Search

OBJECTIVE: To determine the pattern of referral of Dutch patients with a long-QT syndrome (LQTS) on the basis of the postal codes of the LQTS probands from whom blood samples were submitted for DNA diagnostics. DESIGN:. Retrospective cohort study. METHOD: From the databases that are coupled to DNA diagnostics, all index patients were included for whom LQTS diagnostics had been requested during the period 1996-2005 at two clinical genetics centres (the University Medical Centre in Amsterdam and Maastricht University Hospital). The results were related to the postal code of the referred patient and corrected for the number of inhabitants of the region concerned. RESULTS: A total of 421 potential LQTS probands were included. Corrected for the numbers of inhabitants in the various postal codes, the number of referrals varied from 3 per million to 110 per million inhabitants. In view of the most recent estimated prevalence of LQTS (1:2000), this means that only 15% ofthe carriers of the LQTS mutation have so far been detected. CONCLUSION: There were large regional differences in the Netherlands in the requests for DNA diagnostics in patients with clinical LQTS. The overwhelming majority of the LQTS patients in the Netherlands have not yet been referred or identified. Expanding the available courses for general practitioners and cardiologists that are given by the staff of the cardiogenetic centres would seem to be indicated

We recently identified a novel mutation of SCN5A (1795insD) in a large family with features of both long QT syndrome type 3 and the Brugada syndrome. The purpose of this study was to detail the clinical features and efficacy of pacemaker therapy in preventing sudden death in this family. The study group consisted of 116 adult family members: 60 carriers (29 males) and 56 noncarriers (28 males) of the mutant gene. Investigations included 24-hour Holter monitoring, ergometry, and electrophysiologic studies. Mean, lowest, and highest heart rate were lower in the carriers, but heart rate variability was comparable. In carriers, disproportional QT prolongation was present during bradycardia. No complex ventricular ectopy was recorded, and there were fewer isolated premature beats (both ventricular and atrial) in carriers. All patients were asymptomatic, except for two individuals who experienced syncope; in one of these patients, asystolic episodes (up to 9 sec) were repeatedly recorded. Prolonged HV intervals were present in 5 of 6 patients. Thirty carriers received a prophylactic backup pacemaker. During median follow-up of 4.5 years (range 0.0 to 22.6), their survival rate was 100%. There were five sudden deaths among the remaining 30 carriers without a pacemaker (P = 0.019). This family with a high incidence of nocturnal sudden death is characterized by bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, and generalized conduction abnormalities. There is a striking absence of complex ventricular ectopy, and pacemaker implantation was effective in preventing sudden death. These findings raise the possibility of a bradycardic rather than tachycardic mode of death

DNA diagnostics were carried out in a family after the long QT interval syndrome had been diagnosed in one of its members. The psychic reactions to this testing were different from those seen in other hereditary diseases such as Huntington's disease. This was probably due to the sudden and unexpected occurrence of the arrhythmia. The family members in whom clinical and DNA diagnostics gave purely negative findings were not relieved, owing to solidarity with the affected relatives. Their partners did not understand this response. The anxiety and concern of the gene carriers had nothing to do with their own health status but with that of their carrier children. These parents were in need of educational counselling and advice. The results of clinical and DNA diagnostics affected the family relationships: in carriers the feeling of closeness grew, while the non-carriers were afraid of loss of family closeness

The long QT syndrome is characterised by QT prolongation on the ECG, repeated syncope and sudden cardiac death. QT prolongation is the result of delayed repolarisation at the cellular level, secondary to dysfunctioning ion channels. Ventricular arrhythmias underlie syncope and death. At least six genes, all encoding (parts of) ion channels, are causally involved. A molecular diagnosis is often feasible and can be reached reasonably straightforwardly, based on the clinical (family) history and the ECG pattern

Sudden cardiac death without ischaemic heart disease may be due to a hereditary heart disease with an autosomal dominant heredity. The occurrence, if any, of sudden death in such a family is a main indicator for the risk of sudden cardiac death in other family members. Cardiological and/or genetic investigation may reveal a hereditary disease in relatives without symptoms. Of some of these pathological conditions, the corresponding chromosomal localizations and sometimes the gene mutations have been identified. The psychic burden of family investigation and the socio-economic consequences (insurances, occupation, family relationships) are potentially heavy. Prophylactic treatment of asymptomatic persons in whom a gene mutation is established may comprise advice about lifestyle (e.g. avoidance of peak exercise in patients with hypertrophic cardiomyopathy), medication (e.g. beta-receptor blockers in patients with a long QT interval) or implantation of a pacemaker or internal defibrillator (e.g. in asymptomatic persons with the Brugada syndrome, a form of right bundle branch block). Presymptomatic investigation must be performed multidisciplinary

Mutations in SCN5A, the gene encoding the cardiac Na(+) channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT(3)) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the "Brugada ECG" occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, n=43; noncarriers, n=36). In affected individuals, PR and QRS durations and QT intervals are prolonged (P

Three people applied for genetic counselling, but during the consultations the clinical geneticist discovered other problems for which advice could have been given but was not asked. This caused a serious dilemma. The first person was a woman who wanted to know the risks of epilepsy for her potential offspring, but then it became clear that she appeared to have Huntington's disease in the family. The second person was a man who wanted to know about the genetic risks for his offspring of a borderline psychiatric disorder, but the geneticist, seeing that the partner had severe limb defects, wondered whether these were caused by a genetic disorder. The third patient was a pregnant woman who came asking about the risks caused by mental retardation in one of her ancestors, but who appeared to be a heavy drinker and user of cocaine and ecstasy. In dealing with such 'secondary' problems, it should be kept in mind that persons seeking advice must decide for themselves whether or not they want to be informed regarding these problems or not

We report on a boy with mild dysmorphic features and developmental delay, in whom karyotyping showed an additional minute ring chromosome in 60% of metaphases. Fluorescence in situ hybridization (FISH) with a centromere specific probe demonstrated that the ring chromosome contained the centromeric region of chromosome 20. The ring was highlighted completely using a chromosome 20 painting probe. A cosmid probe for 20p 12-13 gave a positive signal and hybridization with an all-telomere probe showed on signal, suggesting a breakpoint in the 20p telomere. The results suggested that only a small part of 20q was involved in this ring. The ring was also detected in 18% of nuclei of a buccal smear. The phenotypic similarities of symptoms in the proband to patients with a (partial) trisomy 20p and the dissimilarities to symptoms in patients with (partial) trisomy 20q were in agreement with the FISH results