CLINICAL STUDIES
Familial dilated cardiomyopathy
Evidence for genetic and phenotypic heterogeneity
Luisa Mestroni, MD, FACC*  ,
Chiara Rocco, MD,
Dario Gregori, PhD ,
Gianfranco Sinagra, MD,
Andrea Di Lenarda, MD,
Snjezana Miocic, MD*,
Matteo Vatta, PhD*,
Bruno Pinamonti, MD,
Francesco Muntoni, MD ,
Alida L. P. Caforio, MD, PhD|| ¶,
William J. McKenna, MD, FRCP, FACC¶,
Arturo Falaschi, MD, PhD*,
Mauro Giacca, MD, PhD*,
Fulvio Camerini, MD the Heart Muscle Disease Study Group#
* International Centre for Genetic Engineering and Biotechnology, AREA Science Park, Trieste, Italy
Division of Cardiology, Ospedale Maggiore and School of Medicine, Trieste, Italy
Department of Statistical and Economical Sciences, University of Trieste, Trieste, Italy
Neuromuscular Unit, Department of Paediatrics and Neonatal Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
|| Department of Clinical and Experimental Medicine, Division of Cardiology, University of Padua, Padua, Italy
¶ Department of Cardiological Sciences, St. Georges’s Hospital Medical School, London, United Kingdom
Manuscript received November 20, 1998;
revised manuscript received February 24, 1999,
accepted March 29, 1999.
Reprint requests and correspondence: Luisa Mestroni, MD, FACC, FESC, Molecular Genetics, University of Colorado Cardiovascular Institute, Fitzsimons, Mail Stop F442, Aurora, Colorado 80045-0508 USA
Luisa.Mestroni{at}uchsc.edu
OBJECTIVES
This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC).
BACKGROUND
A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients.
METHODS
Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed.
RESULTS
Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific.
CONCLUSIONS
Familial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.
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Abbreviations and Acronyms
| | AD | = autosomal dominant | | AR | = autosomal recessive | | CK | = creatine kinase | | DCM | = dilated cardiomyopathy | | FDC | = familial dilated cardiomyopathy | | MDDC | = autosomal dominant dilated cardiomyopathy with subclinical muscle involvement | | XLDC | = X-linked dilated cardiomyopathy |
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