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
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Figure 1 Pedigrees of families with different forms of familial dilated cardiomyopathy (FDC). 1. AD-FDC1: the key members of this family after the last follow-up screening (1997), consistent with autosomal dominant inheritance (male to male transmission) and age-related penetrance (almost complete absence of affected in the last generation). 2. AR-FDC3: autosomal recessive FDC, in which the affected were respectively 12 and 16 years old at diagnosis. 3. XLDC2: FDC with X-linked transmission, in this family due to a deletion of exons 48–49 (24). 4. MDDC1: autosomal dominant transmission and subclinical skeletal muscle involvement. 5. AD-HDC1: a form of unclassifiable FDC with autosomal dominant transmission and a phenotype characterized by mild dilation, systolic dysfunction and apical hypertrophy. 6. AR-RPDC1: another unclassifiable FDC with autosomal recessive transmission associated with retinitis pigmentosa and hearing loss. Finally, CDDC1: autosomal dominant family with conduction defects and subsequent development of severe ventricular dilation and dysfunction. Individuals are indicated by generation and pedigree number. Affected status is indicated by filled symbols, unaffected status by clear symbols and unknown status (individuals with equivocal or suspected dilated cardiomyopathy) by gray symbols. The probands are indicated by arrows.
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Figure 2 Samples from the proband of a family with autosomal dominant familial dilated cardiomyopathy showing myocarditis at the histologic examination of the endomyocardial biopsy. (A) Acute active myocarditis, with massive infiltration of lymphocytic, monocytic and plasma cells, necrosis of adjacent myocardial fibers, interstitial edema and disarrangement of the muscle bundles (hematoxylin–eosin, x120, reduced by 54%). (B) Healing myocarditis, with interstitial edema and a focal inflammatory infiltration with myocyte necrosis (hematoxylin–eosin, x180, reduced by 54%).
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Figure 3 Echocardiographic features of autosomal dominant hypertrophic–hypokinetic cardiomyopathy (AD-HDC). Apical four-chamber view of individual III-3 of family AD-HDC1 (see Fig. 1). Left frame: end-diastole; right frame: end-systole. The left ventricle (LV) is only mildly dilated (end-diastolic volume 112 ml); a severe apical hypertrophy is present (arrows). The left ventricle is diffusely hypokinetic, with moderate systolic dysfunction (ejection fraction 44%). LA = left atrium.
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