Andersen–Tawil Syndrome

Abstract

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.

Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome

“…The channels that mediate I K1 are comprised of Kir2.x subunits, with KCNJ2 -encoded Kir2.1 strongly expressed in both atria and ventricles [ 103 , 104 ]. Loss-of-function KCNJ2 mutations underlie Andersen-Tawil syndrome (also known as the LQT7 form of LQTS [ 105 ]). The first KCNJ2 mutation reported to underlie the SQT3 form of SQTS was identified in a 5-year-old girl from whom an abnormal ECG was obtained during routine physical examination [ 53 ]: a short QT c interval of 315 ms and a narrow, asymmetric T wave with a rapid terminal phase.…”

Relevance of KCNJ5 in Pathologies of Heart Disease

“…Long QT syndrome (LQTS) is a potentially life-threatening arrhythmic condition characterized by delayed myocardial repolarization that causes QT prolongation and increased risk for torsades de pointes (TdP), syncope, and even sudden cardiac death (SCD) [ 35 ]. A subtype of long QT syndrome (long QT 7), Andersen–Tawil syndrome is a rare genetic disease predominantly caused by pathogenic variants in the KCNJ2 gene, which encodes for Kir2.1 [ 36 ]. However, in 2014, G387R, and T158A, KCNJ5 variants were implicated in Anderson–Tawil syndrome [ 37 ].…”

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

“…Cardiac arrhythmias include ventricular arrhythmia, prolonged QT interval at the ECG, and prominent U waves. Malformations include ocular hypertelorism, low-set ears, small mandible, scoliosis, fifth digit clinodactyly, syndactyly, short stature, and a broad forehead [ 162 ]. However, a great variety of symptoms has been reported, making the diagnosis quite challenging.…”

“…Mutations of the KCNJ5 -encoding Kir3.4 channel are found in about 15% of ATS cases (ATS type 2; LQT13) [ 162 ]. As for KCNJ2 , KCNJ5 mutations may have incomplete penetrance, and the expression of symptoms is variable [ 168 , 185 , 186 ].…”