Potassium Channel Mutations Research Articles

Efficacy and safety of octreotide treatment for diazoxide-unresponsive congenital hyperinsulinism in China.

ABSTRACTImportanceOctreotide is an off‐label medicine for congenital hyperinsulinism (CHI), but is currently widely used for treatment of patients with CHI. Thus far, variable efficacy and adverse effects have been reported for octreotide.ObjectiveThe present study evaluated the efficacy and safety of a subcutaneous octreotide injection for treatment of diazoxide‐unresponsive CHI in China.MethodsThis study was a retrospective review of children with diazoxide‐unresponsive CHI who were treated with a subcutaneous octreotide injection. The efficacy and side effects of the treatment were assessed.ResultsTwenty‐five Chinese children (15 boys) were involved in the study. Their median age at diagnosis was 8 weeks (range, 1–24 weeks) and median age at the final follow‐up was 1.8 years (range, 0.3–3.3 years). Octreotide therapy effectively increased blood glucose levels in all patients. The intravenous glucose infusion rate was reduced in all patients. Twenty‐one patients gradually discontinued the intravenous glucose infusion while receiving octreotide combined with frequent carbohydrate/glucose‐rich feeding. Among patients with a monoallelic ATP‐sensitive potassium (KATP) channel mutation, 50.0% showed gradual remission during follow up, indicating that the octreotide treatment may be a feasible alternative to surgery, especially for patients with monoallelic KATP‐channel mutations. Transient elevation of liver enzymes occurred in 20.0% of patients, while asymptomatic gallbladder pathology occurred in one patient. The growth rates of these patients were normal (height standard deviation score was 0.3 ± 1.5 at the final follow‐up).InterpretationOctreotide was a well‐tolerated, effective therapy for most children with diazoxide‐unresponsive CHI.

"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.

Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.

Patent Highlights April–May 2019

Patent Highlights April–May 2019

Retracted: Mutations in KCNQ potassium channels cause pharyngeal pumping defects in C. elegans

[This retracts the article DOI: 10.17912/W2MW2D.].

MON-428 More Danger Than We Knew: Hypokalemic Periodic Paralysis Triggered by Alcohol Consumption

Introduction: Alcohol use disorder affects close to 20 million people in the United States. Alcohol causes long term damage in various organs including the muscles resulting in alcoholic myopathy. However, other less common etiologies for acute muscle weakness should be considered in these patients. Case presentation: Our patient is a 25 year-old Hispanic male, who presented with 2 hours of acute lower extremity weakness. He had difficulty walking, clothing, grasping and reported myalgia. He admitted to partying and binge drinking while consuming pizza and burgers the night before. He denied similar episodes in the past or any family history of weakness. His physical exam was remarkable for 2/5 strength in the hip flexors bilaterally, hip and knee extension was 4/5 bilaterally, knee flexion was 4/5 bilaterally. He had hyporeflexia, normal muscle bulk and tone and normal sensation. Diagnostic work up revealed a potassium of 1.9 mmol/L, phosphorus 1.9 mmol/L and CK of 176 IU/L (22-269 IU/L). Due to concern for thyrotoxic periodic paralysis, TSH was checked which was normal at 0.47 MCIU/ml (0.550-4.780 MCIU/ml). He was given 40meq IV potassium by slow infusion, followed by 40meq PO. His potassium improved to 2.4mmol/L after supplementation and there was a rapid recovery in his muscle weakness. Potassium levels were monitored for 24 hours. He had persistently normal potassium levels during his stay. His lower motor strength remained to be a 5/5 throughout the hospitalization. He was discharged with counseling and emphasis on alcohol cessation. Discussion: Beer contains 13 grams of CHO in 1 can. It’s high carbohydrate content can result in an insulin surge producing a rapid intracellular shift of potassium through N-K ATPase channels. This produces hypokalemic periodic paralysis (HPP) in predisposed patients. HPP is an uncommon neuromuscular disorder with 1 in 100,000 cases. It results from mutations in sodium, calcium and potassium channels in the skeletal muscles. It is an autosomal dominant disease and found predominantly in young Asian males. These patients are at risk for fatal cardiac arrhythmias due to their significantly low potassium levels on presentation. They carry the same risk for arrhythmias in the treatment period due to increased risk of over-correction resulting in hyperkalemia. Long term recurrent HPP can result in progressive proximal myopathy and reduced functional mobility that may affect quality of life. These short and long term complications in HPP can only be prevented by avoidance of triggers, in our case avoidance of alcohol consumption. Rapid recognition for close electrolyte monitoring and effective counseling by physicians to establish a clear understanding in patients is imperative for their long term health. (1)Vilarinho S, Siegel M D. Paralysis caused by a large carbohydrate meal. J Postgrad Med 2012;58:60-1

Patient-Specific Identification of Atrial Flutter Vulnerability-A Computational Approach to Reveal Latent Reentry Pathways.

Atypical atrial flutter (AFlut) is a reentrant arrhythmia which patients frequently develop after ablation for atrial fibrillation (AF). Indeed, substrate modifications during AF ablation can increase the likelihood to develop AFlut and it is clinically not feasible to reliably and sensitively test if a patient is vulnerable to AFlut. Here, we present a novel method based on personalized computational models to identify pathways along which AFlut can be sustained in an individual patient. We build a personalized model of atrial excitation propagation considering the anatomy as well as the spatial distribution of anisotropic conduction velocity and repolarization characteristics based on a combination of a priori knowledge on the population level and information derived from measurements performed in the individual patient. The fast marching scheme is employed to compute activation times for stimuli from all parts of the atria. Potential flutter pathways are then identified by tracing loops from wave front collision sites and constricting them using a geometric snake approach under consideration of the heterogeneous wavelength condition. In this way, all pathways along which AFlut can be sustained are identified. Flutter pathways can be instantiated by using an eikonal-diffusion phase extrapolation approach and a dynamic multifront fast marching simulation. In these dynamic simulations, the initial pattern eventually turns into the one driven by the dominant pathway, which is the only pathway that can be observed clinically. We assessed the sensitivity of the flutter pathway maps with respect to conduction velocity and its anisotropy. Moreover, we demonstrate the application of tailored models considering disease-specific repolarization properties (healthy, AF-remodeled, potassium channel mutations) as well as applicabiltiy on a clinical dataset. Finally, we tested how AFlut vulnerability of these substrates is modulated by exemplary antiarrhythmic drugs (amiodarone, dronedarone). Our novel method allows to assess the vulnerability of an individual patient to develop AFlut based on the personal anatomical, electrophysiological, and pharmacological characteristics. In contrast to clinical electrophysiological studies, our computational approach provides the means to identify all possible AFlut pathways and not just the currently dominant one. This allows to consider all relevant AFlut pathways when tailoring clinical ablation therapy in order to reduce the development and recurrence of AFlut.

Progressive myoclonus epilepsy caused by a gain-of-function KCNA2 mutation

Progressive myoclonus epilepsy caused by a gain-of-function KCNA2 mutation

Genetics of Atrial Fibrillation.

BackgroundAtrial fibrillation (AF) is a common arrhythmia seen in clinical practice. Occasionally, no common risk factors are present in patients with this arrhythmia. This suggests the potential underlying role of genetic factors associated with predisposition to developing AF.Methods and ResultsWe conducted a comprehensive review of the literature through large online libraries, including PubMed. Many different potassium and sodium channel mutations have been discussed in their relation to AF. There have also been non–ion channel mutations that have been linked to AF. Genome‐wide association studies have helped in identifying potential links between single‐nucleotide polymorphisms and AF. Ancestry studies have also highlighted a role of genetics in AF. Blacks with a higher percentage of European ancestry are at higher risk of developing AF. The emerging field of ablatogenomics involves the use of genetic profiles in their relation to recurrence of AF after catheter ablation.ConclusionsThe evidence for the underlying role of genetics in AF continues to expand. Ultimately, the role of genetics in risk stratification of AF and its recurrence is of significant interest. No established risk scores that are useful in clinical practice are present to date.

Contribution of systemic inflammation to permanence of KATP-induced neonatal diabetes in mice.

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (KATP) channels cause neonatal diabetes. Despite the well-established genetic root of the disease, pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family, suggesting that subtle modifiers can influence disease outcome. We have tested the underlying mechanism of transient vs. permanent neonatal diabetes in KATP-GOF mice treated for 14 days with glibenclamide. Some KATP-GOF mice show remission of diabetes and enhanced insulin sensitivity long after diabetes treatment has ended, while others maintain severe insulin-resistance. However, insulin sensitivity is not different between the two groups before or during diabetes induction, suggesting that improved sensitivity is a consequence, rather than the cause of, remission, implicating other factors modulating glucose early in diabetes progression. Leptin, glucagon, insulin, and glucagon-like peptide-1 are not different between remitters and nonremitters. However, liver glucose production is significantly reduced before transgene induction in remitter, relative to nonremitter and nontreated, mice. Surprisingly, while subsequent remitter animals exhibited normal serum cytokines, nonremitter mice showed increased cytokines, which paralleled the divergence in blood glucose. Together, these results suggest that systemic inflammation may play a role in the remitting versus non-remitting outcome. Supporting this conclusion, treatment with the anti-inflammatory meloxicam significantly increased the fraction of remitting animals. Beyond neonatal diabetes, the potential for inflammation and glucose production to exacerbate other forms of diabetes from a compensated state to a glucotoxic state should be considered.

NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes

Long QT syndrome type 2 (LQT2) is a congenital disease characterized by loss of function mutations in hERG potassium channels (IKr). LQT2 is associated with fatal ventricular arrhythmias promoted by triggered activity in the form of early afterdepolarizations (EADs). We previously demonstrated that intracellular Ca2+ handling is remodeled in LQT2 myocytes. Remodeling leads to aberrant late RyR-mediated Ca2+ releases that drive forward-mode Na+-Ca2+ exchanger (NCX) current and slow repolarization to promote reopening of L-type calcium channels and EADs. Forward-mode NCX was found to be enhanced despite the fact that these late releases do not significantly alter the whole-cell cytosolic calcium concentration during a vulnerable period of phase 2 of the action potential corresponding to the onset of EADs. Here, we use a multiscale ventricular myocyte model to explain this finding. We show that because the local NCX current is a saturating nonlinear function of the local submembrane calcium concentration, a larger number of smaller-amplitude discrete Ca2+ release events can produce a large increase in whole-cell forward-mode NCX current without increasing significantly the whole-cell cytosolic calcium concentration. Furthermore, we develop novel insights, to our knowledge, into how alterations of stochastic RyR activity at the single-channel level cause late aberrant Ca2+ release events. Experimental measurements in transgenic LTQ2 rabbits confirm the critical arrhythmogenic role of NCX and identify this current as a potential target for antiarrhythmic therapies in LQT2.

Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities

Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.

Ambigous phenotipic expression of some mutations in the cardiac Nav1.5 sodium channel

Introduction Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since 1995, hundreds of mutations have been found in more than twenty genes coding for cardiac ion channel subunits or proteins regulating cardiac ion channels. The main ECG syndromes caused by those mutations are outlined but there are many mixed and intermediate phenotypes. The phenotype-genotype correlations are not well understood but expected to be related to a functional effect on the ion conductivity. Material and methods Clinical examination including family history taking, ECG, 24-h Holter monitoring, and pharmacological testing with Na + -blockers (by indication) was performed for 192 families with suspected primary arrhythmic syndromes. Diagnoses were established using conventional criteria. Genetic screening of KCNQ1 , KCNE1 , KCNH2 , KCNE2 , KCNJ2 , KCNE3 , SCN5A , and SCN1B-SCN4B was performed for 192 probands by bi-directional Sanger sequencing. Phenotype-genotype correlations had been analyzed. Results and discussion Totally we had found 58 mutations in the genes encoding potassium channels (39 in the KCNQ1 gene, 14 in the KCNH2 gene, 2 in the KCNE1 gene, 1 in the KCNE2, and 1 in the KCNJ2 gene) and 23 mutations in the genes encoding sodium channels (22 in the SCN5A and 1 on the SCN1B). Most of mutations were found in a single family. Patients caring two mutations had more sever clinical appearance of cardiac arrhythmia and high risk of cardiac sudden death. We had found 5 mutations encoding sodium channel mutations (4 in the SCN5A gene and 1 in the SCN1B gene), which lead to the different and sometimes opposite phenotypes in different probands (LQTS and/or BrS, IVF, various cardiomyopathies) or even within the same family members. This phenomenon was not observed in clinical expression of the potassium channel mutations. All mutations found in the genes encoding potassium channels subunits had univocal and predictable phenotype. Mutations leading to the haplo-insufficiency or “loss-of-function” of the potassium channels had caused Long QT Syndrome; “gain-of-function” mutations were responsible for Short QT Syndrome and/or Brugada Syndrome. Conclusion Despite the fairly detailed biophysical characterizations of the mutant variants of Nav1.5 protein, the stages of the molecular pathogenesis leading from the disruption of sodium conductance to the clinical phenotype are not fully understood. «Non-canonical» functions of the Nav1.5 channel beside ion conductance might be crucial for the resulting clinical appearance.

Hemodynamic and Pathologic Characterization of the TASK-1-/- Mouse Does Not Demonstrate Pulmonary Hypertension.

Pulmonary hypertension (PH) carries significant associated morbidity and mortality and the underlying molecular mechanisms of PH are not well understood. Loss-of-function mutations in TASK-1 potassium channels are associated with PH in humans. Although TASK-1 has been considered in the development of PH for over a decade, characterization of TASK-1 knockout mice has been limited to in vitro studies or in vivo studies in room air at isolated time points. The purpose of this study was twofold. First, we sought to determine if TASK-/- male and female mice developed PH over the span of one year. Second, we sought to determine the effect of chronic hypoxia, a stimulus for PH, and its recovery on PH in TASK-1-/- mice. We measured right ventricular systolic pressure (RVSP) and vascular remodeling in male and female C57BL/6 WT and TASK-1-/- mice at separate time points: 20-24 weeks and 1 year of age. Additionally, we measured RVSP and vascular remodeling in TASK-1-/- and wild-type mice between 13 and 16 weeks of age exposed to 10% hypoxia for 3 weeks followed by recovery to room air conditions for an additional 6 weeks. RVSP was similar between WT and TASK-/- mice. Male and female WT and TASK-1-/- mice all demonstrated age-related increases in RVSP, which correlated to age-related vascular remodeling in male mice but not in female mice. Male TASK-1-/- and WT mice exposed to chronic hypoxia demonstrated increased RVSP, which decreased following room air recovery. WT and TASK-1-/- male mice demonstrated vascular remodeling upon exposure to hypoxia that persisted in room air recovery. Female and male TASK-1-/- mice do not develop hemodynamic or vascular evidence for PH, but RVSP rises in an age-dependent manner independent of genotype. TASK-1-/- and WT male mice develop hypoxia-induced elevations in RVSP that decrease to baseline after recovery in room air. TASK-1-/- and WT male mice demonstrate vascular remodeling after exposure to hypoxia that persists despite recovery to room air conditions and does not correlate with RVSP normalization.

In Vivo Analysis of Potassium Channelopathies: Loose Patch Recording of Purkinje Cell Firing in Living, Awake Zebrafish.

Zebrafish is a lower vertebrate model organism that facilitates integrative analysis of the in vivo effects of potassium and other ion channel mutations at the molecular, cellular, developmental, circuit, systems, and behavioral levels of analysis. Here, we describe a method for extracellular, loose patch electrophysiological recording of electrical activity in cerebellar Purkinje cells in living, awake zebrafish, with the goal of investigating pathological mechanisms underlying channelopathies or other diseases that disrupt cerebellar function. Purkinje cell excitability and a functional cerebellar circuit develop rapidly in zebrafish and show strong conservation with the mammalian cerebellum.

Methods for Characterizing Disease-Associated ATP-Sensitive Potassium Channel Mutations.

The ATP-sensitive potassium (KATP) channel formed by the inwardly rectifying potassium channel Kir6.2 and the sulfonylurea receptor 1 (SUR1) plays a key role in regulating insulin secretion. Genetic mutations in KCNJ11 or ABCC8 which encode Kir6.2 and SUR1 respectively are major causes of insulin secretion disorders: those causing loss of channel function lead to congenital hyperinsulinism, whereas those causing gain of channel function result in neonatal diabetes and in some cases developmental delay, epilepsy, and neonatal diabetes, referred to as the DEND syndrome. Understanding how disease mutations disrupt channel expression and function is important for disease diagnosis and for devising effective therapeutic strategies. Here, we describe a workflow including several biochemical and functional assays to assess the effects of mutations on channel expression and function.

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties.

To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability. MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

Mutations in KCNQ potassium channels cause pharyngeal pumping defects in C. elegans.

Mutations in KCNQ potassium channels cause pharyngeal pumping defects in C. elegans.

Prematurity and Genetic Testing for Neonatal Diabetes.

Hyperglycemia in premature infants is usually thought to reflect inadequate pancreatic development rather than monogenic neonatal diabetes. No studies, to our knowledge, have investigated the prevalence of monogenic forms of diabetes in preterm infants. We studied 750 patients with diabetes diagnosed before 6 months of age. We compared the genetic etiology and clinical characteristics of 146 preterm patients born <37 weeks and compared them with 604 born ≥37 weeks. A genetic etiology was found in 97/146 (66%) preterm infants compared with 501/604 (83%) born ≥37weeks, P < .0001. Chromosome 6q24 imprinting abnormalities (27% vs 12%, P = .0001) and GATA6 mutations (9% vs 2%, P = .003) occurred more commonly in preterm than term infants while mutations in KCNJ11 were less common (21 vs 34%, P = .008). Preterm patients with an identified mutation were diagnosed later than those without an identified mutation (median [interquartile range] 35 [34 to 36] weeks vs 31 [28 to 36] weeks, P < .0001). No difference was seen in other clinical characteristics of preterm patients with and without an identified mutation including age of presentation, birth weight, and time to referral. Patients with neonatal diabetes due to a monogenic etiology can be born preterm, especially those with 6q24 abnormalities or GATA6 mutations. A genetic etiology is more likely in patients with less severe prematurity (>32 weeks). Prematurity should not prevent referral for genetic testing as 37% have a potassium channel mutation and as a result can get improved control by replacing insulin with sulphonylurea therapy.

Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) is caused by heterozygous KCNC1 mutations.

Progressive myoclonus epilepsy (PME) is a distinct group of seizure disorders characterized by gradual neurological decline with ataxia, myoclonus and recurring seizures. There are several forms of PME, among which the most recently described is MEAK - myoclonus epilepsy and ataxia due to potassium channel mutation. This particular subtype is caused by a recurrent de novo heterozygous mutation (c.959G>A, p.Arg320His) in the KCNC1 gene, which maps to chromosome 11 and encodes for the Kv3.1 protein (a subunit of the Kv3 subfamily of voltage-gated potassium channels). Loss of Kv3 function disrupts the firing properties of fast-spiking neurons, affects neurotransmitter release and induces cell death. Specifically regarding Kv3.1 malfunctioning, the most affected neurons include inhibitory GABAergic interneurons and cerebellar neurons. Impairment of the former cells is believed to contribute to myoclonus and seizures, whereas dysfunction of the latter to ataxia and tremor. Phenotypically, MEAK patients generally have a normal early development. At the age of 6 to 14 years, they present with myoclonus, which tends to progressively worsen with time. Tonic-clonic seizures may or may not be present, and some patients develop mild cognitive impairment following seizure onset. Typical electroencephalographic features comprise generalized epileptiform discharges and, in some cases, photosensitivity. Brain imaging is either normal or shows cerebellar atrophy. The identification of MEAK has both expanded the phenotypic and genotypic spectra of PME and established an emerging role for de novo mutations in PME.