Congenital Long Qt Syndrome

The Big Heart Disease Lie

Cardiovascular Disease Homeopathic Treatments

Get Instant Access

The hereditary long QT syndrome (LQTS) is a rare disorder characterized by prolongation of the QT interval on the electrocardiogram (ECG) and a propensity for syncope, torsades de pointes, ventricular arrhythmias, and sudden death. One form of LQTS, described by Jervell and Lange-Neilsen in 1957, is characterized by deafness and autosomal recessive inheritance (1). The most common form of LQTS was initially described by Romano (2) and Ward (3), and is characterized by autosomal dominant inheritance and normal hearing. Remarkable progress has been made in the last several years in our understanding of the pathogenesis of LQTS. It is now clear that LQTS is a heterogeneous disorder caused by mutations in specific ion channels that play a critical role in the control of cardiac repolarization (4). These findings have revolutionized our understanding of LQTS, and may yield new insights into other conditions characterized by ventricular arrhythmias in the absence of ischemia or structural heart disease. Recent work has also identified LQTS as an important cause of sudden infant death syndrome (SIDS) (5,6).

From: Contemporary Cardiology: Management of Cardiac Arrhythmias Edited by: L. I. Ganz © Humana Press Inc., Totowa, NJ

Molecular Genetics of LQTS

At present, mutations in four cardiac ion-channel genes have been identified which cause the clinical manifestations of LQTS (LQT1, 2, 3, and 5) (7). An additional LQTS gene has bee mapped to chromosome 4, but the mutant gene has not yet been identified (LQT4) (8). These mutations account for only 50% of the known families with LQTS, which has important implications for molecular diagnosis (9). In most instances, multiple mutations have been identified in each gene, which vary in their functional consequences (degree of current alteration and QT prolongation) (10). This genetic heterogeneity contributes to a marked variability in clinical manifestations of the disorder. In addition, substantial variability in the clinical severity of the disorder exists among unrelated kindreds with identical mutations. These data suggest that "modifier genes" may exist, which also influence the prognosis.

The mutations that have been identified to date fall into two general categories. One type of mutation results in reduced function of the outward potassium currents that govern the repolarization process (I& and IKs). The LQT1 gene (KvLQTl) on chromosome 11 encodes an abnormal a-subunit of IKs (11). The LQT2 gene on chromosome 7 (also known as HERG) encodes an abnormal IKr protein, resulting in the clinical Romano-Ward syndrome (12). The LQT5 gene (KCNE1) on chromosome 21 encodes the minK protein, which is the P-subunit of IKs (13). The minK protein also complexes with HERG to regulate I& (14). LQT1 and LQT5 patients share an interesting clinical feature: some mutations cause Romano-Ward syndrome (autosomal dominant inheritance, normal hearing), and other distinct mutations are associated with Jervell and Lange-Neilsen syndrome (autosomal recessive inheritance, deafness) (15). Many of the potassium-channel mutations that cause Romano-Ward syndrome exert a "dominant negative" effect, in that the degree of current reduction is greater than the expected 50% (2 mutant-channel proteins, 2 normal-channel protein incorporated in the channel tetramer) (16). This property may result from a conformational change in the overall channel structure induced by a single mutant subunit. The second general class of mutations involves a "gain of function" of inward depolarizing sodium currents. The LQT3 gene on chromosome 3 (also known as SCN5A) encodes an abnormal Na+ channel protein with alteration in rapid inactivation, leading to continued leakage of depolarizating Na+ current into the cell and prolonged repolarization (17).

A rapidly growing body of literature has emerged to support the hypothesis that the LQTS genotype influences the clinical phenotype that is observed. This correlation was first reported by Moss et al., who observed distinctive T-wave patterns that were characteristic of the LQT1, LQT2, and LQT3 genotypes (Fig. 1) (18). Schwartz (19) and others (20) subsequently reported that the precipitants of arrhythmic events differ markedly among patients with the various genotypes. Auditory stimuli precipitate cardiac events more commonly in LQT2 patients than LQT1 patients (20); LQT3 patients are more prone to cardiac events during rest or sleep, which are rare among LQT1 patients (19). Interestingly, LQT3 patients exhibit an exaggerated shortening of the QT interval during exercise, which may be protective against exertional events (9). A mutation in the LQT3 (SCN5A) gene was recently identified in an infant who survived SIDS (6). It must be emphasized that considerable overlap in phenotype exists among patients with the various genotypes, which prohibits definitive classification of patients based on the ECG T-wave pattern or the clinical presentation. The characteriza-

Chromosome 3 Chromosome 7 Chromosome 11

Chromosome 3 Chromosome 7 Chromosome 11

Congenital Lqt1
Fig. 1. ECG recordings from three patients from families with long QT syndrome (LQTS) linked to genes on chromosomes 3, 7, and 11. (Reproduced with permission from: Moss et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2933.)

tion of the precise abnormality in ion channel function that is associated with specific genotypes may ultimately yield novel pharmacologic therapies designed to improve ion-channel function ("gene-specific therapy").

Criteria for Diagnosis

The criteria developed to assist in the diagnosis of hereditary LQTS incorporate clinical features, electrocardiographic findings, and family history (21) (Table 1). The initial work-up should consist of a resting 12-lead ECG, a 24-h Holter monitor, and an exercise ECG. The baseline ECG is evaluated for the degree of QT prolongation (corrected for heart rate using the method of Bazett) as well as morphologic abnormalities of the T wave, such as notched T waves, TU complexes, or T-wave alternans (TWA). The morphologic T-wave abnormalities are believed to reflect increased dispersion of repolarization, which may have prognostic significance (22,23). Rarely, visible TWA or episodes of torsades de pointes are observed during exercise stress testing or ambulatory monitoring, which can assist in diagnosis (24). In rare cases, exercise stress testing can evoke QT prolongation and morphologic T-wave abnormalities that were not present in the resting state. Additional diagnostic criteria derived from the ECG and Holter monitoring have been proposed, but they remain investigational at present (25,26). An echocardiogram should be performed in all cases to exclude underlying structural heart disease with secondary QT prolongation. It should be noted that some LQTS patients exhibit a characteristic wall-motion abnormality that can be eliminated by verapamil, and is believed to be another manifestation of repolarization heterogeneity (27).

Only a few research laboratories worldwide now perform molecular diagnostic screening for all mutations that have been identified. Although a positive result establishes a definitive diagnosis for patients with borderline QT prolongation, a negative result does not exclude LQTS, since only 40-50% of LQT1 and LQT2 families have been genetically characterized (9). In fact, it appears that every kindred has its own "private" mutation in the case of LQT2 (28). The process of molecular diagnosis is time-consuming and expensive, and is not usually covered by insurance reimbursements; the cost of screening is presently covered by research funds in most instances (9). Despite these limitations, molecular screening should be performed whenever possible

Table 1

Diagnostic Criteria for Congenital Long QT Syndrome

Points

ECG findings* A. QTcf

Table 1

Diagnostic Criteria for Congenital Long QT Syndrome

Points

ECG findings* A. QTcf

Was this article helpful?

0 0
Hearing Aids Inside Out

Hearing Aids Inside Out

Have you recently experienced hearing loss? Most probably you need hearing aids, but don't know much about them. To learn everything you need to know about hearing aids, read the eBook, Hearing Aids Inside Out. The book comprises 113 pages of excellent content utterly free of technical jargon, written in simple language, and in a flowing style that can easily be read and understood by all.

Get My Free Ebook


Post a comment