Molecular genetics of hypertrophic cardiomyopathy.
Explore the source record for details and available documents.
Cardiomyopathy, Hypertrophic↗
Biomedical subjects
R Roberts
Publications and source records attributed to R Roberts.
Familial hypertrophic cardiomyopathy: diagnostic and therapeutic implications of recent genetic studies.
Familial hypertrophic cardiomyopathy is the first primary cardiomyopathy to have yielded to the techniques of modern molecular genetics. In the past few years, four genes responsible for this disease have been identified, all of which code for sarcomeric structural proteins. In addition, structure-function analysis and genotype-phenotype correlation studies have shed significant light on the molecular basis of this disease. It is hoped that within the next few years the application of molecular genetic tools will not only facilitate the diagnosis of hypertrophic cardiomyopathy but will also provide prognostic and therapeutic stratification for more definitive therapy.
Cardiomyopathy, Hypertrophic↗
Novel proteins with binding specificity for DNA CTG repeats and RNA CUG repeats: implications for myotonic dystrophy.
While an unstable CTG triplet repeat expansion is responsible for myotonic dystrophy, the mechanism whereby this genetic defect induces the disease remains unknown. To detect proteins binding to CTG triplet repeats, we performed bandshift analysis using as probes double-stranded DNA fragments having CTG repeats [ds(CTG)6-10] and single-stranded oligonucleotides having CTG repeats ss(CTG)8 or RNA CUG triplet repeats (CUG)8. The source of protein was nuclear and cytoplasmic extracts of HeLa cells, fibroblasts and myotubes. Proteins binding to the double-stranded DNA repeat [ds(CTG)6-10], were inhibited by nonlabeled ds(CTG)6-10, but not by a non-specific DNA fragment (USF/AD-ML). Another protein binding to ssCTG probe and RNA CUG probe was inhibited by nonlabeled (CTG)8 and (CUG)8. Nonlabeled oligos with different triplet repeat sequences, ss(CAG)8 or ss(CGG)8, did not inhibit binding to the ss(CTG)8 probe. However, when labeled as probes, the (CAG)8 and (CGG)8 bound to proteins distinct from the CTG proteins and binding was inhibited by nonlabeled (CAG)8 or (CGG)8 respectively. The protein binding only to the RNA repeat (CUG)8 was inhibited by nonlabeled (CUG)8 but not by nonlabeled single- or double-stranded CTG repeats. Furthermore, the CUG-BP exhibited no binding to an RNA oligonucleotide of triplet repeats of the same length but having a different sequence, CGG. The CUG binding protein was localized to the cytoplasm, whereas dsDNA binding proteins were localized to the nuclear extract. Thus, several trinucleotide binding proteins exist and their specificity is determined by the triplet sequence. The novel protein, CUG-BP, is particularly interesting since it binds to triplet repeats known to be present in myotonin protein kinase mRNA which is responsible for myotonic dystrophy.
Base Sequence↗
Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs.
The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.
Adult↗
Familial colloid cyst of the third ventricle: case report and review of associated conditions.
The cases of a father and his son who were diagnosed with pathologically confirmed colloid cysts of the third ventricle are presented. The familial occurrence of this tumor is rare and suggests that genetic factors may play a role in its formation. Consistent with the concept that the cyst originates as a developmental abnormality, it is associated with a variety of congenital defects. The conditions that are associated with these tumors are discussed.
Adult↗
Maternal phenylketonuria 1987 to 1993, pregnancy outcome and early infant development: the Northern Ireland experience.
Explore the source record for details and available documents.
Adolescent↗
Interictal temporal hypoperfusion is related to early-onset temporal lobe epilepsy.
Previous studies of interictal regional cerebral blood flow (rCBF) in temporal lobe epilepsy have shown variable correlations with clinical measures. We used high spatial resolution hexamethyl propyleneamine oxime single photon emission computed tomography (HMPAO SPECT) in 80 consecutive patients with complex partial seizures (CPS), comparing results with those from a large series of normal subjects. Visual image analysis detected abnormalities of rCBF in 41 of 80 (51%; numeric analysis detected abnormalities in 38 of 80). Age at epilepsy onset was significantly younger in patients with temporal hypoperfusion (p = 0.002), and the frequency distribution of hypoperfusion versus age at epilepsy onset was reverse exponential. The results of numerical image analysis showed that degree of hypoperfusion did not vary with age at epilepsy onset. These data suggest a single insult operating early in life as a cause of temporal hypoperfusion, as has been shown for mesial temporal sclerosis (MTS). We could not demonstrate relationships with other clinical variables, including time since last seizure.
Adolescent↗
Evaluation of bronchial responsiveness to exercise in children as an objective measure of asthma in epidemiological surveys.
BACKGROUND: Exercise has been proposed as a useful challenge test for the measurement of bronchial responsiveness in community surveys of the prevalence of childhood asthma. This study aimed to develop a standardised exercise challenge in which the sensitivity to detect asthma was increased by inhalation of dry air. METHODS: Sixty four children aged 12-13 years who had reported wheeze in the past 12 months and 70 control subjects were invited to participate in an exercise challenge at school. Subjects performed eight minutes of cycle exercise while breathing dry air at a workload calculated to produce a minute ventilation of 60% maximum voluntary ventilation during the final three minutes. A fall in forced expiratory volume in one second (FEV1) of 10% or more from baseline was considered a positive test. Data on recent asthma symptoms, asthma morbidity, and use of medication were collected by parent completed questionnaires in those subjects who reported wheeze in the past 12 months. Repeatability of the exercise test was determined in a further 13 children with known asthma. RESULTS: Fifty five children (88%) who reported wheeze in the previous 12 months and 54 control subjects (77%) were studied. Nine subjects in whom baseline FEV1 was less than 75% predicted did not perform the exercise test. Technically unsatisfactory tests were obtained in five subjects. Twenty six (57%) subjects who reported wheeze and three controls (6%) had a positive exercise test, giving a sensitivity of 57% (26 of 46) and specificity of 94% (47 of 50). Estimates of the repeatability of the exercise test showed a mean difference in percentage fall in FEV1 for patients with asthma of 3.08% (95% limits of agreement -7.76% to 13.92%). CONCLUSIONS: Despite attempts to maximise the stimulus to bronchoconstriction in this exercise challenge test, its sensitivity and specificity were not improved in comparison with previous epidemiological studies of the prevalence of asthma.
Adolescent↗
Short communication: portal imaging with film-cassette combinations: what film should we use?
A large number of commercially available X-ray films were obtained to assess their suitability for megavoltage radiotherapy portal imaging. The speed (represented by optimum film dose), gamma (gamma) and latitude of all these films were determined. Films with high gamma values are recommended for clinical use to maximize the low levels of radiation contrast produced by a megavoltage beam.
Humans↗
Comparison of percutaneous and surgical tracheostomies.
OBJECTIVE: To compare the safety and efficacy of percutaneous dilational tracheostomy (PDT) with surgical tracheostomy (ST). DESIGN: Prospective randomized trial. SETTING: Public urban teaching hospital. PATIENTS: Twenty-six patients were randomized to undergo PDT and 27 patients to ST. RESULTS: The time from randomization into the study until tracheostomy was performed was 28.5 +/- 27.9 h in the PDT group and 100.4 +/- 95.0 h in the ST group (p < 0.001). PDT was performed in 8.2 +/- 4.9 min vs 33.9 +/- 14.0 min for ST (p < 0.0001). There was no significant difference in intraprocedural complications between the groups. Postprocedural complication rates were 12% for PDT and 41% for ST (p = 0.008). CONCLUSION: PDT is superior to ST logistically. PDT can be performed at the bedside eliminating the risk of patient transport. Because operating room scheduling is not necessary, PDT can be performed earlier once the decision to do a tracheostomy is made, which will improve ICU utilization. PDT is a faster procedure to perform and has fewer postprocedural complications.
Female↗
A variant of beta fibrinogen is a genetic risk factor for coronary artery disease and myocardial infarction.
BACKGROUND: Coronary artery disease is a complex trait caused by a number of genetic and environmental factors. Genes involved in hemostasis and coagulation are excellent candidate genes for CAD and its thrombotic complications, i.e., myocardial infarction (MI) and unstable angina. METHODS: We determined the frequency of beta-fibrinogen genotypes in a homogenous patient population with CAD undergoing coronary angioplasty and in a comparable group in the general population. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hha-1 and gel electrophoresis. Cases and controls were also genotyped for a G17382T polymorphism in the (beta-Myosin heavy chain) (beta-MyHC) gene, which is not a candidate gene for CAD. RESULTS: The distribution of beta-MyHC G/T genotypes and the frequency of alleles were similar in cases and controls. However, the beta-fibrinogen G/G genotype was present in 71% of patients with CAD as compared to 54% in the general population (p = 0.00001, OR: 2.1, 95% CI: 1.7-2.8). Seventy-one percent of patients with MI and 72% of patients with unstable angina had G/G genotype (p = 0.003, OR: 2.0, 95% CI: 1.3-3.3, and p = 0.005, OR: 2.1, 95% CI: 1.3-3.7, respectively). Sixty-nine percent of male and 82% of female patients with CAD had the G/G genotype as compared to 56% and 53% in in general population, respectively (p = 0.0381, and 0.0003, respectively). Multivariate regression analysis showed that the allele G was an independent predictor of case-control status or risk of MI in a codominant manner (F = 86.8 p < 0.0001). CONCLUSIONS: beta-fibrinogen G/G genotype is a genetic risk factor for predisposition to CAD and its thrombotic complications.
Adult↗
Expression of brain-type creatine kinase and ubiquitous mitochondrial creatine kinase in the fetal rat brain: evidence for a nuclear energy shuttle.
To test the hypothesis that embryonic brain cells utilize a creatine phosphate energy shuttle, we examined the pattern of creatine kinase (CK) isoform expression and localization in the fetal rat brain. Moderate levels of CK activity are present at embryonic day 14 (7 U/mg protein) and decrease slightly until 3 days postpartum followed by a rapid, fourfold up-regulation to adult levels by 1 month (18 U/mg protein). In parallel with changes in enzyme activity, there is a biphasic and coordinate pattern of expression of brain-type CK (BCK) and ubiquitous mitochondrial CK (uMtCK) determined by nondenaturing electrophoresis and immunoblot analysis. The localization of CK isoforms was examined by immunocytochemistry, and, during the fetal period, BCK and uMtCK immunoreactivity was detected throughout the central and peripheral nervous system, especially in neuroepithelial regions of the cerebral vesicles and spinal cord. In large cells within the olfactory neuroepithelium and ventral spinal cord, differential compartmentation of CK isoforms was evident, with BCK localized primarily in cell nuclei, whereas uMtCK immunoreactivity was present in the cell body (but not within nuclei). In olfactory bulb neuroepithelium, both isoforms were expressed in the middle zone of the germinal layer associated with DNA synthesis. In embryonic skeletal and cardiac muscle, which also express BCK, the same compartmentation of BCK was seen, with BCK localized primarily in the cell nucleus of cardiac and skeletal myoblasts. These results demonstrate a coordinate pattern of expression and compartmentation of BCK and uMtCK isoforms in the fetal brain that, in some cells, provides the anatomic basis for a nuclear energy shuttle.
Animals↗
Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy.
BACKGROUND: The variability of the phenotypic expression of left ventricular hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) indicates a potential role for additional modifying genes. Variants of angiotensin-I converting enzyme (ACE) gene have been implicated in cardiac hypertrophy. To assess whether ACE genotypes influence the phenotypic expression of hypertrophy, we determined the left ventricular mass index (LVMI) and extent of hypertrophy in 183 patients with HCM. METHODS AND RESULTS: LVMI was derived by the area-length method using two-dimensional echocardiograms. Extent of LVH was determined by a point score method (1 to 10 points). DNA was extracted from blood, and ACE genotyping was performed by polymerase chain reaction (PCR) with an established protocol. Amplification of DNA in the region of polymorphism by PCR of alleles I and D showed 490- and 190-bp products, respectively. ACE genotypes DD, ID, and II were present in 60, 90, and 33 patients with HCM, respectively. In genetically independent patients (n = 108), the mean LVMI (g/m2) was 148 +/- 35.3 in those with DD (n = 35) and 134.2 +/- 33.3 in those with ID and II (n = 73) genotypes (P = .046). LVH score was 6.69 +/- 1.71 in patients with DD and 5.55 +/- 2.19 in those with ID and II genotypes (P = .004). Regression analysis showed that ACE genotypes accounted for 3.7% and 6.5% of the variability of LVMI and LVH score (P = .046 and P = .008, respectively). In 26 patients from a single family, LVMI and LVH score were also greater in patients with DD than in those with ID and II genotypes. ACE genotypes accounted for 14.7% and 10.4% of the variability of the LVMI and extent of hypertrophy, respectively. CONCLUSIONS: ACE genotypes influence the phenotypic expression of hypertrophy in HCM.
Adult↗
Recent advances in the molecular genetics of hypertrophic cardiomyopathy.
Explore the source record for details and available documents.
Biomarkers↗
Genomic organization of the human dystrophin gene across the major deletion hot spot and the 3' region.
The genomic organization of most of the human dystrophin gene has not been defined at single-exon level, owing to its enormous size (2300 kb). By taking advantage of a YAC-based restriction map of the gene previously constructed, we have localized individual dystrophin exons from 42 to 79 along the central and 3' regions of the gene. These data elucidate the general organization of this large portion of the gene (1250 kb) and, in particular, characterize the genomic region most frequently involved in deletion mutations responsible for Duchenne and Becker muscular dystrophies.
Dystrophin↗
Precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus.
OBJECTIVE: To determine the precision (interobserver agreement) and accuracy (agreement with criterion standard) of clinical and radiological signs in premature infants at risk of patent ductus arteriosus (PDA) with left-to-right shunting. DESIGN: Masked comparison of clinical and radiological examination with Doppler flow echocardiography (criterion standard). SETTING: Neonatal intensive care unit. PATIENTS: One hundred infants with birth weights less than 1750 g were studied once between days 3 and 7 of life. A third of the cohort was intubated at the time of study. INTERVENTION: Five independent observers noted the presence or absence of an increased pulse volume, an active precordium, a heart murmur, a cardiothoracic ratio greater than 60%, increased pulmonary vascular markings on a concurrent chest x-ray film, and a relative increase of the cardiothoracic ratio compared with that from the previous chest x-ray film. Pulsed and color flow Doppler echocardiography was performed within 4 hours. All 100 tapes were reviewed by a second pediatric cardiologist. RESULTS: Twenty-three infants had a PDA with left-to-right shunting. The precision of clinical signs was modest, with average kappa values of 0.15 for pulse volume, 0.32 for precordium, and 0.41 for murmur. Pulse quality (43%) and murmur (42%) had the highest mean sensitivities. Corresponding specificities were 74% for pulse volume and 87% for murmur. The combination of a cardiac murmur with an abnormal pulse volume had the highest positive predictive value (77%). The radiological examination did not improve the observers' ability to distinguish between patients with and without PDA. CONCLUSIONS: The precision and accuracy of clinical and radiological signs of a PDA with left-to-right shunting are unsatisfactory. Therefore, Doppler flow echocardiography is required to diagnose PDA confidently in preterm infants between days 3 and 7 of life.
Ductus Arteriosus, Patent↗
Molecular genetics: cardiac disease and risk-related genes.
Molecular genetics is playing an increasing role in the diagnosis, treatment, and prevention of cardiac disease. Moreover, most of the genes that may cause cardiac disease or predispose an individual to cardiac disease are anticipated to be identified within the next 10 years. Several genes with risk for heart disease have been identified, such as the ACE genotype DD. Replacement gene therapy as well as use of promoter-specific drugs to act on genetic regulatory elements will encompass the future treatment of cardiovascular disease. This article provides a summary of the potential roles of genetic screening for cardiac risk factors and genetic interventions in cardiovascular disease.
Cardiomyopathy, Hypertrophic↗
Genetic heterogeneity in familial dilated cardiomyopathy.
Familial dilated cardiomyopathy (FDCM), an inherited primary form of myocardial disease, is a significant cause of morbidity and mortality at all ages and the leading reason for cardiac transplantation worldwide. Although typically inherited as an autosomal dominant disorder, all forms of inheritance have been recognized. FDCM appears to be responsible for approximately 20-30% of all cases of dilated cardiomyopathy, the most common form of cardiomyopathy. Recently, two families having autosomal dominant FDCM were mapped. The first family had conduction abnormalities and FDCM and was mapped to 1p1-1q1, while the second family, which had pure FDCM, was mapped to 9q13-q22. Neither gene has been identified to date. In this report, one family with pure FDCM was analyzed for linkage to the 1p1-1q1 and 9q13-q22 loci using parameteric linkage analysis, with linkage to both regions excluded. This demonstrates that the pure form of FDCM is caused by multiple different genes, i.e., genetic heterogeneity. Identification of large families with FDCM will be required to identify the various genes responsible for this important clinical entity.
Cardiomyopathy, Dilated↗