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Biomedical subjects

K Schwartz

Publications and source records attributed to K Schwartz.

At least 19 recordsLinked to original sources
PubMed1998

Familial hypertrophic cardiomyopathy: from mutations to functional defects.

Hypertrophic cardiomyopathy is characterized by left and/or right ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typical morphological changes include myocyte hypertrophy and disarray surrounding the areas of increased loose connective tissue. Arrhythmias and premature sudden deaths are common. Hypertrophic cardiomyopathy is familial in the majority of cases and is transmitted as an autosomal-dominant trait. The results of molecular genetics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes encoding proteins of the myofibrillar apparatus: ss-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, alpha-tropomyosin, and cardiac myosin binding protein C. In addition to this locus heterogeneity, there is a wide allelic heterogeneity, since numerous mutations have been found in all these genes. The recent development of animal models and of in vitro analyses have allowed a better understanding of the pathophysiological mechanisms associated with familial hypertrophic cardiomyopathy. One can thus tentatively draw the following cascade of events: The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of a "hypocontractile" state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and determine a "hypercontractile" state that would directly induce cardiac hypertrophy. The development of other animal models and of other mechanistic studies linking the genetic mutation to functional defects are now key issues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart.

Animals↗
PubMed1998

Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene.

BACKGROUND: Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis. METHODS AND RESULTS: We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02). CONCLUSIONS: These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.

Adolescent↗
PubMed1998

Apolipoprotein(a) gene enhancer resides within a LINE element.

Apolipoprotein(a), (apo(a)), is the distinguishing protein portion of the lipoprotein(a) particle, elevated plasma levels of which are a major risk factor for cardiovascular disease. A search for enhancer elements that control the transcription of the apo(a) gene led to the identification of an upstream element that contains target binding sites for members of the Ets and Sp1 nuclear protein families. The enhancer element functions in either orientation to confer a greater than 10-fold increase in the activity of the apo(a) minimal promoter in cultured hepatocyte cells. Unexpectedly, the enhancer element is located within a LINE retrotransposon element, suggesting that LINE elements may function as mobile regulatory elements to control the expression of nearby genes.

Apolipoproteins↗
PubMed1998

Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene.

Troponin T (TnT) is a component of the troponin complex which regulates muscle contraction in response to alterations in intracellular calcium ion concentration. In human heart, multiple isoforms of cardiac TnT have been described on the basis of antibody studies and molecular cloning of corresponding cDNAs. These isoforms are all derived from the transcription of a single gene, TNNT2, located on chromosome 1q32, and generated by alternative splicing. We show here that isoform diversity is achieved by the use of both alternative exons and alternative acceptor sites and present the organisation of the human TNNT2 gene, which is composed of 17 exons spread over 17 kb. A potential structure of the promoter region is also presented. Several polymorphisms in both the exonic and intronic regions were identified, some of which may act as modulators of the expression of this gene.

Alternative Splicing↗
PubMed1998

Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.

Adolescent↗
PubMed1998

Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes.

BACKGROUND: The gene involved in familial hypertrophic cardiomyopathy on chromosome 11 was recently identified as the cardiac myosin binding protein-C (MyBP-C) gene. The phenotype of two families associated with mutation in this gene is described here and compared to that of five families with mutations in the beta-myosin heavy chain gene. METHODS AND RESULTS: In adults (n = 33) bearing a splice acceptor site mutation in the MyBP-C gene, penetrance of familial hypertrophic cardiomyopathy was incomplete (69%) and ventricular hypertrophy mild. Among 37 clinical, electrocardiographic and echocardiographic parameters analysed, the only difference with the beta-MHC group (n = 35) was a shorter acceleration time of systolic flow in the pulmonary artery (P < 0.05). Sensitivity and specificity of diagnostic criteria were similar for the two genes. Cumulative survival rate for the splice acceptor site mutation (90% at 50 years old) was mid-way between that observed with a malignant (Arg403Leu: 42%) and a benign mutation (Arg403Trp: 100%) in the beta myosin heavy chain gene (P = 0.002). CONCLUSIONS: The detailed phenotype associated with a mutation in the MyBP-C gene was no different from that associated with mutations in the beta myosin heavy chain gene, except for prognosis which appeared more benign. These preliminary results suggest that there is no locus-specific genotype-phenotype correlation for the two genes analysed.

Adult↗
PubMed1998

Diagnostic performance of QT interval variables from 24-h electrocardiography in the long QT syndrome.

AIMS: The long QT syndrome is mainly defined by QT interval prolongation (QTc > 0.44s). However, data obtained in genotyped patients showed that resting QTc measurement alone may be inaccurate for ascertaining the phenotype. The aim of this study was to evaluate the diagnostic performance of QT interval rate-dependence in untreated chromosome 11-linked patients. METHODS: The study population consisted of 25 untreated long QT patients linked to chromosome 11 and 25 age- and gender-matched controls. QTc intervals were measured on 12-lead resting ECG recordings. From 24-h Holter recordings, the slope of the relationship between ventricular repolarization and heart rate was studied separately day and night to assess neural modulation. Mean heart rates and rate-dependences of QT and Q-maximum of T (QTm) intervals were compared between long QT patients and controls for both time periods. RESULTS: In both groups, the rate-dependences were modulated by day-night influences. When compared to controls, long QT patients showed a significant increase at night in QT/RR slopes (0.158 +/- 0.05 vs 0.117 +/- 0.03, P = 0.002) and QTm/RR slopes (0.163 +/- 0.05 vs 0.116 +/- 0.04, P = 0.0006). Multivariate analysis, adjusting QTc interval on age and gender, discriminated between long QT patients and controls with a 76% sensitivity and a 84% specificity. A 96% sensitivity and a 96% specificity were reached by taking into account the QTm/RR slope at night, the QTc interval and the mean heart rate during the day. CONCLUSION: QT interval variables obtained from 24-h ECG recordings improve long QT syndrome diagnosis by showing an increased nocturnal ventricular repolarization rate-dependence in genotyped chromosome 11-linked patients.

Adolescent↗
PubMed1998

Familial hypertrophic cardiomyopathy. Cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy.

AIMS: It is not known whether the apparent normality of echocardiographic examination results, in subjects bearing a mutation for hypertrophic cardiomyopathy but without ultrasonic left ventricular hypertrophy, is due to incomplete phenotypic expression, or inaccurate echocardiographic criteria. The aim of this study was to search for echocardiographic abnormalities in these patients. METHODS AND RESULTS: Echocardiography was performed in 100 subjects from two families with a mutation in the beta-MHC (720) or My-BPC (714) genes. We compared genetically affected subjects with an apparently normal left ventricle (thickness < 13 mm) (20 patients), and nonaffected first-degree relatives (61 normal subjects). (1) Patients had a thicker left ventricular wall (9.7 +/- 1.4 vs 8.9 +/- 1.4 mm, P = 0.03), a greater indexed mass (107 +/- 18 vs 97 +/- 17 g. m-2, P = 0.03), a larger left atrium (27 +/- 9 vs 23 +/- 10 mm3, P = 0.09) and lower wall stress (78 +/- 11 vs 89 +/- 15 10(3) dynes. cm-2, P = 0.002); these differences were highly significant after adjustment for height, age and systolic blood pressure either for wall thickness (P = 0.000003), mass (P = 0.005) or atrial volume (P = 0.001), and the ventricular systolic dimension appeared smaller (P = 0.01); (2) results remained significant (P < 0.01) when a lower cut-off value (< or = 11 mm) or only adults (> or = 18 years) were considered; (3) a subanalysis of Family 714 (13 patients, 25 normals matched for sex, age and height) showed the same trends. CONCLUSION: In familial hypertrophic cardiomyopathy, genetically affected subjects with an apparently normal heart by echocardiography show slight ultrasonic structural and functional left ventricular modifications, suggesting that the phenotype of the disease is a continuous spectrum from normal structure to typical hypertrophy.

Adolescent↗
PubMed1998

Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in genotyped children.

AIM: The aim of the study was to evaluate electrocardiography and echocardiography in the diagnosis of familial hypertrophic cardiomyopathy in children, using the genetic status as the criterion of reference. METHODS AND RESULTS: We analysed 35 children (<18 years) from 13 families with identified mutations: 16 were genetically affected (11.2 +/- 3 years), 19 unaffected (13.1 +/- 2.8 years). Conventional major diagnostic criteria were: left ventricular wall thickness >95% confidence interval on the echocardiogram; abnormal Q waves, left ventricular hypertrophy (voltage >95th percentile), or marked ST-T changes on the electrocardiogram. Twenty-two minor electrocardiographic and echocardiographic criteria were also analysed. Using major criteria, the specificity of the electrocardiogram and echocardiogram was excellent (100% for both) but sensitivity was particularly low (38% and 50% respectively). However, when four relevant additional criteria (QRS axis, left atrium dimension, intraventricular septum/posterior wall ratio, E/A wave ratio) were taken into account, sensitivity increased to 88% and specificity remained high (95%). CONCLUSIONS: (1) Familial hypertrophic cardiomyopathy was diagnosed in only approximately 50% of genetically affected children by conventional electrocardiographic and/or echocardiographic criteria. (2) Relevant additional diagnostic criteria were selected so that nearly all children considered as healthy carriers of a mutation (based on conventional criteria) could be identified with excellent specificity.

Adolescent↗
PubMed1998

Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene.

DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown that it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes result from missense changes, although one of the most recent genes to be identified (cardiac myosin binding protein C gene, MYBPC3) has predominantly DNA mutations which produce truncated proteins. Both dominant negative and haploinsufficiency models have been proposed to explain the molecular changes in FHC. This study describes two Australian families with FHC caused by different mutations in MYBPC3. The first produces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncated protein. Neither mutation has previously been found in the MYBPC3 gene. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular models for this disorder.

Amino Acid Sequence↗
PubMed1998

PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy.

Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the laminin alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy.

Child↗
PubMed1998

Myosin heavy chain gene expression changes in the diaphragm of patients with chronic lung hyperinflation.

In striated muscle, chronic increases in workload result in changes in myosin phenotype. The aim of this study was to determine whether such changes occur in the diaphragm of patients with severe chronic obstructive pulmonary disease, a situation characterized by a chronic increase in respiratory load and lung volume. Diaphragm biopsies were obtained from 22 patients who underwent thoracic surgery. Myosin was characterized with electrophoresis in nondenaturing conditions, SDS-glycerol PAGE, and Western blotting with monoclonal antibodies specific for slow and fast myosin heavy chain (MHC) isoforms. Flow volume curves, total lung capacity, and functional residual capacity were measured before surgery in 20 patients. We found that the human diaphragm is composed of at least four myosin isoforms, one slow and three fast, resulting from the combination of three MHC species. Chronic overload was associated with an increase in the slow beta-MHC species at the expense of the fast species (beta-MHC, 78.2 +/- 4.6 and 50.0 +/- 6.5% in emphysematous and control patients, respectively; P < 0.005). Linear correlations were found between beta-MHC percentage and forced expiratory volume in 1 s (r = -0.52; P < 0.02), total lung capacity (r = 0.44; P < 0.05), and functional residual capacity (r = 0.65; P < 0.003). The human adult diaphragm is composed of a balanced proportion of slow and fast myosin isoforms. In patients with chronic obstructive pulmonary disease, the proportion of fast myosins decreases, whereas that of slow myosin increases. This increase appears to be closely related to lung hyperinflation and may reflect an adaptation of the diaphragm to the new functional requirements.

Adult↗
PubMed1998

Assessment of motor function after stereotactic pallidotomy.

Despite a paucity of controlled data, stereotactic pallidotomy is increasingly used for the treatment of advanced Parkinson's disease (PD). To study the efficacy of the procedure on the cardinal PD features of rigidity, tremor, bradykinesia, and postural instability, we blindly rated randomized videos of 34 patients recorded in the "off' state immediately before and 3 months after unilateral stereotactic lesioning of the globus pallidus internus. Total "off' time Unified Parkinson's Disease Rating Scale motor scores improved 13.6% from 28.9 +/- 7.5 to 25.0 +/- 7.0 (p < 0.001). Particularly robust improvement was seen in contralateral tremor, gait, and arising from a chair (p < 0.001). Significant improvement was also seen in ipsilateral tremor, contralateral and some ipsilateral dexterity measures, and body bradykinesia. Most other features tended toward improvement but did not reach statistical significance. We conclude that pallidotomy is a safe and effective treatment of parkinsonian symptoms, many of which improve bilaterally.

Adult↗
PubMed1998

Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor.

OBJECTIVE: To determine the efficacy and tolerability of unilateral thalamic deep brain stimulation (DBS) for patients with medically refractory essential tremor (ET) and the tremor associated with Parkinson's disease (PD). BACKGROUND: The tremor of ET and PD may produce functional disability despite optimal medical therapy. Several reports have demonstrated efficacy of thalamic DBS in this scenario. METHODS: Preoperative and 3-month postoperative tremor ratings were compared in 33 patients (14 ET and 19 PD) with severe tremor. Evaluations included Unified Parkinson's Disease Rating Scale (UPDRS) scores for PD patients and a modified Unified Tremor Rating Scale in ET patients. Open-label and blinded data (unknown activation status) were obtained. RESULTS: ET patients demonstrated an 83% reduction (p < 0.0001) in observed contralateral arm tremor. All measures of tremor including writing samples, pouring tests, subjective functional surveys, and disability scores improved significantly. PD patients demonstrated an 82% reduction (p < 0.0001) in contralateral tremor and significant improvement in disability and global impressions. There was, however, no meaningful improvement in other motor aspects of the disease, and the total UPDRS part II (activities of daily living) score did not change. Adverse events, more common in ET patients, were generally mild and were usually eliminated by adjustment of the device parameters. CONCLUSIONS: Thalamic DBS is a safe and effective treatment of ET and the tremor of PD. In PD, its use should be limited to patients in whom high-amplitude tremor results directly in significant functional disability.

Aged↗
PubMed1998

Small bowel obstruction as a complication of laparoscopic extraperitoneal inguinal hernia repair.

Laparoscopic hernia repair is associated with its own set of complications, such as intra-abdominal organ and vascular injury, gas embolism, penumoperitoneum, small bowel obstruction secondary to trocar site fascial defects, intra-abdominal adhesion, and reaction to synthetic mesh. With the extraperitoneal approach, the abdominal cavity is not violated, thereby eliminating the risks for these complications. However, small bowel obstruction, albeit rarely, do occur with this approach because of inadvertent violation of the peritoneal cavity, or failure to close the peritoneal opening of the hernia sac, as shown in this case presentation.

Adult↗
PubMed1997

KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.

BACKGROUND: KVLQT1, the gene encoding the alpha-subunit of a cardiac potassium channel, is the most common cause of the dominant form of long-QT syndrome (LQT1-type), the Romano-Ward syndrome (RWS). The overall phenotype of RWS is characterized by a prolonged QT interval on the ECG and cardiac ventricular arrhythmias leading to recurrent syncopes and sudden death. However, there is considerable variability in the clinical presentation, and potential severity is often difficult to evaluate. To analyze the relationship between phenotypes and underlying defects in KVLQT1, we investigated mutations in this gene in 20 RWS families originating from France. METHODS AND RESULTS: By PCR-SSCP analysis, 16 missense mutations were identified in KVLQT1, 11 of them being novel. Fifteen mutations, localized in the transmembrane domains S2-S3, S4-S5, P, and S6, were associated with a high percentage of symptomatic carriers (55 of 95, or 58%) and sudden deaths (23 of 95, or 24%). In contrast, a missense mutation, Arg555Cys, identified in the C-terminal domain in 3 families, was associated with a significantly less pronounced QT prolongation (459+/-33 ms, n=41, versus 480+/-32 ms, n=70, P=.0012), and significantly lower percentages of symptomatic carriers (7 of 44, or 16%, P<.001) and sudden deaths (2 of 44, or 5%, P<.01). Most of the cardiac events occurring in these 3 families were triggered by drugs known to affect ventricular repolarization. CONCLUSIONS: Our data show a wide KVLQT1 allelic heterogeneity among 20 families in which KVLQT1 causes RWS. We describe the first missense mutation in the C-terminal domain of KVLQT1, which is clearly associated with a fruste phenotype, which could be a favoring factor of acquired LQT syndrome.

Adult↗
PubMed1997

Convergent evolution of apolipoprotein(a) in primates and hedgehog.

Apolipoprotein(a) [apo(a)] is the distinguishing protein component of lipoprotein(a), a major inherited risk factor for atherosclerosis. Human apo(a) is homologous to plasminogen. It contains from 15 to 50 repeated domains closely related to plasminogen kringle four, plus single kringle five-like and inactive protease-like domains. This expressed gene is confined to a subset of primates. Although most mammals lack apo(a), hedgehogs produce an apo(a)-like protein composed of highly repeated copies of a plasminogen kringle three-like domain, with complete absence of protease domain sequences. Both human and hedgehog apo(a)-like proteins form covalently linked lipoprotein particles that can bind to fibrin and other substrates shared with plasminogen. DNA sequence comparisons and phylogenetic analysis indicate that the human type of apo(a) evolved from a duplicated plasminogen gene during recent primate evolution. In contrast, the kringle three-based type of apo(a) evolved from an independent duplication of the plasminogen gene approximately 80 million years ago. In a type of convergent evolution, the plasminogen gene has been independently remodeled twice during mammalian evolution to produce similar forms of apo(a) in two widely divergent groups of species.

Animals↗