Andersen-Tawil Syndrome: A Comprehensive Review.

Andersen-Tawil syndrome (ATS) is a very rare orphan genetic multisystem channelopathy without structural heart disease (with rare exceptions). ATS type 1 is inherited in an autosomal dominant fashion and is caused by mutations in the KCNJ2 gene, which encodes the α subunit of the K+ channel protein Kir2.1 (in ≈ 50-60% of cases). ATS type 2 is in turn linked to a rare mutation in the KCNJ5-GIRK4 gene that encodes the G protein-sensitive-activated inwardly rectifying K+ channel Kir3.4 (15%), which carries the acetylcholine-induced potassium current. About 30% of cases are de novo/sporadic, suggesting that additional as-yet unidentified genes also cause the disorder. A triad of periodic muscle paralysis, repolarization changes in the electrocardiogram, and structural body changes characterize ATS. The typical muscular change is episodic flaccid muscle weakness. Prolongation of the QU/QUc intervals and normal or minimally prolonged QT/QTc intervals with a tendency to ventricular arrhythmias are typical repolarization changes. Bidirectional ventricular tachycardia is the hallmark ventricular arrhythmia, but also premature ventricular contractions, and rarely, polymorphic ventricular tachycardia of torsade de pointes type may be present. Patients with ATS have characteristic physical developmental dysmorphisms that affect the face, skull, limbs, thorax, and stature. Mild learning difficulties and a distinct neurocognitive phenotype (deficits in executive function and abstract reasoning) have been described. About 60% of affected individuals have all features of the major triad. The purpose of this review is to present historical aspects, nomenclature (observations/criticisms), epidemiology, genetics, electrocardiography, arrhythmias, electrophysiological mechanisms, diagnostic criteria/clues of periodic paralysis, prognosis, and management of ATS.

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

Phenotype variability in patients carrying KCNJ2 mutations.

BACKGROUND: Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with "atypical ATS." METHODS AND RESULTS: Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (≥2 ATS features) and atypical (only 1 of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were 75% (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100% (2/2) in periodic paralysis, and 7% (2/28) in CPVT. We divided all carriers (n=45, including family members) into 2 groups: typical ATS (A) (n=21, 47%) and atypical phenotype (B) (n=24, 53%). Patients in (A) had a longer QUc interval [(A): 695 ± 52 versus (B): 643 ± 35 ms] and higher U-wave amplitude (0.24 ± 0.07 versus 0.18 ± 0.08 mV). C-terminal mutations were more frequent in (A) (85% versus 38%, P<0.05). There were no significant differences in incidences of ventricular tachyarrhythmias. Functional analyses of 4 mutations found in (B) revealed that R82Q, R82W, and G144D exerted strong dominant negative suppression (current reduction by 95%, 97%, and 96%, respectively, versus WT at -50 mV) and T305S moderate suppression (reduction by 89%). CONCLUSIONS: KCNJ2 gene screening in atypical ATS phenotypes is of clinical importance because more than half of mutation carriers express atypical phenotypes, despite their arrhythmia severity.