CLINICAL STUDY: CARDIOMYOPATHY
Natural history of dilated cardiomyopathy due to lamin A/C gene mutations
Matthew R. G. Taylor, MD*,
Pamela R. Fain, PhD*  ,
Gianfranco Sinagra, MD, FESC ,
Misi L. Robinson||,
Alastair D. Robertson, PhD*,
Elisa Carniel, MD,
Andrea Di Lenarda, MD, FESC,
Teresa J. Bohlmeyer, MD*,
Debra A. Ferguson, MS*,
Gary L. Brodsky, PhD*,
Mark M. Boucek, MD*¶,
Jean Lascor, MS¶,
Andrew C. Moss, BA*,
Wai-Lun P. Li, BS*,
Gary L. Stetler, PhD,
Francesco Muntoni, MD, FRCPCH#,
Michael R. Bristow, MD, PhD, FACC*,
Luisa Mestroni, MD, FACC, FESC*,* Familial Dilated Cardiomyopathy Registry Research Group
* University of Colorado Cardiovascular Institute, Denver, Colorado USA
Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado USA
Department of Internal Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
Division of Cardiology, Ospedale Maggiore and University of Trieste, Trieste, Italy
|| Transgenomic, Inc., Omaha, Nebraska, USA
¶ Division of Cardiology, The Children’s Hospital, Denver, Colorado, USA
# Neuromuscular Unit, Department of Pediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
Manuscript received May 16, 2002;
revised manuscript received August 23, 2002,
accepted October 4, 2002.
* Reprint requests and correspondence: Dr. Luisa Mestroni, University of Colorado Cardiovascular Institute, Bioscience Park Center, #150, 12635 East Montview Boulevard, Aurora, Colorado 80010-7116, USA.
Luisa.Mestroni{at}uchsc.edu
OBJECTIVES: We examined the prevalence, genotype-phenotype correlation, and natural history of lamin A/C gene (LMNA) mutations in subjects with dilated cardiomyopathy (DCM).
BACKGROUND: Mutations in LMNA have been found in patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis, and clinical relevance of laminopathies in DCM are unknown.
METHODS: A cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNA using denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNA mutation carrier status and Kaplan-Meier survival analysis were performed.
RESULTS: Mutations in LMNA were detected in four families (8%), three with familial (R89L, 959delT, R377H) and one with sporadic DCM (S573L). There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and "mildly" DCM (p = 0.006) were predictors of LMNA mutations. The LMNA mutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers.
CONCLUSIONS: Mutations in LMNA cause a severe and progressive DCM in a relevant proportion of patients. Mutation screening should be considered in patients with DCM, in particular when clinical predictors of LMNA mutation are present, regardless of family history.
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Abbreviations and Acronyms
| | DCM | | dilated cardiomyopathy | | DHPLC | | denaturing high-performance liquid chromatography | | DNA | | deoxyribonucelic acid | | EDMD | | Emery-Dreifuss muscular dystrophy | | FDC | | familial dilated cardiomyopathy | | LGMD | | limb-girdle muscular dystrophy | | LMNA | | lamin A/C gene | | MDDC | | dilated cardiomyopathy with muscle disease | | PCR | | polymerase chain reaction | | RNA | | ribonucelic acid | | SNP | | single-nucleotide polymorphism |
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