Kamisago et al. (2000) studied affected members of a large 4-generation family segregating autosomal dominant dilated cardiomyopathy (CMD). Seventeen family members had dilated cardiomyopathy without conduction system disease, skeletal muscle dysfunction, or other phenotypes. The authors noted that ... Kamisago et al. (2000) studied affected members of a large 4-generation family segregating autosomal dominant dilated cardiomyopathy (CMD). Seventeen family members had dilated cardiomyopathy without conduction system disease, skeletal muscle dysfunction, or other phenotypes. The authors noted that previous clinical studies of 12 affected individuals showed no evidence of ventricular hypertrophy. In many family members, the onset of disease occurred early in life: one patient was hospitalized with heart failure at 2 years of age; another developed heart failure followed by sudden death at 20 years of age; and another underwent cardiac transplantation for end-stage heart failure at 23 years of age. Histopathologic study of the explanted heart from the last patient showed mildly increased interstitial fibrosis without myocyte or myofibrillar disarray. - Left Ventricular Noncompaction 5 Sasse-Klaassen et al. (2003) studied a family (designated 'INVM-101') segregating autosomal dominant left ventricular noncompaction (LVNC), in which there were 5 affected individuals over 2 generations. The proband underwent diagnostic evaluation because of inverted T waves seen on routine electrocardiogram at 60 years of age, and was found to have marked noncompaction confined to the left ventricular apex and an enlarged left ventricle with a left ventricle end-diastolic diameter (LVEDD) of 66 mm and reduced systolic function (left ventricle fractional shortening, 14%; left ventricle ejection fraction, 27%). Two asymptomatic daughters with LVNC were identified at 40 and 23 years of age, respectively. Sasse-Klaassen et al. (2003) also studied 2 brothers with LVNC ('family INVM-107'). The probands from both families were originally characterized by Oechslin et al. (2000). Klaassen et al. (2008) provided follow-up on families INVM-101 and INVM-107, stating that clinical evaluation of family 101 was remarkable for the very pronounced morphology of LVNC. The proband, who had suffered a stroke and systemic peripheral emboli, had an affected brother who initially presented with decompensated heart failure and pulmonary emboli; both patients remained stable over a period of 8 years. Other affected members of family INVM-101 fulfilled morphologic LVNC criteria but were clinically asymptomatic. The 4 affected individuals in family INVM-107 all had noncompaction involving the apex and mid-left ventricular wall, and the right ventricle was involved as well in 2 patients. The 25-year-old male proband, who had been diagnosed with LVNC after developing cardiogenic shock and pulmonary and systemic peripheral emboli, received a cardiac transplant at age 26 years. His 32-year-old affected brother also carried the mutation, as did their 65-year-old mother, who had typical LVNC morphology but remained clinically asymptomatic. The brother's son fulfilled criteria for LVNC at 2 years of age. Uro-Coste et al. (2009) studied a family in which the mother had myosin storage myopathy (608358) and later developed hypertrophic cardiomyopathy (CMH1; 192600), whereas the daughter had early symptomatic LVNC. The mother presented at age 30 years with proximal muscle weakness, which progressed to the point of her being wheelchair-bound by age 48 years. At age 51, hypertrophic cardiomyopathy was diagnosed; echocardiography revealed no atrial or ventricular dilatation, and no abnormal appearance of the ventricular walls. Skeletal muscle biopsy at age 53 years showed subsarcolemmal accumulation of hyaline material in type 1 fibers. Her 24-year-old daughter presented with heart failure at 3 months of age and was diagnosed with early-onset cardiomyopathy. Angiography revealed a less-contractile, irregular 'spongiotic' wall in the inferior left ventricle; on echocardiography, the left ventricle was dilated and fulfilled the criteria for LVNC, with a severely thickened, 2-layered myocardium and numerous prominent trabeculations and deep intertrabecular recesses. The daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment and she had some difficulty with heel-walking.
In a large 4-generation family segregating autosomal dominant dilated cardiomyopathy mapping to chromosome 14q11.2-q13, Kamisago et al. (2000) analyzed the candidate gene MYH7 (160760) and identified heterozygosity for a missense mutation (S532P; 160760.0022). In an unrelated family with ... In a large 4-generation family segregating autosomal dominant dilated cardiomyopathy mapping to chromosome 14q11.2-q13, Kamisago et al. (2000) analyzed the candidate gene MYH7 (160760) and identified heterozygosity for a missense mutation (S532P; 160760.0022). In an unrelated family with CMD, in which a father and 2 daughters were affected, the authors identified a different heterozygous missense mutation (F764L; 160760.0023). In a series of 46 young patients with CMD, Daehmlow et al. (2002) screened 4 sarcomere genes and identified 2 probands with heterozygous missense mutations in the MYH7 gene: A223T (160760.0026) and S642L (160760.0027). The patients were diagnosed at ages 35 years and 18 years, respectively. Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in 63 unrelated adult probands with left ventricular noncompaction but no other congenital heart anomalies. They identified 7 different heterozygous mutations in the MYH7 gene in the probands from 4 families, 2 of which were previously studied by Sasse-Klaassen et al. (2003) (families INVM-101 and INVM-107), and in 4 sporadic patients, respectively (see, e.g., 160760.0040-160760.0042). Klaassen et al. (2008) stated that the most frequent symptom at presentation for patients with MYH7 mutations was dyspnea, followed by atypical chest pain and palpitations. LVNC was always present in the ventricular apex, and in all but 2 probands, the midventricular inferior and lateral walls were involved, whereas there was sparing of the basal left ventricular segments. Five of 8 probands had biventricular involvement. Left ventricular end-diastolic dimensions were enlarged and systolic function was impaired in 5 of 8 probands, and heart failure was present at initial diagnosis or occurred during follow-up in all but 2 probands. Stroke or pulmonary or systemic peripheral thromboemboli occurred in 4 of 8 probands. In a mother with myosin storage myopathy (608358) and hypertrophic cardiomyopathy (CMH1; 192600) and her daughter with early symptomatic LVNC, Uro-Coste et al. (2009) identified heterozygosity for an L1793P mutation in the MYH7 gene (160760.0037). In an analysis of the MYH7 gene in 141 white probands of western European descent diagnosed with Ebstein anomaly (see 224700), Postma et al. (2011) identified heterozygous mutations in 8 (see, e.g., 160760.0045 and 160760.0046). Of these 8 probands, LVNC was present in 7 and uncertain in 1, whereas none of the 133 mutation-negative probands had LVNC. Evaluation of all available family members of mutation-positive probands revealed 3 families in which additional mutation-positive individuals had cardiomyopathy or congenital heart malformations, including type II atrial septal defect, ventricular septal defect, bicuspid aortic valve, aortic coarctation, and pulmonary artery stenosis/hypoplasia.