Cardiomyopathy, Familial Restrictive, 1

A number sign (#) is used with this entry because of evidence that familial restrictive cardiomyopathy-1 (RCM1) is caused by heterozygous mutation in the gene encoding the cardiac muscle isoform of troponin I (TNNI3; 191044) on chromosome 19q13.

Genetic Heterogeneity of Familial Restrictive Cardiomyopathy

Other forms of familial restrictive cardiomyopathy include RCM2 (609578), mapped to chromosome 10q23; RCM3 (612422), caused by mutation in the TNNT2 gene (191045) on chromosome 1q32; RCM4 (see 615248), caused by mutation in the MYPN gene (608517) on chromosome 10q21; and RCM5 (see 617047), caused by mutation in the FLNC gene (102565) on chromosome 7q32.

Clinical Features

Aroney et al. (1988) described father and daughter with idiopathic restrictive cardiomyopathy. The hemodynamic profile was characteristic, and there was echocardiographic evidence of diastolic dysfunction and atrial enlargement without ventricular dilatation.

Kushwaha et al. (1997) reviewed the evidence for a familial basis of idiopathic restrictive cardiomyopathy. Fitzpatrick et al. (1990) reported an Italian family in which autosomal dominant restrictive cardiomyopathy with atrial ventricular block and skeletal myopathy occurred in members of 5 generations. Symptoms developed in the third to fourth decade of life, with the eventual appearance of atrial ventricular block and skeletal muscle weakness. Katritsis et al. (1991) and Ishiwata et al. (1993) likewise described familial restrictive cardiomyopathy associated with distal skeletal myopathy. Feld and Caspi (1992) described familial cardiomyopathy with variable hypertrophic (see 192600) and restrictive features. A familial nonhypertrophic restrictive cardiomyopathy with autosomal dominant inheritance and incomplete penetrance was described by Cooke et al. (1994) in association with Noonan syndrome (163950).

Chen et al. (2001) reviewed the clinical spectrum of restrictive cardiomyopathy in 14 children, 7 of whom had familial cardiomyopathy. The patients were diagnosed from age 4 months to 17.3 years (mean, 7.8 years); presenting symptoms included dyspnea, pneumonia, syncope, ascites, inability to walk, and heart murmur, and some were screened due to positive family history. On electrocardiogram there was biatrial enlargement without significant dysrhythmia; chest x-ray showed cardiomegaly with pulmonary congestion, and 2 patients had pulmonary edema. Echocardiogram revealed marked dilation of the left atrium with normal-sized left ventricle (LV) and normal LV shortening fraction. Six patients had mid-septal bulging with an hourglass appearance of the LV on 4-chamber view, and 3 patients had mild apical LV hypertrophy. There was increased early diastolic filling and decreased atrial filling velocity by Doppler; reversal of pulmonary vein A-waves was common. Endomyocardial biopsy was performed in 11 patients and showed fibrosis with myocardial hypertrophy of various degrees in 7 patients, myofiber hypertrophy with increased number of mitochondria in 2, endocardial fibroelastosis in 1, and fibrosis with myocardial degeneration in 1 patient with eosinophilia. Autopsy in 1 patient showed mitochondrial abnormality with foamy myocardial transformation. Skeletal muscle biopsy was performed in 8 patients, but none had specific diagnostic findings. The clinical course was variable, although the majority of patients deteriorated rapidly: 5 patients died 1 week to 1.3 years after presentation (mean, 13.2 months), but 2 patients remained well for 8.3 and 9.1 years.

Molecular Genetics

Mogensen et al. (2003) studied a large family in which individuals were affected by either idiopathic restrictive cardiomyopathy or hypertrophic cardiomyopathy. Linkage analysis to selected sarcomeric contractile protein genes identified TNNI3 as a likely disease gene. Mutation analysis revealed a novel missense mutation that cosegregated with the disease in the family (191044.0005). Mogensen et al. (2003) investigated an additional 9 unrelated RCM patients with restrictive filling patterns, biallelic dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in 6 of these 9 patients (see 191044.0006-191044.0008). Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene.