Due to its varied and variable phenotypes, Andersen-Tawil syndrome (ATS) holds a unique place in the field of channelopathies. Patients with ATS typically present with the triad of periodic paralysis, cardiac arrhythmias, and developmental dysmorphisms. Although penetrance of ATS is high, disease expression and severity are remarkably variable. Mutations in KCNJ2 are the primary cause of ATS with 21 mutations discovered in 30 families. These mutations affect channel function through heterogeneous mechanisms, including reduced PIP2-related channel activation and altered pore function. Aside from KCNJ2-based ATS, the genetic basis of this disease in nearly 40% of cases is unknown. Other ATS genes likely share a common pathway or function with Kir2.1 or facilitate the activity of this ion channel. In this review, we explore hypotheses explaining the pathogenesis, expression, and variability of ATS.
"The majority of KCNJ2 mutations exert a dominant - negative effect on channel function ( Plaster et al . , 2001 ; Lange et al . , 2003 ; Donaldson et al . , 2004 ) . Most mutant channels traffic normally to the cell surface , but fail to conduct appropriately ( Bendahhou et al . , 2003 ) . Many mutations alter the binding of phosphatidylinositol 4 , 5 bisphosphate , which is an important regulator of Kir2 . 1 channel function ( Lopes et al . , 2002 ; Donaldson et al . , 2003 ) . While limited in"
[Show abstract][Hide abstract] ABSTRACT: Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.
"While other mutations have been described involving the external pore forming loop of Kir2.1, mutations in KCNJ2 impairing channel interactions with phosphatidylinositol 4,5-bisphosphonate (PIP2) are thought to play a significant role as pathogenic mechanism in ATS. PIP2 is a membrane-bound second messenger which activates Kir2.1, among other inward-rectifiers, and promotes an open-channel position . Also, in vitro it was demonstrated that in general (and especially with the previously described R218W mutation), these mutations resulted in impaired channel- PIP2 interactions, affecting whole-cell current and marked decreases in open-channel probability . "
[Show abstract][Hide abstract] ABSTRACT: Andersen-Tawil syndrome (ATS) is a rare condition consisting of ventricular arrhythmias, periodic paralysis, and dysmorphic features. In 2001, mutations in KCNJ2, which encodes the a subunit of the potassium channel Kir2.1, were identified in patients with ATS. To date, KCNJ2 is the only gene implicated in ATS, accounting for approximately 60% of cases. ATS is a unique channelopathy, and represents the first link between cardiac and skeletal muscle excitability. The arrhythmias observed in ATS are distinctive; patients may be asymptomatic, or minimally symptomatic despite a high arrhythmia burden with frequent ventricular ectopy and bidirectional ventricular tachycardia. However, patients remain at risk for life-threatening arrhythmias, including torsades de pointes and ventricular fibrillation, albeit less commonly than observed in other genetic arrhythmia syndromes. The characteristic heterogeneity at both the genotypic and phenotypic levels contribute to the continued difficulties with appropriate diagnosis, risk stratification, and effective therapy. The initial recognition of a syndromic association of clinically diverse symptoms, and the subsequent identification of the underlying molecular genetic basis of ATS has enhanced both clinical care, and our understanding of the critical function of Kir2.1 on skeletal muscle excitability and cardiac action potential.
Indian pacing and electrophysiology journal 02/2006; 6(1):32-43.
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