Andersen-Tawil syndrome.

Andersen-Tawil syndrome (ATS) is one of the periodic paralyses, a set of skeletal muscle disorders that cause transient weakness of the arms and legs lasting minutes to many hours. Distinguishing features of ATS include facial and limb dysmorphisms, cardiac arrhythmia, difficulties with executive function, and association with dominant mutations in the potassium channel, KCNJ2. In this review, we discuss the key features of ATS, diagnostic testing, pathophysiology and treatment of ATS, and compare them with other periodic paralyses.

The Role of Nutrition and Physical Activity as Trigger Factors of Paralytic Attacks in Primary Periodic Paralysis.

BACKGROUND: Primary periodic paralysis (PPP) are rare inherited neuromuscular disorders including Hypokalemic periodic paralysis (HypoPP), Hyperkalemic periodic paralysis (HyperPP) and Andersen-Tawil syndrome (ATS) characterised by attacks of weakness or paralysis of skeletal muscles. Limited effective pharmacological treatments are available, and avoidance of lifestyle related triggers seems important. OBJECTIVE: Our aim was to search and assess the scientific literature for information on trigger factors related to nutrition and physical activity in PPP. METHODS: We searched Ovid Medline and Embase database for scientific papers published between January 1, 1990, to January 31, 2020. RESULTS: We did not identify published observation or intervention studies evaluating effect of lifestyle changes on attacks. Current knowledge is based on case-reports, expert opinions, and retrospective case studies with inadequate methods for description of nutrition and physical activity. In HypoPP, high carbohydrate and salt intake, over-eating, alcohol, dehydration, hard physical activity, and rest after exercise are frequently reported triggers. Regarding HyperPP, fasting, intake of potassium, alcohol, cold foods or beverages, physical activity, and rest after exercise are frequently reported triggers. No nutrition related triggers are reported regarding ATS, exercise can however induce ventricular arrhythmias. CONCLUSIONS: Our results support that dietary intake and physical activity may play a role in causing paralytic attacks in PPP, although the current scientific evidence is weak. To provide good evidence-based patient care, several lifestyle aspects need to be further assessed and described.

Andersen-Tawil Syndrome Presenting with Complete Heart Block.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.

Impaired cytoplasmic domain interactions cause co-assembly defect and loss of function in the p.Glu293Lys KNCJ2 variant isolated from an Andersen-Tawil syndrome patient.

AIMS: Subunit interactions at the cytoplasmic domain interface (CD-I) have recently been shown to control gating in inward rectifier potassium channels. Here we report the novel KCNJ2 variant p.Glu293Lys that has been found in a patient with Andersen-Tawil syndrome type 1 (ATS1), causing amino acid substitution at the CD-I of the inward rectifier potassium channel subunit Kir2.1. Neither has the role of Glu293 in gating control been investigated nor has a pathogenic variant been described at this position. This study aimed to assess the involvement of Glu293 in CD-I subunit interactions and to establish the pathogenic role of the p.Glu293Lys variant in ATS1. METHODS AND RESULTS: The p.Glu293Lys variant produced no current in homomeric form and showed dominant-negative effect over wild-type (WT) subunits. Immunocytochemical labelling showed the p.Glu293Lys subunits to distribute in the subsarcolemmal space. Salt bridge prediction indicated the presence of an intersubunit salt bridge network at the CD-I of Kir2.1, with the involvement of Glu293. Subunit interactions were studied by the NanoLuc® Binary Technology (NanoBiT) split reporter assay. Reporter constructs carrying NanoBiT tags on the intracellular termini produced no bioluminescent signal above background with the p.Glu293Lys variant in homomeric configuration and significantly reduced signals in cells co-expressing WT and p.Glu293Lys subunits simultaneously. Extracellularly presented reporter tags, however, generated comparable bioluminescent signals with heteromeric WT and p.Glu293Lys subunits and with homomeric WT channels. CONCLUSIONS: Loss of function and dominant-negative effect confirm the causative role of p.Glu293Lys in ATS1. Co-assembly of Kir2.1 subunits is impaired in homomeric channels consisting of p.Glu293Lys subunits and is partially rescued in heteromeric complexes of WT and p.Glu293Lys Kir2.1 variants. These data point to an important role of Glu293 in mediating subunit assembly, as well as in gating of Kir2.1 channels.

Skeletal Muscle Channelopathies.

Skeletal muscle channelopathies are rare genetic neuromuscular conditions that include the nondystrophic myotonias and periodic paralyses. They cause disabling muscle symptoms and can limit educational potential, work opportunities, socialization, and quality of life. Effective therapy is available, making it essential to recognize and treat this group of disorders. Here, the authors highlight important aspects regarding diagnosis and management using illustrative case reports.

"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.

Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents.

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1WTversus Kir2.1Δ314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

Multivariate analysis of TU wave complex on electrocardiogram in Andersen-Tawil syndrome with KCNJ2 mutations.

BACKGROUND: The exact differences between the TU wave complex of ATS1 and that of healthy individuals remain to be investigated. We sought to characterize the TU wave complex of Andersen-Tawil syndrome type 1 (ATS1) using high frequency electrocardiogram (ECG) data. METHODS: Electrocardiograms were recorded as time series data with a 2 kHz frequency ECG amplifier in 13 patients with ATS1 (positive for KCNJ2 mutation, ATS1 group) and age-matched healthy individuals (control group). Conventional ECG parameters were measured, and principal component analysis (PCA) and independent component analysis (ICA) were applied to the TU wave complex. RESULTS: Time from T peak (Tp) to U peak (Up), time from bottom (B) to Up, and time from B to U end (BUe, U duration) (0.232 ± 0.018 vs. 0.165 ± 0.017, p < .0001), where B is the lowest point between T and U waves, were all longer in the ATS1 group than the control group. Multivariate logistic regression analysis revealed that BUe could completely differentiate the two groups. PCA ratios in the ATS1 group were significantly larger than the control group (26.5 ± 12.3 vs. 10.4 ± 6.2, p = .0005). ICA revealed 1 or 2 U-wave-specific independent components (ICs) that exclusively comprise the U wave in ATS1, whereas U waves in the control group were composed of some ICs that also comprised T waves. CONCLUSIONS: U-wave-related temporal parameters, particularly BUe, and the existence of U-wave-specific ICs, extracted in the ICA, are useful for differentiation of U waves in ATS1 from those in healthy individuals.

Clinical and neurophysiological variability in Andersen-Tawil syndrome.

INTRODUCTION: Andersen-Tawil syndrome (ATS) is characterized by a triad of periodic paralysis, ventricular arrhythmias, and dysmorphism. However, patients often lack one or more of these features. METHODS: Clinical and neurophysiological features were reviewed of five members in two families with heterozygous mutations in KCNJ2 (R218Q and R67W). RESULTS: Only one patient had all features of the triad of ATS. One patient had low-set ears, and the others had minor anomalies. Bidirectional ventricular tachycardias were seen in two patients. Two patients (R67W) never had episodes of paralysis. The long exercise test was abnormal in three patients with episodes of paralysis, but normal in two without paralytic episodes. DISCUSSION: ATS patients without skeletal muscle symptoms can have normal neurophysiological examinations. They can show variability in phenotype or the severity of arrhythmias. Such variability among patients who share the same gene mutations may result in underdiagnosis of ATS.

Usefulness of the intravenous flecainide challenge test before oral flecainide treatment in a patient with Andersen-Tawil syndrome.

Andersen-Tawil syndrome (ATS) is an inherited disorder characterised by the triad of ventricular arrhythmias (VAs), periodic paralysis and dysmorphic features. A 31-year-old woman diagnosed with ATS caused by a KCNJ2 mutation (p.R228ins) was urgently admitted to our hospital following an episode of syncope during exercise. Electrocardiography revealed frequent premature ventricular complexes and non-sustained ventricular tachycardias (VTs) with pleomorphic QRS patterns. During the intravenous flecainide test (30 mg), the frequent VAs were inhibited completely. After oral flecainide (100 mg) was started, VAs, except for a brief bigeminy, were suppressed during the exercise test. On 24-hour Holter recordings, the VAs decreased from 50 133 to 13 363 beats/day (-73%). Sustained VT and syncope were not observed during a 3-year follow-up period. Intravenous flecainide challenge test may be useful in predicting the efficacy of oral flecainide treatment for patients with ATS.

Different responses to exercise between Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia.

Aims: Andersen-Tawil Syndrome (ATS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are both inherited arrhythmic disorders characterized by bidirectional ventricular tachycardia (VT). The aim of this study was to evaluate the diagnostic value of exercise stress tests for differentiating between ATS and CPVT. Methods and results: We included 26 ATS patients with KCNJ2 mutations from 22 families and 25 CPVT patients with RyR2 mutations from 22 families. We compared the clinical and electrocardiographic (ECG) characteristics, responses of ventricular arrhythmias (VAs) to exercise testing, and the morphology of VAs between ATS and CPVT patients. Ventricular arrhythmias were more frequently observed at baseline in ATS patients compared with CPVT patients [the ratio of ventricular premature beats (VPBs)/sinus: 0.83 ± 1.87 vs. 0.06 ± 0.30, P = 0.01]. At peak exercise, VAs were suppressed in ATS patients, whereas they were increased in CPVT patients (0.14 ± 0.40 vs. 1.94 ± 2.71, P < 0.001). Twelve-lead ECG showed that all 25 VPBs and 15 (94%) of 16 bidirectional VTs were right bundle branch block (RBBB) morphology in ATS patients, whereas 19 (86%) of 22 VPBs had left bundle branch block (LBBB), and 12 (71%) of 17 bidirectional VT had LBBB and RBBB morphologies in CPVT patients. Conclusion: In patients with ATS, VAs with RBBB morphology were frequently observed at baseline and suppressed at peak exercise. In contrast, exercise provoked VAs with mainly LBBB morphology in patients with CPVT. In adjunct to clinical and baseline ECG assessments, exercise testing might be useful for making the diagnosis of ATS vs. CPVT, both characterized by bidirectional VT.

Andersen's syndrome mutants produce a knockdown of inwardly rectifying K+ channel in mouse skeletal muscle in vivo.

Andersen's syndrome (AS) is a rare autosomal disorder that has been defined by the triad of periodic paralysis, cardiac arrhythmia, and developmental anomalies. AS has been directly linked to over 40 different autosomal dominant negative loss-of-function mutations in the KCNJ2 gene, encoding for the tetrameric strong inward rectifying K+ channel KIR2.1. While KIR2.1 channels have been suggested to contribute to setting the resting membrane potential (RMP) and to control the duration of the action potential (AP) in skeletal and cardiac muscle, the mechanism by which AS mutations produce such complex pathophysiological symptoms is poorly understood. Thus, we use an adenoviral transduction strategy to study in vivo subcellular distribution of wild-type (WT) and AS-associated mutant KIR2.1 channels in mouse skeletal muscle. We determined that WT and D71V AS mutant KIR2.1 channels are localized to the sarcolemma and the transverse tubules (T-tubules) of skeletal muscle fibers, while the ∆314-315 AS KIR2.1 mutation prevents proper trafficking of the homo- or hetero-meric channel complexes. Whole-cell voltage-clamp recordings in individual skeletal muscle fibers confirmed the reduction of inwardly rectifying K+ current (IK1) after transduction with ∆314-315 KIR2.1 as compared to WT channels. Analysis of skeletal muscle function revealed reduced force generation during isometric contraction as well as reduced resistance to muscle fatigue in extensor digitorum longus muscles transduced with AS mutant KIR2.1. Together, these results suggest that KIR2.1 channels may be involved in the excitation-contraction coupling process required for proper skeletal muscle function. Our findings provide clues to mechanisms associated with periodic paralysis in AS.

Intrafamilial phenotypic variability in Andersen-Tawil syndrome: A diagnostic challenge in a potentially treatable condition.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant channelopathy characterized by periodic paralysis, cardiac dysrhythmias, and distinct facial and skeletal characteristics, that may be variably present in the affected members. Mutations in the KCNJ2 and KCNJ5 gene have been associated with this disorder. We describe a family in which several members presented with different ATS phenotypes. The proband, a 4-year-old boy, presented with recurrent episodes of muscle weakness from an early age; two siblings suffered cardiac arrhythmia but had never experienced episodes of paralysis; their mother reported occasional muscle pain after exercise and unspecified cardiac arrhythmias. The analysis of KCNJ2 gene in the proband disclosed the presence of a pathogenic mutation (p.R218W), that was subsequently confirmed in the other affected subjects. Our results underline the possible intrafamilial phenotypic variability, ranging from full clinical triad to exclusive cardiac or muscular involvement, representing a diagnostic challenge that may also delay adequate management. There are still limited data on the treatment of ATS; in our patient there was clinical improvement with dichlorphenamide.

Reversible Dilated Cardiomyopathy Caused by a High Burden of Ventricular Arrhythmias in Andersen-Tawil Syndrome.

Andersen-Tawil syndrome (ATS) is caused by mutations in KCNJ2 (Kir2.1). It remains unclear whether dilated cardiomyopathy (DCM) is a primary feature of ATS. We studied a proband with typical physical features of ATS plus DCM and moderate to severe left ventricular dysfunction (left ventricular ejection fraction = 30.5%). Genetic screening revealed a novel mutation in Kir2.1 (c.665T>C, p.L222S). Functional studies showed that this mutation reduced ionic currents in a dominant-negative manner. Suppression of ventricular arrhythmias with bisoprolol led to normalization of left ventricular size and function. We conclude that DCM is likely a secondary phenotype in ATS and is caused by high ventricular arrhythmia burden.

Clinical features and long exercise test in Chinese patients with Andersen-Tawil syndrome.

INTRODUCTION: Andersen-Tawil syndrome (ATS) is a rare multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and developmental dysmorphology. There are few reports concerning ATS in the Chinese population. We analyzed clinical features and evaluated the long exercise test as a tool for diagnosis of periodic paralysis in ATS. METHODS: Direct sequencing of KCNJ2 was performed in 12 subjects from mainland China with suspected ATS. Clinical features, therapeutic responses, and long exercise tests (LET) were retrospectively analyzed. RESULTS: Twelve patients were genetically confirmed to have ATS. A small mandible and clinodactyly were demonstrated in all patients. Premature ventricular contractions were the most prevalent form of cardiac arrhythmia. The LET revealed an early amplitude decrement. CONCLUSIONS: Chinese ATS patients shared some common clinical features with reported subjects in other countries. An early amplitude decrement in LET may be useful for diagnosis of ATS. Muscle Nerve 54: 1059-1063, 2016.