Background: Mutations in the cardiac -myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC). Although there are no mutational hotspots, most of the mutations are located in specific exons of the MYH7 and TNNT2 genes. Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy. Methods: We sequenced exons 8, 9, 13-16, 19, 20, 22-24, and 30 of the MYH7 gene and exons 8, 9, 11, and 14 -16 of the TNNT2 gene in 30 HC patients (18 -60 years of age) from the region of Asturias (Northern Spain); 25 cases (80%) had a family history of the disease. Genomic DNA was amplified, and fragments were directly sequenced. Each DNA variant found in the patients was also analyzed in 200 healthy controls through single-strand conformation analysis. Results: Four of the probands had nucleotide changes absent in the healthy controls. Two cases had mutations previously described in the MYH7 gene (exon 14, Arg453Cys) or the TNNT2 gene (exon 16, Arg278Cys). Two cases had new mutations (MYH7 exon 22, Met822Val;
A 59 year old white woman who had been treated with chloroquine phosphate for 25 years presented with signs of congestive heart failure and was diagnosed as having restrictive cardiomyopathy by non-invasive methods. Electron microscopy of a biopsy specimen of skeletal muscle showed lesions compatible with chloroquine myopathy. The patient died five weeks after presentation. Electron microscopy of heart tissue showed similar lesions to those of the skeletal muscle.
Genetic studies have identified polymorphisms at the apolipoprotein (Apo) A1 gene associated with HDL cholesterol and apolipoprotein levels, and a relationship between the severity of coronary artery disease and polymorphisms at the 5′-end of Apo A1 has been also reported. This study was designed to examine the relationship between polymorphism at the Apo A1 gene and the risk of early coronary artery disease. Furthermore, the association of the polymorphism with the classical risk factors was analyzed. A total of 176 male patients (mean age 43 ± 5 years) diagnosed as having unstable angina (53 cases) or myocardial infarction (123 cases) were prospectively evaluated. Data referring to hypertension, diabetes and tobacco consumption were recorded. The levels of total cholesterol, HDL cholesterol, Apo A1 and B and triglycerides were determined. DNA was obtained from the 176 patients and from 200 controls. In order to determine the Apo A1 genotypes at two polymorphic sites (G/A at –75 bp, and C/T at +83 bp), DNA was PCR amplified and digested with MspI. The frequency of carriers of the rare allele at the –75 bp site (M1–) was 0.34 in cases and 0.24 in controls (p < 0.05). The frequencies of the M1– allele among patients with angina and myocardial infarction were 0.43 (p = 0.009, angina vs. controls) and 0.30, respectively. No significant association between this polymorphism and other cardiovascular risk factors was found. No difference in the frequencies for carriers of the rare allele at the +83-bp polymorphism (M2) was observed among patients with angina (0.08 vs. 0.07) or myocardial infarction (0.04 vs. 0.07), and no association between this polymorphism and tobacco, hypertension and diabetes was noted. Patients carrying the rare M2– allele had a lower concentration of total cholesterol compared to those without this allele (183 ± 29 vs. 223 ± 54, p < 0.04) and HDL cholesterol was also lower among patients carrying the M2– (26 ± 4 vs. 33 ± 9, p < 0.02). In our community male patients with a diagnosis of coronary artery disease and age less than 50 years showed a higher frequency of the M1– allele at the –75-bp site of the Apo A1 gene. There was a significant increase in the frequency of the M1– allele in patients with unstable angina and no association with risk factors. In the +83-bp polymorphism there was no difference in the allelelic frequencies or the risk factors, except for the HDL cholesterol and total cholesterol where the patients with the allele M2– had lower levels than those homozygous for the M2+.
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