Sodium channel blocker tests allow a clear distinction of electrophysiological characteristics and prognosis in patients with a type 2 or 3 Brugada electrocardiogram pattern.

BACKGROUND: Patients with a type 2 or 3 Brugada syndrome (BS) pattern and a negative sodium channel blocker challenge (SCBC) are not considered as affected. Their arrhythmic prognosis is generally considered good, but it has never been specifically evaluated. OBJECTIVE: The purpose of this study was to evaluate the arrhythmic prognosis in patients with a type 2 or 3 electrocardiogram (ECG) not converted to type 1 ECG during an SCBC. METHODS: Clinical data, 12-lead ECG, results of the SCBC and electrophysiological study (EPS), and follow-up were collected. RESULTS: Among the 500 patients who underwent an SCBC in our institution, 158 displayed a type 2 or 3 ECG. After the SCBC, 93 (59%) had a type 1 ECG (positive group [PG]), whereas 65 (41%) remained negative (negative group [NG]). An EPS was performed in 31 (33%) PG patients and 15 (23%) NG patients. Ventricular fibrillation was induced in 21 PG patients (67%), whereas no patient in the NG was inducible (P <.001). During a follow-up of 37 +/- 17 months, no sudden death occurred. Three syncopes were observed in the NG versus one syncope, two ventricular tachycardias, and one appropriate shock in the PG. CONCLUSION: This study demonstrates that the presence or absence of coved type ST-segment elevation during the SCBC denotes a profound electrophysiological difference as demonstrated by the absence of inducibility during EPS in the NG that may be responsible for the good prognosis of patients with a type 2 or 3 ECG pattern not converted to type 1.

[Genetic aspects of valvulopathies]. / Aspects Génétiques des Valvulopathies.

Valvular dystrophies due to myxoid degeneration are common and potentially serious cardiac pathologies. They constitute a heterogeneous group of which the most usual is idiopathic mitral valvular prolapse (Barlow's disease). The majority of mitral valvular prolapses are sporadic, but there are several familial forms. Transmission is usually autosomal dominant with incomplete penetrance and variable expression. The first chromosomal location to be identified was on the 16p11-13 chromosome. Since then, two other loci have been identified on the 11p15.4 and 13q31-32 chromosomes. Our team has recently identified the first gene responsible for myxoid valvulopathy linked to the X chromosome, from a large family of 318 members. This is the gene that codes for filamin A, which is a cytoskeleton protein. The frequency of mutations in this gene is still unknown, but out of 7 families in which transmission was compatible with X-linked transmission, mutations were discovered in 4 of the families. Thanks to a genetic epidemiological approach, we have also demonstrated that there are familial forms of aortic stenosis, which are probably common. Identification of the genes implicated in these common forms of valvular pathology is important, as it will allow a better understanding of the pathophysiology of these valvular disorders and could lead to better therapeutic management in the future.

[Genetics and cardiac arrhythmias]. / Génétique des troubles du rythme cardiaque.

The identification of the first gene locus of hereditary arrhythmias was made over 10 years ago. In the last few years, considerable progress has been made and the number of culprit genes for cardiac arrhythmias has rapidly increased. This has been the fruit of close collaboration between clinicians, geneticists and physiologists. This work has demonstrated the heterogenous nature of genetics of diseases. It has led to a better understanding of underlying physiopathological mechanisms by the study of the relationship between gene and clinical abnormalities. In addition, analysis of phenotypes and genotypes has improved our knowledge of the clinical presentation of diseases and opened up new therapeutic approaches. These new diagnostic methods have enabled preventive measures to be taken to avoid potentially serious arrhythmias. The genetics of cardiac arrhythmias is still in its infancy: many culprit genes remain undetected and their identification should led to considerable progress in the understanding of the physiopathology of arrhythmias and their treatment.

[Genetic aspects of cardiac conduction defects]. / Aspect génétique des troubles de la conduction cardiaque.

Degenerative conduction defects are usually considered to be exaggerated ageing affecting the conduction pathways. For several years familial forms have been described, and a first locus on chromosome 19 and then a first gene, SCN5A on chromosome 3 (coding for the sodium channel alpha subunit), have been identified. Mutations of this gene can lead not only to congenital conduction defects but also to progressive forms of conduction defects similar to Lenègre disease. A third locus on chromosome 16 at 16q23-24 has been identified, as have other families not linked to the loci described previously. Although it now seems clear that conduction defects can have a genetic component, the frequency of the familial forms remains to be determined. Important progress could be made in the understanding of this disease if other implicated genes were identified. It would then become possible to elucidate the different pathophysiological mechanisms responsible for conduction defects.

Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.

BACKGROUND: The SCN5A gene encoding the human cardiac sodium channel alpha subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). METHODS AND RESULTS: In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein trafficking. CONCLUSIONS: We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.

Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype.

AIMS: In families with the long QT syndrome penetrance may be low: up to 70% of gene carriers may have a normal QTc interval. These patients require therapy, similar to that in those with longer QTc intervals, but identifying them, using molecular analysis, is difficult to apply on a large scale. A large French family affected by the long QT1 syndrome was followed-up over a 25-year period. In adult males but not in females, the QTc interval normalized after puberty. We aimed to find clinical criteria, based on ambulatory ECG recordings so that we could improve diagnosis in affected members with a normal QTc. METHODS AND RESULTS: Linkage analysis and direct sequencing were an indicator of the long QT1 gene in our family. Reverse transcription-polymerase chain reaction analysis demonstrated abnormal transcripts in lymphocytes from silent gene carriers. The functional profile of mutated protein isoforms was investigated using the patch-clamp technique. Dynamic analysis of ventricular depolarization was conducted using Holter recordings in patients, and in sex- and age-matched controls. Circadian variations of the QTc interval and the QT/RR relationship were assessed. Sensitivity, specificity, and predictive values were evaluated for proposed clinical criteria. We found that dynamic analysis of the QT interval permitted individual diagnosis in mutation carriers even when the QTc interval was normal (adult males). CONCLUSION: Dynamic analysis of the QT interval is of diagnostic value in the long QT1 syndrome in patients with a normal phenotype. Clinical implications include improvement in screening and patient management.

Clinical characteristics of a familial inherited myxomatous valvular dystrophy mapped to Xq28.

OBJECTIVES: The purpose of this study was to describe the phenotypic characteristics of an inherited myxomatous valvular dystrophy mapped to Xq28. BACKGROUND: Myxomatous valve dystrophies are a frequent cause of valvular diseases, the most common being idiopathic mitral valve prolapse. They form a group of heterogeneous diseases difficult to subclassify. The first mapping of the gene for a myxoid valvular dystrophy to Xq28 allowed investigation of the phenotype of affected members in a large family and characterization of the disease. METHODS: Among the 318 members in the pedigree, 89 agreed to participate in this study. Phenotypic characteristics were investigated using clinical examination, transthoracic echocardiography and biological analysis (F.VIII activity). Genetic status was based on haplotype analysis. RESULTS: Among 46 males, 9 were hemizygous to the mutant allele and had an obvious mitral and/or aortic myxomatous valve defect, and 4 had undergone valvular surgery. All had typical mitral valve prolapse associated in six cases with moderate to severe aortic regurgitation. The valve defect cosegregated with mild hemophilia A (F.VIII activity = 0.32 +/- 0.05). The 37 remaining males had normal valves and normal F.VIII activity. Heterozygous women were identified on the basis of their haplotypes. Among the 17 women heterozygous to the mutant allele, moderate mitral regurgitation was present in 8, associated with mild mitral valve prolapse in 1 and aortic regurgitation in 3, whereas 2 women had isolated mild aortic regurgitant murmur. In heterozygotes, the penetrance value was 0.60 but increased with age. CONCLUSION: X-linked myxomatous valvular disease is characterized by mitral valve dystrophy frequently associated with degeneration of the aortic valves affecting males and, to a lower severity, females. The first localization of a gene for myxomatous valvular diseases is the first step for the subclassification of these diseases.

Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias.

The long QT syndrome is characterized by prolonged cardiac repolarization and a high risk of sudden death. Mutations in the KCNQ1 gene, which encodes the cardiac KvLQT1 potassium ion (K+) channel, cause both the autosomal dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome. JLN presents with cardiac arrhythmias and congenital deafness, and heterozygous carriers of JLN mutations exhibit a very mild cardiac phenotype. Despite the phenotypic differences between heterozygotes with RW and those with JLN mutations, both classes of variant protein fail to produce K+ currents in cultured cells. We have shown that an N-terminus-truncated KvLQT1 isoform endogenously expressed in the human heart exerts strong dominant-negative effects on the full-length KvLQT1 protein. Because RW and JLN mutations concern both truncated and full-length KvLQT1 isoforms, we investigated whether RW or JLN mutations would have different impacts on the dominant-negative properties of the truncated KvLQT1 splice variant. In a mammalian expression system, we found that JLN, but not RW, mutations suppress the dominant-negative effects of the truncated KvLQT1. Thus, in JLN heterozygous carriers, the full-length KvLQT1 protein encoded by the unaffected allele should not be subject to the negative influence of the mutated truncated isoform, leaving some cardiac K+ current available for repolarization. This is the first report of a genetic disease in which the impact of a mutation on a dominant-negative isoform correlates with the phenotype.

Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28.

Myxoid heart disease is frequently encountered in the general population. It corresponds to an etiologically heterogeneous group of diseases, idiopathic mitral valve prolapse (IMVP) being the most common form. A rarely observed form of myxoid heart disease, X-linked myxomatous valvular dystrophy (XMVD), is inherited in an X-linked fashion and is characterized by multivalvular myxomatous degeneration; however, the histopathological features of the mitral valve do not differ significantly from the severe form of IMVP. In this article, we describe the genetic analysis of a large family in which XMVD is associated with a mild hemophilia A. The coagulation factor VIII gene position in Xq28 provided a starting point for the genetic study, which was conducted by use of polymorphic markers. Two-point linkage analysis confirmed this localization, and a maximum LOD score of 6.57 was found at straight theta=0 for two polymorphic microsatellite markers, INT-3 and DXS1008, the first one being intronic to the factor VIII gene. Haplotype analysis of this chromosomal region allowed the definition of an 8-cM minimal interval containing the gene for XMVD, between DXS8011 and Xqter.