Review
Andersen–Tawil syndrome: Clinical and molecular aspects

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Abstract

Andersen–Tawil syndrome (ATS) is a rare hereditary multisystem disorder. Ventricular arrhythmias, periodic paralysis and dysmorphic features constitute the classic triad of ATS symptoms. The expressivity of these symptoms is, however, extremely variable, even within single ATS affected families, and not all ATS patients present with the full triad of symptoms. ATS patients may show a prolongation of the QT interval, which explains the classification as long QT syndrome type 7 (LQT7), and specific neurological or neurocognitive defects. In ATS type 1 (ATS1), the syndrome is associated with a loss-of-function mutation in the KCNJ2 gene, which encodes the Kir2.1 inward rectifier potassium channel. In ATS type 2 (ATS2), which does not differ from ATS1 in its clinical symptoms, the genetic defect is unknown. Consequently, ATS2 comprises all cases of ATS in which genetic testing did not reveal a mutation in KCNJ2. The loss-of-function mutations in KCNJ2 in ATS1 affect the excitability of both skeletal and cardiac muscle, which underlies the cardiac arrhythmias and periodic paralysis associated with ATS. Thus far, the molecular mechanism of the dysmorphic features is only poorly understood. In this review, we summarize the clinical symptoms, the underlying genetic and molecular defects, and the management and treatment of ATS.

Introduction

Andersen–Tawil syndrome (ATS), also classified as long QT syndrome type 7 (LQT7) [1], is a rare genetic disorder, characterized by ventricular arrhythmias, periodic paralysis and physical dysmorphologies. Probably the first mention of the syndrome was made in 1963 by Klein et al. [2], who described a particular form of periodic paralysis paired with premature ventricular contractions. Several more descriptions of this periodic paralysis subtype followed before the first complete description of the syndrome with the aforementioned triad of symptoms was made in 1971 by Ellen Damgaard Andersen and her colleagues [3]. Still, the syndrome was not properly characterized until multiple patients were described by Tawil and coworkers in 1994 [4], who deliberately chose the eponym “Andersen's syndrome” [5], [6]. In 2003 it was suggested to name the syndrome “Andersen–Tawil syndrome” out of recognition for Tawil's clinical work on the syndrome [7]. Today, “Andersen–Tawil syndrome” has become widely accepted, although “Andersen's syndrome” (or “Andersen syndrome”) is also used. The syndrome should not be confused with glycogen storage disease type IV, which is an autosomal recessive disorder due to deficiency of glycogen branching enzyme and is named ‘Andersen disease’ after Dorothy Hansine Andersen [8].

ATS occurs sporadically, but can also be inherited in an autosomal dominant fashion [9]. The degree of manifestation of ATS related symptoms is extremely variable, even within single ATS affected families, and not all ATS patients present with all symptoms [9]. So far, only mutations in the KCNJ2 gene have been found to cause ATS. This gene codes for the inward rectifier potassium channel protein Kir2.1. ATS patients who have defects in this gene are commonly designated as ATS type 1 (ATS1), whereas patients with an unknown mutation are designated as ATS type 2 (ATS2) [10]. Mutations in KCNJ2 are de novo in approximately 30% of the ATS1 probands [7], [9], [11], [12]. It should be kept in mind that parental germline mosaicism, although relatively rare, may underlie an apparent de novo mutation. This has, for example, been reported for the Timothy syndrome [13], which is also known as long QT syndrome type 8 (LQT8).

The exact prevalence of ATS is unknown, but rough estimates of 1/1,000,000 have been made [14], [15]. From data collected over a 15-year period, a minimum point prevalence of 0.8/1,000,000 was estimated for England, December 2011 [16]. Since this estimate is obtained from patients referred to the UK national channelopathy service with a clinical diagnosis of periodic paralysis that could be confirmed with a mutation in KCNJ2, the actual prevalence of ATS is probably significantly higher than 1/1,000,000 (see also Section 2.6). In 2004, at least 104 ATS patients from 35 kindreds had been reported in the literature [10]. Today, this number has approximately doubled. It has become difficult to provide an absolute number, because several patients have, either explicitly or implicitly, been presented in multiple papers.

In this review, we will first describe the clinical symptoms of ATS. Next, the genetic background of ATS and the consequences of genetic defects will be elucidated. Finally, the management and treatment of ATS will be discussed.

Section snippets

Clinical phenotype

In this section, we will discuss the ventricular arrhythmias, periodic paralysis and dysmorphic features that constitute the ‘classic’ clinical triad of ATS symptoms as first described by Tawil et al. [4]. Additional cardiac symptoms, potential neurological or neurocognitive aspects of ATS and the clinical diagnosis of ATS are also addressed.

Molecular and genetic causes

In this section, we will discuss the molecular and genetic background of the ATS symptoms that we presented in the previous section. We will also briefly touch upon KCNJ2 mutations in related syndromes.

Treatment

Treatment and management of ATS is focused on reducing the amount of arrhythmias and preventing episodes of periodic paralysis as much as possible.

Discussion and future directions

Several investigators have emphasized that ATS type 1 should not have been designated as LQT7 [11], [12], [159]. A major argument is that the QT prolongation is only modest, as illustrated by the observation that the majority of ATS1 patients has a normal-range QTc interval < 440 ms (64% [11]), whereas the far majority (75%) of LQTS patients of the major types 1–3 has a clinically prolonged QTc interval > 440 ms [160]. We feel that the prolongation of the QT interval in ATS patients is an

Concluding remarks

ATS is a rare hereditary multisystem disorder with an estimated prevalence in the order of 1:100,000. Yet, it is a highly interesting ‘model disease’ and as such it has been, and still is, the subject of numerous studies in clinical and preclinical research. In this review, we have provided an overview of the symptoms that can be present in ATS patients, the molecular and genetic background of these symptoms as well as ways to most effectively treat the diseases associated with the syndrome.

Acknowledgment

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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    Statement of authorship: Each author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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    Both authors contributed equally.

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