Progressive Familial Heart Block, Type Ia

A number sign (#) is used with this entry because progressive familial heart block type IA (PFHB1A) can be caused by mutation in the SCN5A gene (600163) on chromosome 3p21.

Description

Progressive familial heart block type I (PFHBI, PFHB1) is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block (Brink and Torrington, 1977; van der Merwe et al., 1986; van der Merwe et al., 1988). It is defined on electrocardiogram by evidence of bundle branch disease, i.e., right bundle branch block, left anterior or posterior hemiblock, or complete heart block, with broad QRS complexes. Progression has been shown from a normal electrocardiogram to right bundle branch block and from the latter to complete heart block. These electrocardiographic features differentiate PFHB type I from progressive familial heart block type II (PFHBII, PFHB2; 140400), in which the onset of complete heart block is associated with narrow complexes. Electrocardiographically the changes represent, respectively, bundle branch disease (PFHB1) and atrioventricular nodal disease with an atrioventricular block and an idionodal escape rhythm (PFHB2). PFHBI is manifested symptomatically when complete heart block supervenes, either with dyspnea, syncopal episodes, or sudden death. Treatment, which is best managed by regular electrocardiographic follow-up, is by the timely implantation of a pacemaker (Brink et al., 1995).

Genetic Heterogeneity of Progressive Familial Heart Block Type I

Progressive familial heart block type IB (PFHB1B; 604559) is caused by mutation in the TRPM4 gene (606936) on chromosome 19q13.32.

Clinical Features

Progressive cardiac conduction defect (PCCD), also called Lenegre-Lev disease (Lenegre, 1964; Lev et al., 1970), is one of the most common cardiac conduction disturbances. It is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrioventricular block and causing syncope and sudden death. It represents the major cause of pacemaker implantation in the world (0.15 implantations per 1,000 inhabitants per year in developed countries). PCCD is considered a primary degenerative disease or an exaggerated aging process with sclerosis affecting only the conduction tissue.

DeForest (1956) studied a kindred in which uncomplicated left bundle branch block occurred in 4 persons in 2 generations. Segall (1961) described an instance of father, son, and daughter (of French-Canadian and black intermixture) with right bundle branch block (RBBB) and repeated Stokes-Adams attacks with various atrial arrhythmias and ventricular extrasystoles. The father died at 74 years, 14 years after the first fainting episode. Two asymptomatic brothers showed the electrocardiographic changes of Wolff-Parkinson-White.

Combrink et al. (1962) described a South African family in which the mother had RBBB and died at age 35 years in a Stokes-Adams attack. Of 4 children, 3 had RBBB. The mother's parents had both died suddenly in their 30s. One of her brothers was said to have a cardiac conduction disturbance, another had dextrocardia, while 3 other sibs were apparently normal. Follow-up of this kindred revealed RBBB in 1 of 7 grandchildren (Myburgh et al., 1980). Steenkamp (1972) described a South African family in which 6 of 17 members studied showed disturbance of rhythm or conduction. Brink and Torrington (1977) suggested that the disorder they referred to as progressive familial heart block type I is prevalent in South Africa and is the same disorder as that reported by Combrink et al. (1962) and Steenkamp (1972). Type I heart block in their description tends to have the pattern of a right bundle branch block and/or left anterior hemiblock, manifesting clinically when complete heart block supervenes with syncopal episodes, Stokes-Adams seizures, or sudden death. The risk to life appeared to be greatest at or soon after birth, during puberty and the early twenties, and again toward middle age.

Greenspahn et al. (1976) presented evidence suggesting that a susceptibility to disorder in conduction that is expressed late in life is inherited. Lorber et al. (1988) observed a father and 2 sons with an electrocardiographic pattern of pseudo left posterior hemiblock and incomplete right bundle branch block that resulted in right axis deviation.

Husson et al. (1973) reported a family in which a girl had complete heart block at age 2 years and died at age 10 with ventricular fibrillation. A brother had right bundle branch block at age 15 years and complete heart block at age 17. A sister, aged 17 years, had prolonged intraventricular conduction time with incomplete right bundle branch block. In this family, complete heart block and bundle branch block were expressions of the same genotype.

Molecular Genetics

In a French family with Lenegre-Lev disease, Schott et al. (1999) excluded linkage to the cardiac conduction defect locus on chromosome 19 and to other loci for inherited cardiac diseases associated with conduction defects. Because of the potential role of the sodium current in the infranodal conduction of the cardiac impulse, Schott et al. (1999) analyzed the SCN5A gene and identified a splice site mutation (600163.0009) in affected members of the French family.

In a Dutch family with congenital nonprogressive conduction defect, Schott et al. (1999) identified a deletion in the SCN5A gene (600163.0010). The authors suggested that, depending on the consequences of a mutation on the sodium channel characteristics, the resulting phenotype may be progressive or intermediate.

History

Morquio (1901) and Osler (1903), whose names are known in other connections, are credited with the earliest reports of familial disturbance in cardiac conduction. Although most reports of congenital heart block have concerned affected sibs (most of which may represent cases of congenital complete heart block due to circulating autoantibodies in the mother with lupus), 2 or more generations have been affected often enough to prove dominant inheritance of one or more forms (Fulton et al., 1910; Wallgren and Winblad, 1937; Wendkos and Study, 1947). Similarly, late-onset heart block may be heritable as a dominant; variability in expression is common.

In the family reported by Gazes et al. (1965), conduction disturbances occurred in 3 or 4 generations. In most of the affected persons the heart block was of second degree with episodes of third-degree (complete) atrioventricular dissociation, leading to Adams-Stokes seizures. The family of Wendkos and Study (1947) consisted of a father with the Wolff-Parkinson-White syndrome and 2 offspring with congenital complete heart block. In the family reported by Fulton et al. (1910), 3 to 1 block was thought to be present in the father, complete block in a 22-month-old son, and 2 to 1 block in a 20-year-old daughter. Amatller-Trias et al. (1966) described father (aged 43), son (aged 19) and daughter (aged 22) with first-degree heart block (prolonged PR interval).

Sarachek and Leonard (1972) reviewed 19 reports of familial bradycardia. Ten families had pure AV block, 6 had members with AV block or sinus bradycardia, and 3 had pure sinus bradycardia. Eight families had congenital heart block and 8 had onset in adulthood. Schaal et al. (1973) studied the family of a 69-year-old woman with right bundle branch block and left axis deviation, who later developed complete heart block. Six relatives had heart block and 26 had abnormal electrocardiograms. First-degree heart block is a feature of a form of familial atrial septal defect and has been reported to precede more severe disturbances of AV conduction in cases of familial heart block (Paul et al., 1958).

Gambetta et al. (1973) described a kindred in which 8 persons in 4 generations had prolonged PR interval. There was male-to-male transmission and 2 instances of skipped generation.

Fauchier et al. (1979) described 4 brothers, with a maximal age difference of 20 years, who showed sinoatrial block, supra-hisian atrioventricular block, and paroxysmal atrial arrhythmias. The disorder had progressed to partial atrial standstill in the eldest. Left anterior hemiblock was also present in the 2 youngest brothers. The disorder was well tolerated. The authors referred to the disorder as familial idiopathic binodal block and supported autosomal dominant inheritance. Variable degrees of nonspecific fibrosis of the nodal and atrial tissues were thought to be present. See also cardiac conduction defect (115080).

Barak et al. (1987) described studies of an instructive family ascertained through a fetus found to have second-degree AV block at 35 weeks of gestation. The conduction disturbance was diagnosed by ultrasonography. Seven of the family members were found to have sinus node dysfunction ('sick sinus syndrome') and/or various degrees of atrioventricular block. Three of them were children aged 9 months to 6 years, and all were asymptomatic. The symptomatic family members were 2 adults. One of them had a pacemaker inserted for a complete AV block and Adams-Stokes attacks, while the other had had several fainting attacks.