Voltage-gated Ion Channel Genes Research Articles

Identification and validation of a signature involving voltage-gated chloride ion channel genes for prediction of prostate cancer recurrence.

Voltage-gated chloride ion channels (CLCs) are transmembrane proteins that maintain chloride ion homeostasis in various cells. Accumulating studies indicated CLCs were related to cell growth, proliferation, and cell cycle. Nevertheless, the role of CLCs in prostate cancer (PCa) has not been systematically profiled. The purpose of this study was to investigate the expression profiles and biofunctions of CLCs genes, and construct a novel risk signature to predict biochemical recurrence (BCR) of PCa patients. We identified five differentially expressed CLCs genes in our cohort and then constructed a signature composed of CLCN2 and CLCN6 through Lasso-Cox regression analysis in the training cohort from the Cancer Genome Atlas (TCGA). The testing and entire cohorts from TCGA and the GSE21034 from the Gene Expression Omnibus (GEO) were used as internal and independent external validation datasets. This signature could divide PCa patients into the high and low risk groups with different prognoses, was apparently correlated with clinical features, and was an independent excellent prognostic indicator. Enrichment analysis indicated our signature was primarily concentrated in cellular process and metabolic process. The expression patterns of CLCN2 and CLCN6 were detected in our own cohort based immunohistochemistry staining, and we found CLCN2 and CLCN6 were highly expressed in PCa tissues compared with benign tissues and positively associated with higher Gleason score and shorter BCR-free time. Functional experiments revealed that CLCN2 and CLCN6 downregulation inhibited cell proliferation, colony formation, invasion, and migration, but prolonged cell cycle and promoted apoptosis. Furthermore, Seahorse assay showed that silencing CLCN2 or CLCN6 exerted potential inhibitory effects on energy metabolism in PCa. Collectively, our signature could provide a novel and robust strategy for the prognostic evaluation and improve treatment decision making for PCa patients.

Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study.

Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999-2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70years vs. 9.23 ± 5.21years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.

Abstract 216: Functional annotations of membrane transport genes using genetic perturbation screens

Abstract Dysregulation of membrane transport and ion channels genes have been associated with through their role in cellular communication, regulation of cell size through osmoregulation and inflammation. However, a systematic profiling of the biological functions that are affected downstream of ion channels is not well studied due to challenges in monitoring their activity. Depleting known ligand-gated and voltage-gated ion channels has been shown to have a distinct phenotypic signature in HCT116 colorectal cells which is associated with their size and collective arrangement. These results were based on data from a genome-wide image-based siRNA screen where more than 500 million cells were segmented, and their shape and organisation were quantified. Single cells data were aggregated for each gene to capture cell heterogeneity and partial penetrance effects resulting in more than 1700 features per gene. Predictions of multiple functions for each gene were generated using KCML, a machine learning platform that automatically links gene perturbation phenotypes to molecular and biological function. Here we analysed the predicted functions for known ligand-gated and voltage-gated ion channel genes using KCML. Top predicted functions included ubiquitin protein ligase activity, phosphatase activity, stress-activated protein kinase signalling cascade, positive regulation of inflammatory response and cellular response to starvation. To validate these predictions, we applied KCML to independent genome-wide CRISPR screens measuring cell viability in 60 cancer cell lines from different tissue types. We focused on the functional association between ion channels and inflammatory response which is well recognised. We confirmed the prediction of 62/86 ion channel genes role in positive regulation of inflammatory response based on viability phenotypes. Many of these genes are documented to play a role in inflammation but has not annotated with inflammatory function in the gene ontology including GAS1, CHRNA2, and TMEM37. Pathway analysis revealed that seven of these genes are associated with gastric acid secretion (p-value =3.4E-5) including KCNQ1 gene that its loss that has been linked to the expression of inflammatory genes in colon cancer and worse patient outcomes. These results show that a comprehensive analysis of gene perturbation screens utilising siRNA or CRISPR technologies allows functional annotation of different roles for known ion channel genes. In particular, we identify 62 ion channel genes to be associated with inflammation and therefore would be promising therapeutic targets in colorectal cancer. Citation Format: Heba Sailem. Functional annotations of membrane transport genes using genetic perturbation screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 216.

The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.

There is still no comprehensive description of the general population regarding clinical features and genetic etiology for co-occurring epilepsy and autism spectrum disorder (ASD) in Chinese children. This study was a retrospective study of children diagnosed with epilepsy and ASD from January 1st, 2015, to May 1st, 2018, at the Children's Hospital of Fudan University. A total of 117 patients met the inclusion criteria, and 103 subjects were eligible. Among them, 88 underwent genetic testing, and 47 children (53.4%) were identified as having pathogenic or likely pathogenic variants: 39 had single gene mutations (83.0%, 39/47), and eight had copy number variants (17.0%, 8/47), with SCN1A (14.9%, 7/47) and MECP2 (10.6%, 5/47) gene mutations being the most common. Mutations in other genes encoding voltage-gated ion channels including SCN2A, CACNA1A, CACNA1H, CACNA1D, and KCNQ2 were also common, but the number of individual cases for each gene was small. Epilepsy syndrome and epilepsy-associated syndrome were more common (P = 0.014), and higher rates of poly-therapy (P = 0.01) were used in the positive genetic test group than in the negative group. There were no statistically significant differences in drug-refractory epilepsy, ASD severity, or intellectual disability between the positive genetic test group and the negative genetic group. These data strongly indicate the need for ASD screening in children with epilepsy with voltage-gated ion channel gene variants for better diagnosis and early intervention.

A Novel Model for Studying Voltage-Gated Ion Channel Gene Expression during Reversible Ischemic Stroke.

The dysfunction of voltage-gated ion channels contributes to the pathology of ischemic stroke. In this study, we developed rat models of transient ischemic attack (TIA) and reversible ischemic neurological deficit (RIND) that was induced via the injection of artificial embolic particles during full consciousness, that allow us to monitor the neurologic deficit and positron emission tomography (PET) scans in real-time. We then evaluated the infarction volume of brain tissue was confirmed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and gene expressions were evaluated by quantitative real-time PCR (qPCR). We found that rats with TIA or RIND exhibited neurological deficits as determined by negative TTC and PET findings. However, the expression of voltage-gated sodium channels in the hippocampus was significantly up-regulated in the qPCR array study. Furthermore, an altered expression of sodium channel β-subunits and potassium channels, were observed in RIND compared to TIA groups. In conclusion, to our knowledge, this is the first report of the successful evaluation of voltage-gated ion channel gene expression in TIA and RIND animal models. This model will aid future studies in investigating pathophysiological mechanisms, and in developing new therapeutic compounds for the treatment of TIA and RIND.

The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder

Considerable evidence suggests that autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive-compulsive disorder (OCD) share a common molecular aetiology, despite their unique clinical diagnostic criteria. The aim of this study was therefore to determine and characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD. Gene lists were obtained from previously published studies for ASD, BD, SCZ and for OCD. Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using the web-server tool Enrichr. Ten genes were identified to be commonly associated with the aetiology of ASD, SCZ, BD and OCD. Enrichment analyses determined that these genes are predominantly involved in the dopaminergic and serotonergic pathways, the voltage-gated calcium ion channel gene network, folate metabolism, regulation of the hippo signaling pathway, and the regulation of gene silencing and expression. In addition to well-characterised and previously described pathways, regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders. In contrast, a large number of previously associated genes were shown to be disorder-specific. And unique disorder-specific pathways and biological processes were presented for ASD, BD, SCZ and OCD aetiology. Considering the current global incidence and prevalence rates of mental health disorders, focus should be placed on cross-disorder commonalities in order to realise actionable and translatable results to combat mental health disorders.

Electric organ discharge diversification in mormyrid weakly electric fish is associated with differential expression of voltage-gated ion channel genes.

In mormyrid weakly electric fish, the electric organ discharge (EOD) is used for species recognition, orientation and prey localization. Produced in the muscle-derived adult electric organ, the EOD exhibits a wide diversity across species in both waveform and duration. While certain defining EOD characteristics can be linked to anatomical features of the electric organ, many factors underlying EOD differentiation are yet unknown. Here, we report the differential expression of 13 Kv1 voltage-gated potassium channel genes, two inwardly rectifying potassium channel genes, two previously studied sodium channel genes and an ATPase pump in two sympatric species of the genus Campylomormyrus in both the adult electric organ and skeletal muscle. Campylomormyrus compressirostris displays a basal EOD, largely unchanged during development, while C. tshokwe has an elongated, putatively derived discharge. We report an upregulation in all Kv1 genes in the electric organ of Campylomormyrus tshokwe when compared to both skeletal muscle and C. compressirostris electric organ. This pattern of upregulation in a species with a derived EOD form suggests that voltage-gated potassium channels are potentially involved in the diversification of the EOD signal among mormyrid weakly electric fish.

Spectrum of Nondystrophic Skeletal Muscle Channelopathies in Children

BackgroundThe nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic myotonia and periodic paralysis. MethodsWe identified patients with a diagnosis of muscle channelopathy from our neuromuscular database in a tertiary care pediatric center from 2005 to 2015. We then performed a retrospective review of their medical records for demographic characteristics, clinical features, investigations, treatment, and follow-up. ResultsThirty-three patients were identified. Seventeen had nondystrophic myotonia. Seven of them had chloride channelopathy (four Becker disease and three Thomsen disease). Warm-up phenomenon and muscle hypertrophy were common clinical manifestations in this subgroup. Ten patients had sodium channelopathy (four paramyotonia congenita and six other sodium channel myotonia). Stiffness of the facial muscles was an important presenting symptom, and eyelid myotonia was a common clinical finding in this subgroup. The majority of these patients had electrical myotonia. Mexiletine was effective in controlling the symptoms in patients who had received treatment. Sixteen children had periodic paralysis (four hyperkalemic periodic paralysis, eight hypokalemic periodic paralysis, and four Andersen-Tawil syndrome). Acetazolamide was commonly used to prevent paralytic attacks and was found to be effective. ConclusionsNondystrophic muscle channelopathies present with diverse clinical manifestations (myotonia, muscle hypertrophy, proximal weakness, swallowing difficulties, and periodic paralysis). Cardiac arrhythmias are potentially life threatening in Andersen-Tawil syndrome. Timely identification of these disorders is helpful for effective symptomatic management and genetic counseling.

337. CRISPR/Cas9 Mediated Highly Efficient Genome Engineering in Mouse Embryos

CRISPR/Cas9 is an RNA-based adaptive immune system used by bacteria and archaea to cleave foreign nucleic acids (e.g. bacteriophage DNA). This system has been adapted as a tool to edit mammalian genes with high efficiency and specificity. Here, we describe our use of the CRISPR/Cas9 system to achieve targeted gene knock outs and targeted gene repair in one cell stage mouse embryos. We have efficiently mutated tyrosinase (a coat color gene), p53 (a tumor suppressor gene), and Cacna1a (a voltage-gated ion channel gene) in mouse embryos by injection of Cas9 mRNA plus either a single or paired guide RNAs (sgRNAs). Single sgRNAs typically induced deletions of 1 bp to several hundred bp at their target site whereas paired sgRNAs generated localized deletions at high efficiency. For gene repair, we used 700 bp to 2 kb donor DNAs and a single sgRNA to promote gene correction by homology-mediated repair. Our experimental data revealed 8 to 18% efficiency of gene correction. When we used two sgRNAs to target a single exon, all of the newborn mice from one experiment showed targeted therapy for an inherited genetic disorder, albinism. No one has previously published a protocol that has achieved gene repair with this level of effectiveness. Our results confirm that the CRISPR/Cas9 system can be used for efficient gene targeting and gene repair in vivo.

A Novel GABRG2 mutation, p.R136*, in a family with GEFS + and extended phenotypes

Genetic mutations in voltage-gated and ligand-gated ion channel genes have been identified in a small number of Mendelian families with genetic generalised epilepsies (GGEs). They are commonly associated with febrile seizures (FS), childhood absence epilepsy (CAE) and particularly with generalised or genetic epilepsy with febrile seizures plus (GEFS+). In clinical practice, despite efforts to categorise epilepsy and epilepsy families into syndromic diagnoses, many generalised epilepsies remain unclassified with a presumed genetic basis. During the systematic collection of epilepsy families, we assembled a cohort of families with evidence of GEFS+ and screened for variations in the γ2 subunit of the γ-aminobutyric acid (GABA) type A receptor gene (GABRG2). We detected a novel GABRG2(p.R136*) premature translation termination codon in one index-case from a two-generation nuclear family, presenting with an unclassified GGE, a borderline GEFS+ phenotype with learning difficulties and extended behavioural presentation. The GABRG2(p.R136*) mutation segregates with the febrile seizure component of this family's GGE and is absent in 190 healthy control samples. In vitro expression assays demonstrated that γ2(p.R136*) subunits were produced, but had reduced cell-surface and total expression. When γ2(p.R136*) subunits were co-expressed with α1 and β2 subunits in HEK 293T cells, GABA-evoked currents were reduced. Furthermore, γ2(p.R136*) subunits were highly-expressed in intracellular aggregations surrounding the nucleus and endoplasmic reticulum (ER), suggesting compromised receptor trafficking. A novel GABRG2(p.R136*) mutation extends the spectrum of GABRG2 mutations identified in GEFS+ and GGE phenotypes, causes GABAA receptor dysfunction, and represents a putative epilepsy mechanism.

Non-Silent Story on Synonymous Sites in Voltage-Gated Ion Channel Genes

Synonymous mutations are usually referred to as “silent”, but increasing evidence shows that they are not neutral in a wide range of organisms. We looked into the relationship between synonymous codon usage bias and residue importance of voltage-gated ion channel proteins in mice, rats, and humans. We tested whether translationally optimal codons are associated with transmembrane or channel-forming regions, i.e., the sites that are particularly likely to be involved in the closing and opening of an ion channel. Our hypothesis is that translationally optimal codons are preferred at the sites within transmembrane domains or channel-forming regions in voltage-gated ion channel genes to avoid mistranslation-induced protein misfolding or loss-of-function. Using the Mantel-Haenszel procedure, which applies to categorical data, we found that translationally optimal codons are more likely to be used at transmembrane residues and the residues involved in channel-forming. We also found that the conservation level at synonymous sites in the transmembrane region is significantly higher than that in the non-transmembrane region. This study provides evidence that synonymous sites in voltage-gated ion channel genes are not neutral. Silent mutations at channel-related sites may lead to dysfunction of the ion channel.

Evolution of CpG island promoter function underlies changes in KChIP2 potassium channel subunit gene expression in mammalian heart

Scaling of cardiac electrophysiology with body mass requires large changes in the ventricular action potential duration and heart rate in mammals. These changes in cellular electrophysiological function are produced by systematic and coordinated changes in the expression of multiple ion channel and transporter genes. Expression of one important potassium current, the transient outward current (I(to)), changes significantly during mammalian evolution. Changes in I(to) expression are determined, in part, by variation in the expression of an obligatory auxiliary subunit encoded by the KChIP2 gene. The KChIP2 gene is expressed in both cardiac myocytes and neurons and transcription in both cell types is initiated from the same CpG island promoter. Species-dependent variation of KChIP2 expression in heart is mediated by the evolution of the cis-regulatory function of this gene. Surprisingly, the major locus of evolutionary change for KChIP2 gene expression in heart lies within the CpG island core promoter. The results demonstrate that CpG island promoters are not simply permissive for gene expression but can also contribute to tissue-selective expression and, as such, can function as an important locus for the evolution of cis-regulatory function. More generally, evolution of the cis-regulatory function of voltage-gated ion channel genes appears to be an effective and efficient way to modify channel expression levels to optimize electrophysiological function.

A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia

Many mutations in the skeletal-muscle sodium-channel gene SCN4A have been associated with myotonia and/or periodic paralysis, but so far all of these mutations are located in exons. We found a patient with myotonia caused by a deletion/insertion located in intron 21 of SCN4A, which is an AT-AC type II intron. This is a rare class of introns that, despite having AT-AC boundaries, are spliced by the major or U2-type spliceosome. The patient's skeletal muscle expressed aberrantly spliced SCN4A mRNA isoforms generated by activation of cryptic splice sites. In addition, genetic suppression experiments using an SCN4A minigene showed that the mutant 5' splice site has impaired binding to the U1 and U6 snRNPs, which are the cognate factors for recognition of U2-type 5' splice sites. One of the aberrantly spliced isoforms encodes a channel with a 35-amino acid insertion in the cytoplasmic loop between domains III and IV of Nav1.4. The mutant channel exhibited a marked disruption of fast inactivation, and a simulation in silico showed that the channel defect is consistent with the patient's myotonic symptoms. This is the first report of a disease-associated mutation in an AT-AC type II intron, and also the first intronic mutation in a voltage-gated ion channel gene showing a gain-of-function defect.

An Intronic Mutation of SCN4A Associated with Myotonia Raises an Aberrantly Spliced Isoform with Disrupted Fast Inactivation

Genetic defects of voltage-gated ion channel genes are responsible for several inheritable skeletal muscle diseases. Mutations of skeletal muscle sodium channel, SCN4A, have been shown to associate with myotonia and periodic paralysis. So far, most of the disease mutations of SCN4A are located in coding regions and the mutated channels show disruption of fast inactivation or enhancement of activation. We found a patient with myotonia caused by aberrantly spliced channel due to a mutation located at an intron of SCN4A. Moreover, this mutant channel showed gain of function defect, disruption of fast inactivation.A case was 35 year-old male who showed well-developed Herculean musculature and generalized muscle stiffness aggravated with cold exposure. We performed sequence analysis of SCN4A and CLCN1 using genomic DNA extracted from patient's lymphocytes. Moreover the mRNAs of SCN4A expressed in patient's muscle were analyzed by RT-PCR and nucleotide sequence. We constructed an expression vector of the channel isoform expressed in patient's muscle and measured Na current with whole cell configuration using HEK293t cells on which channels are expressed transiently.No mutations were identified in all exons of either SCN4A or CLCN1. Replacement of 5 nucleotides to a single nucleotide was detected in intron 21 of SCN4A. The mutation is located at downstream of exon 21 which could serve as splicing donor site. RT-PCR and nucleotide sequence analysis of cDNA showed three aberrantly spliced isoforms. The only in-frame isoform should result in insertion of 35 amino acids between domain III and IV. This isoform expressed in HEK cells showed marked defect in fast inactivation.Disease mutations located at non-coding region of voltage-gated ion channel genes usually show loss-of function, and this is the first example which shows gain-of function defect.

Gene expression analysis of the lung following paraquat administration in rats using DNA microarray.

Gene expression changes in the lungs induced by paraquat (PQ) administration were studied in rats using DNA microarrays that were detectable for 1,090 genes per DNA microarray. The rats were subjected to subacute PQ exposure (7 mg/kg, s.c., daily for eight administrations). Two days after the final administration, the rats were divided into two groups. Group 1 experienced significant body weight loss and displayed signs of subacute PQ toxicity, but Group 2 showed no significant effects due to the PQ treatment. A control group, Group 3, was also included. In the comparison of the gene expression levels in the animals from Group 1 or Group 2 to the control animals treated by vehicle, 48 genes in Group 1 and 29 genes from Group 2 were differentially expressed. The twenty-eight genes were common to these two groups. These differentially expressed genes following paraquat treatment were classified as follows: 5 neurotransmitter receptor genes; 4 transporter genes; 4 voltage-gated ion channel genes; 2 lipid metabolism enzyme genes; 2 G-proteins involved in endocytosis and exocytosis genes; 7 cytokine genes; 4 ADP ribosylation genes involved in cell death and regeneration; CFTR gene, which is the causal gene for cystic fibrosis; neurofibromatosis type 1 gene, which is the causal gene for the neurofibromatosis type 1 that is known to accompany pulmonary fibrosis; and the causal gene for spinocerebellar ataxia. These genes may prove to be the keys for the elucidation of the mechanism of PQ toxicity, e.g. PQ-induced pulmonary fibrosis.

AT-AC pre-mRNA splicing mechanisms and conservation of minor introns in voltage-gated ion channel genes.

Shortly after the discovery of split genes in 1977, a conserved sequence feature at both ends of cellular and viral introns was recognized, i.e., the presence of GT at the 5′ splice site and AG at the 3′ splice site, giving rise to the so-called GT-AG rule (8). This rule holds in most cases, but exceptions have been found. For example, GC is occasionally found at the 5′ end of certain introns (Table ​(Table1)1) (38). GC-AG introns are processed by the same splicing pathway as conventional GT-AG introns (3). It had long been assumed that removal of all introns from eukaryotic pre-mRNAs took place by the same splicing pathway, until recent developments demonstrated the existence of a second pre-mRNA splicing pathway. TABLE 1 Compilation of GC-AG intronsa Intron 6 of the gene encoding human P120, a proliferating cell nucleolar antigen, and intron 7 of the gene encoding human CMP, a cartilage matrix protein (matrilin 1), were the first reported examples of introns with AT and AC at the intron ends, instead of GT and AG (38). Intron 6 of the gene encoding Rep-3, a DNA repair protein, and intron 2 of the gene encoding Prospero, a Drosophila melanogaster homeodomain transcription factor, also have AT-AC ends (28). In addition to their distinctive dinucleotide ends, these and other AT-AC introns have highly conserved 5′-splice-site and presumptive branch site 8-nucleotide sequence elements that are not present in the major class of introns, ATATCCTY and TCCTTRAY, respectively. On the basis of these sequence features, it was proposed that the minor U11 and U12 snRNAs, which have regions of complementarity to these elements, are required for splicing of AT-AC introns (28). Important aspects of this prediction were soon verified experimentally (29, 100), and two additional minor snRNAs involved in the novel pre-mRNA splicing pathway were discovered (101). The AT-AC splicing pathway was originally named after the distinctive sequences of the intron ends (100). It was later found that a few introns with AT-AC ends are processed by the major pathway (120) and, conversely, that some introns with GT-AG ends are spliced by the minor pathway (18). Therefore, the name AT-AC no longer reflects the dinucleotide intron ends per se, but rather it refers to the minor pathway itself. An alternative designation for the two pathways—U2 dependent and U12 dependent—reflects their observed or expected requirements for one of the four snRNAs specific to each pathway (86).

S-6-2 Molecular basis of the periodic paralyses

The nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic myotonia and periodic paralysis.We identified patients with a diagnosis of muscle channelopathy from our neuromuscular database in a tertiary care pediatric center from 2005 to 2015. We then performed a retrospective review of their medical records for demographic characteristics, clinical features, investigations, treatment, and follow-up.Thirty-three patients were identified. Seventeen had nondystrophic myotonia. Seven of them had chloride channelopathy (four Becker disease and three Thomsen disease). Warm-up phenomenon and muscle hypertrophy were common clinical manifestations in this subgroup. Ten patients had sodium channelopathy (four paramyotonia congenita and six other sodium channel myotonia). Stiffness of the facial muscles was an important presenting symptom, and eyelid myotonia was a common clinical finding in this subgroup. The majority of these patients had electrical myotonia. Mexiletine was effective in controlling the symptoms in patients who had received treatment. Sixteen children had periodic paralysis (four hyperkalemic periodic paralysis, eight hypokalemic periodic paralysis, and four Andersen-Tawil syndrome). Acetazolamide was commonly used to prevent paralytic attacks and was found to be effective.Nondystrophic muscle channelopathies present with diverse clinical manifestations (myotonia, muscle hypertrophy, proximal weakness, swallowing difficulties, and periodic paralysis). Cardiac arrhythmias are potentially life threatening in Andersen-Tawil syndrome. Timely identification of these disorders is helpful for effective symptomatic management and genetic counseling.

Topographic distribution of quantitative EEG effects of neuroactive drugs : W.G. Sannita, M. Cabri, A. Griss, C. Padovan and G. Rosadini (Genoa, Italy)

The nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic myotonia and periodic paralysis.We identified patients with a diagnosis of muscle channelopathy from our neuromuscular database in a tertiary care pediatric center from 2005 to 2015. We then performed a retrospective review of their medical records for demographic characteristics, clinical features, investigations, treatment, and follow-up.Thirty-three patients were identified. Seventeen had nondystrophic myotonia. Seven of them had chloride channelopathy (four Becker disease and three Thomsen disease). Warm-up phenomenon and muscle hypertrophy were common clinical manifestations in this subgroup. Ten patients had sodium channelopathy (four paramyotonia congenita and six other sodium channel myotonia). Stiffness of the facial muscles was an important presenting symptom, and eyelid myotonia was a common clinical finding in this subgroup. The majority of these patients had electrical myotonia. Mexiletine was effective in controlling the symptoms in patients who had received treatment. Sixteen children had periodic paralysis (four hyperkalemic periodic paralysis, eight hypokalemic periodic paralysis, and four Andersen-Tawil syndrome). Acetazolamide was commonly used to prevent paralytic attacks and was found to be effective.Nondystrophic muscle channelopathies present with diverse clinical manifestations (myotonia, muscle hypertrophy, proximal weakness, swallowing difficulties, and periodic paralysis). Cardiac arrhythmias are potentially life threatening in Andersen-Tawil syndrome. Timely identification of these disorders is helpful for effective symptomatic management and genetic counseling.