Anderson-Tawil Syndrome (ATS)

At a glance

An inherited disorder characterized by the clinical triad of potassium-sensitive periodic flaccid paralysis (low, normal, or high potassium levels), ventricular arrhythmias (bigeminy, long-QT interval, ectopy, bidirectional ventricular tachycardia), and dysmorphic facial features. Sudden death has been reported. ATS must not be confused with Andersen Disease (☞Glycogen Storage Disease Type IV).

Synonyms

Andersen Syndrome; Andersen Cardiodysrhythmic Periodic Paralysis; Long-QT Syndrome Type 7 (LQT7); Cardiodysrhythmic Type of Potassium-Sensitive Periodic Paralysis.

Incidence

The prevalence in the UK has been estimated at approximately 0.08 in 100,000.

Genetic inheritance

This is an autosomal dominant condition with clinical features of periodic paralysis and prolonged-QT Syndrome, but is genetically distinct from these conditions. However, sporadic cases have been reported and the penetrance is highly variable. In approximately 60% of patients, ATS is caused by mutations in the KCNJ2 (potassium voltage-gated channel subfamily J member 2) gene. This gene has been mapped to chromosome 17q23 and encodes the inward rectifier K⁺-channel Kir2.1, which is expressed in cardiac and skeletal muscle, explaining the combination of cardiac and skeletal muscle involvement. Kir-channel activity and function depend heavily on the interaction with phosphatidylinositol 4,5-bisphosphate (PIP2), which must bind to these KCNJ2 protein channels to function properly, ie to open up and allow ions to pass through the cell membrane.

Pathophysiology

Other forms of periodic paralysis result from mutations in skeletal muscle-specific Na⁺-, K⁺-, and Ca²⁺-channels. ATS is unique among the channelopathies due to its combination of a skeletal and a cardiac muscle phenotype. The potassium-sensitive periodic paralysis can be associated with normo-, hypo-, or hyperkalemia. Periodic paralysis occurs with different types of cardiac arrhythmias, most commonly prolonged-QT Syndrome and ventricular arrhythmias (ventricular bigeminy, bidirectional ventricular tachydysrhythmia, non-sustained ventricular tachycardia, frequent ventricular ectopy).

Diagnosis

The clinical triad of potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features are characteristic and should allow for an early diagnosis. To prevent sudden cardiac death, cardiac evaluation with serial ECGs with calculation of corrected QT-intervals (QTc) are essential and should be performed early in all patients undergoing workup for periodic paralysis. A prolonged QTc (QTc = QT/√RR) is present in most patients with ATS and is considered by some experts to be a diagnostic sign. In general, the degree of facial dysmorphism does not correlate with the severity of heart and/or muscle involvement, and the dysmorphic features are often mild. The age at onset of periodic paralysis varies from 4 to 18 years. Patients usually have proximal weakness that may exacerbate upon a hypokalemic challenge with intravenous glucose and insulin. However, because fluctuations in serum K⁺-levels may trigger/exacerbate cardiac arrhythmias in these patients, provocative testing for hypo- or hyperkalemic periodic paralysis is contraindicated in ATS patients.