Progressive Familial Heart Block, Type Ii

Description

Progressive familial heart block type II (PFHB2) is an autosomal dominant disorder, similar to type I progressive familial heart block (PFHB1; see 113900). The pattern of PFHB2, however, tends to develop along the lines of a sinus bradycardia with a left posterior hemiblock, presenting clinically as syncopal episodes, Stokes-Adams seizures, or sudden death when complete heart block supervenes (Brink and Torrington, 1977).

Clinical Features

Brink and Torrington (1977) described a large 4-generation South African family of Dutch ancestry with a strong history of sudden death. Of 24 family members who underwent electrocardiography, 10 had conduction abnormalities, including 3 with sinus bradycardia, 3 with isolated left posterior hemiblock, 1 with atrial fibrillation and a slow ventricular response, and 2 with complete heart block (the latter 2 had pacemakers implanted). Three other family members had died at the relatively young ages of 41, 39, and 16 years, respectively, despite having had pacemakers implanted. The average age of affected family members was progressively lower in more recent generations, and there was an autosomal dominant pattern of inheritance.

Brink et al. (1995) described electrocardiographic features differentiating PFHB1 from PFHB2. PFHB1 is characterized electrocardiographically 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 PFHB1 from PFHB2, in which the onset of complete heart block is associated with narrow QRS complexes.

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.

Mapping

Fernandez et al. (2005) performed linkage analysis in 26 individuals from the South African family of Dutch descent with PFHB2 originally reported by Brink and Torrington (1977) and obtained a maximum multipoint lod score of 3.7 on chromosome 1q32. Fine mapping and haplotype analysis narrowed the disease region to a 3.9-cM (2.85-Mb) interval flanked by D1S70 and D1S505. No mutations were found in the plausible candidate genes in that region, KCNH1 (603305), KIAA0205, LAMB3 (150310), and PPP2R5A (601643).