Dilated cardiomyopathy caused by LMNA mutations. Clinical and morphological studies.
BACKGROUND
Dilated cardiomyopathy (DCM) is familial in about 20-35% of patients. The most frequently encountered mutations associated with DCM are found in LMNA.


OBJECTIVE
To define the frequency of LMNA mutations in a series of consecutive DCM patients and to evaluate the phenotype of mutation carriers.


METHODS
We screened the 12 exons of LMNA in a series of 61 Polish patients with DCM diagnosed angiographically, as well as in two DCM families.


RESULTS
Two mutations were detected in 5 mutation carriers (D192G in one proband and Y481Stop in one proband and 3 of his offspring), which represents 3.3% (2/61) of the DCM patients. These mutations were absent from 100 controls. The D192G mutation was found in a 26-year-old patient with mild DCM and heart failure leading to death within two years after onset of symptoms. Mild conduction disease was also present. Ultrastructural analysis of the endomyocardial biopsy showed a striking alteration of nuclear morphology. This finding can explain nuclear fragility and is in agreement with the pathophysiological mechanical hypothesis of LMNA mutations. All four Y481Stop mutation-carriers were affected. Three phenotypes were found: in the proband, cardiac dysrhythmia and pacemaker requirement preceded DCM leading to heart transplantation; the proband's 13-year old daughter had conduction disease (2nd degree A-V block) with subtle skeletal muscle involvement documented by immunofluorescence study; ventricular arrhythmia was detected in the proband's son at the age of 11 and in the proband's daughter at the age of 18. Serum creatine kinase was normal in all mutation carriers.
Bilińska
Zofia T
ZT
Instytut Kardiologii ul. Alpejska 42, 04-628 Warsaw, Poland. zbilinska@ikard.pl
Sylvius
Nicolas
N
Grzybowski
Jacek
J
Fidziańska
Anna
A
Michalak
Ewa
E
Walczak
Ewa
E
Walski
Michał
M
Bieganowska
Katarzyna
K
Szymaniak
Elzbieta
E
Kuśmierczyk-Droszcz
Beata
B
Lubiszewska
Barbara
B
Wagner
Teresa
T
Tesson
Frederique
F
Ruzyłło
Witold
W
D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D034904:Lamin Type A; D034882:Lamins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure*; D034881:Nuclear Lamina / Q000235:genetics* / Q000648:ultrastructure*; D010375:Pedigree; D011237:Predictive Value of Tests; D015995:Prevalence; D018709:Statistics, Nonparametric
C494847:LMNA protein, human; D034904:Lamin Type A; D034882:Lamins