Pathology of the Specialized Conduction System in Familial Lenègre Disease Due to SCN5A Mutations.
Kalliopi Pilichou, Elisa Carturan, Cristina Basso, Gaetano Thiene. University of Padua, Italy
Background: Progressive cardiac conduction (Lenègre) disease is one of the most common cardiac conduction disturbances due to degenerative changes of the specialized conducting tissue. It constitutes the substrate for bundle branch block and QRS complex widening leading to complete atrioventricular (AV) block at risk of syncope and sudden death. Recent studies indicate that SCN5A loss-of-function mutations account for a familial form of Lenègre disease.
Design: Detailed conduction system investigation by serial section technique was performed in 2 unrelated index cases (M, 35; M, 40) with previous history of syncope and an in vivo diagnosis of AV conduction disturbances, who died suddenly. SCN5A genetic screening was undertaken in 23 family members (13M and 10F). Full clinical evaluation through non- invasive and invasive diagnostic tools was carried out on both probands and their family members respectively.
Results: Severe fibrosis of the bifurcating His and proximal bundle branches with sclerotic interruption of the right bundle branch was determined in probands cardiac tissue at post mortem examination. Genetic screening of family members identified a nonsense mutation in exon 11, E473X (12 carriers, family A) and a missense one on exon 21, E1225K (3 carriers, family B). ECG of 15 SCN5A mutation carriers (2 probands were obligated carriers, 9 M and 6 F, age 38,4±17 yrs, range18-72) was analyzed. None of the non carriers had PQ interval prolongation. Twelve mutation carriers (80%) presented a right ventricular conduction delay and one (6,6%) a first degree left bundle branch block. Mean PQ interval was 211±36 msec. A PQ interval > 200 msec was present in 10 (67%) (mean 232±20 msec, mean age 46,5±15 yrs vs 22,2±4,9 yrs with normal PQ interval, p=0.0004). A QRS complex >110 msec was present in 11 subjects (mean 132±16 msec, mean age 43±17 yrs vs 26±6 yrs with normal QRS duration, p=0.01). A coved ST-segment elevation >2 mm in V1-V2 was present in six cases (40%). Two SCN5A mutation carriers presented normal ECG.
Conclusions: An organic substrate underlies SCN5A-associated Lenègre disease, consisting of sclerotic interruption of the bifurcating His and the proximal bundle branches in young people. Family members investigation highlighted the presence of a heritable "age-related" alteration in the conduction system.
Monday, February 28, 2011 11:30 AM
Platform Session: Section G 2, Monday Morning