of hypoPP and consider how these may relate to the reported beneficial effects of acetazolamide. We also consider potential areas for future therapeutic development.
Rolf M. Paninka - One of the best experts on this subject based on the ideXlab platform.
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Whole genome and exome sequencing realignment supports the assignment of KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic paralysis locus: functional characterization of two polymorphic Kir2.6 isoforms
Molecular Genetics and Genomics, 2016Co-Authors: Rolf M. Paninka, Diego R. Mazzotti, Marina M. L. Kizys, Angela C. Vidi, Hélio Rodrigues, Silas P. Silva, Ilda S. Kunii, Gilberto K. Furuzawa, Manoel Arcisio-miranda, Magnus R. Dias-da-silvaAbstract:Next-generation sequencing (NGS) has enriched the understanding of the human genome. However, homologous or repetitive sequences shared among genes frequently produce dubious alignments and can puzzle NGS mutation analysis, especially for paralogous potassium channels. Potassium inward rectifier (Kir) channels are important to establish the resting membrane potential and regulating the Muscle excitability. Mutations in Kir channels cause disorders affecting the heart and skeletal Muscle, such as arrhythmia and periodic paralysis. Recently, a susceptibility Muscle Channelopathy—thyrotoxic periodic paralysis (TPP)—has been related to Kir2.6 channel ( KCNJ18 gene). Due to their high nucleotide sequence homology, variants found in the potassium channels Kir2.6 and Kir2.5 have been mistakenly attributable to Kir2.2 polymorphisms or mutations. We aimed at elucidating nucleotide misalignments by performing realignment of whole exome sequencing (WES) and whole genome sequencing (WGS) reads to specific Kir2.2, Kir2.5, and Kir2.6 cDNA sequences using BWA-MEM/GATK pipeline. WES/WGS reads correctly aligned 26.9/43.2, 37.6/31.0, and 35.4/25.8 % to Kir2.2, Kir2.5, and Kir2.6, respectively. Realignment was able to reduce over 94 % of misalignments. No putative mutations of Kir2.6 were identified for the three TPP patients included in the cohort of 36 healthy controls using either WES or WGS. We also distinguished sequences for a single Kir2.2, a single Kir2.5 sequence, and two Kir2.6 isoforms, which haplotypes were named RRAI and QHEV, based on changes at 39, 40, 56, and 249 residues. Electrophysiology records on both Kir2.6_RRAI and _QHEV showed typical rectifying currents. In our study, the reduction of misalignments allowed the elucidation of paralogous gene sequences and two distinct Kir2.6 haplotypes, and pointed the need for checking the frequency of these polymorphisms in other populations with different genetic background.
