Summary
Background
Brugada syndrome is a genetic heart disease with autosomal dominant inheritance. Family screening commonly detects one parent responsible for transmission of the disease.
Aims
To describe atypical transmission of Brugada syndrome.
Methods
Between 2001 and 2007, systematic screening, including an electrocardiogram, ajmaline challenge and DNA sequencing of the SCN5A gene, of the first-degree relatives of 62 probands with Brugada syndrome was performed (Programme Hospitalier de Recherche Clinique).
Results
In two families, both parents transmitted Brugada syndrome to their offspring. In the first family, the proband presented Brugada electrocardiogram features with ajmaline challenge and carried a new SCN5A mutation (p.V1281F). The mutation was also identified in the mother, who had a type 1 aspect on inferior leads with ajmaline. The proband’s father presented a typical Brugada electrocardiogram pattern on lead V2 with ajmaline and no SCN5A gene mutation. In the second family, the proband was a boy aged 2.5 years who had been resuscitated from sudden cardiac death. Ajmaline challenge revealed a typical Brugada electrocardiogram pattern in both parents but with no mutation in the genes studied.
Conclusion
Family studies should always be exhaustive and discovery of one parent with Brugada syndrome does not eliminate the need for screening of the other parent.
Résumé
Contexte
Le syndrome de Brugada est une maladie cardiaque génétique dont la transmission est autosomique dominante. L’enquête familiale détecte fréquemment un parent à l’origine de la transmission de la maladie.
Objectifs
Décrire un mode de transmission atypique dans le syndrome de Brugada
Méthodes
Entre 2001 et 2007, une enquête systématique comprenant un ECG, un test à l’ajmaline et un séquençage du gène SCN5A a été réalisée chez les apparentés au premier degré de 62 patients porteurs d’un syndrome de Brugada (Programme Hospitalier de Recherche Clinique).
Résultats
Dans deux familles, les deux parents sont apparus avoir transmis le syndrome de Brugada à leur descendance. Dans la première famille, le propositus avait un aspect ECG de Brugada lors du test à l’ajmaline et une mutation non décrite de SCN5A (p.V1281F). La mutation a été identifiée également chez la mère qui avait un aspect de type 1 dans les dérivations inférieures lors du test à l’ajmaline. Le père du propositus avait un aspect typique de Brugada en V2 lors du test à l’ajmaline mais pas de mutation de SCN5A . Dans la seconde famille, le propositus était un garçon de deux ans et demi, ressuscité d’une mort subite cardiaque. Le test à l’ajmaline a montré un aspect ECG typique de Brugada chez les deux parents mais sans mutation dans les gènes étudiés.
Conclusion
Les études familiales doivent être toujours exhaustives dans le syndrome de Brugada et la découverte d’un des deux parents atteint ne doit pas éliminer la nécessité d’explorer le second parent.
Background
Brugada syndrome (BS) is a genetic heart disease with autosomal dominant inheritance . In about 15–20% of cases the disease is related to a mutation in SCN5A , which encodes the alpha subunit of the sodium ion channel . Inheritance of the disease can be demonstrated in two-thirds of patients but penetrance and expressivity of the disease is highly variable, ranging from a lifelong asymptomatic course to sudden cardiac death in the first year of life.
We report two families presenting dual transmission of the BS phenotype.
Results
First family
A 19-year-old male of Caucasian origin was referred to our hospital for suspicion of BS following a routine electrocardiogram (ECG) that revealed a type 2 Brugada ECG in the right precordial leads ( Fig. 1 ). This was in the context of attempted suicide with ibuprofen. The patient had no history of arrhythmia and no familial history of sudden death; he had been previously treated for epilepsy. Echocardiography, hematology and biochemistry examinations yielded normal findings.
ECG with right precordial leads in the second intercostal spaces, high V1–V2 ( Fig. 1 , II 1 ), revealed ST-segment elevation in the high V2 lead (coved-type). Ajmaline injection (1 mg/kg administered over 10 minutes) induced coved ST-segment elevation in the right precordial leads (V1, V2, in the fourth intercostal space) and a J wave in the inferior leads. SCN5A gene analysis revealed a G to T mutation in position 3841 of the coding sequence (CCDS46799.1 nomenclature) leading to a valine to phenylalanine replacement in position 1281 of the protein (p.V1281F). A molecular modelling study was performed as previously described and revealed that the mutation introduced a loss of flexibility in the helix structure from residues 1272 to 1289 due to increased aliphatic properties. The proband was heterozygous for this mutation. Family screening revealed that the father (aged 43 years) had a history of epilepsy. A type 2 ECG pattern was observed at rest ( Fig. 1 , I 1 ). Ajmaline challenge revealed accentuation of ST-segment elevation in the V2 lead from 0.2 to 0.45 mV. Genetic analysis of the SCN5A gene in the father did not reveal any mutation in the full coding sequence or at the exon-intron boundaries. The coding and flanking intronic regions of other genes recently reported to be linked with BS, namely SCN1B , KCNE3 and SCN3B , were also sequenced and no mutation was observed in either the father or the son.
The mother (aged 41 years) had experienced two vasovagal episodes in the past. ECG at rest showed a type 2 Brugada pattern ( Fig. 1 , I 2 ). Ajmaline challenge did not reveal any change in precordial leads repolarization, but showed a coved-type aspect with an ST-segment elevation of 3.5 mV in the inferior leads. Genetic analysis also found the SCN5A p.V1281F mutation in the mother. The p.V1281F mutation was not found in a set of 162 control alleles.
Second family
A boy aged 2.5 years of North African origin ( Fig. 2 , II 3 ) was admitted following cardiac arrest related to ventricular fibrillation in the early morning; he had no previous history of arrhythmia and no family history of sudden death. Long QT syndrome (LQTS) was diagnosed first (QT 500 ms; QTc 569 ms) ( Fig. 3 ) and the patient was treated with nadolol 50 mg/m 2 . Successive ECGs showed type 1 Brugada pattern ( Fig. 4 ) with persistent long QTc (QTc 615 ms) on nadolol. Echocardiography, hematology and biochemistry examinations were normal. A defibrillator was implanted. The patient received two successful appropriate shocks from the defibrillator during the first year of follow-up ( Fig. 5 ).
