Brugada Syndrome and it's Possible Role in Sudden Infant Death Syndrome
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Idiopathic ventricular fibrillation occurs in up to 10% of individuals surviving episodes of ventricular fibrillation [1-2]. It is suggested that Brugada syndrome may account for up to 40-60% of cases previously categorized as idiopathic.3 The diagnostic criteria for Brugada syndrome vary considerably [3-5]. The most commonly cited clinical findings include an abnormal electrocardiogram (ECG) and possibly also a history of syncope or cardiac arrest and a family history of sudden death [3-5]. However, these may be absent. The ECG is usually the key to the diagnosis. Here the right precordial lead (V1to V3) patterns similar to right-bundle-branch block with an accompanying variable ST-segment elevation and a saddle-type appearance. Occasionally, left-axis deviation is observed [3]. Similar patterns have been reported in arrhythmogenic right-ventricular cardiomyopathy complicating the diagnosis [5] and the ECG patterns can also be confused with those of anteroseptal myocardial infarction. The principal pathology of Brugada syndrome involves a cardiac sodium channel. Therefore, the ECG changes may not be apparent unless an agent that inhibits the cardiac sodium channel, such as flecainide, procainamide, or ajmaline, is administered [3]. There have only been about 200 reported cases of Brugada syndrome in the medical literature, with 90% of these cases occurring in male patients. The reported age at which the first arrhythmic event occurs ranges between 22 and 65 years [3,4,7]. The syndrome seems to be most prevalent in Japan and Southeast Asia [8-9]. Symptoms occur mostly at night [3,9,10]. Folklore originating from these countries contains stories of young men with Lai Tai (Thailand), Bangungut (Philippines), or Pokkuri (Japan), thrashing, screaming, and then dying suddenly in their beds [9]. It is suggested that this syndrome may be the leading cause of natural death among young men in the poverty-stricken northeast of Thailand. The annual mortality rate for this group is as high as 26-38 per 100000 [9]. Brugada syndrome is a diagnosis made mainly by exclusion [3]. Most symptomatic Brugada patients have polymorphic ventricular tachycardia or ventricular fibrillation, which is inducible during an electrophysiological study [4]. Current philosophy suggests that the prognosis is good if the patients are protected from recurring arrhythmias. However, clinical investigations are showing that drug prophylaxis is generally disappointing [4]. Because of this, implantable defibrillators are recommended [3,7,9]. Important questions arise regarding patients who may have an ECG suggestive of Brugada syndrome that is identified by family screening, but no history of symptoms. Of 22 such patients reported in a large prospective study, 27% had ventricular fibrillation during follow-up [4]. Does this finding suggest that these patients should be candidates for prophylactic implantable defibrillators? The identification of those who might benefit from an invasive prophylactic treatment is not possible using current methods of risk stratification [4]. Given this, a future role for molecular screening of some families with the Brugada phenotype may be helpful. It has recently been found that a distinct mutations in the gene (SCN5A) that encodes the pore-forming subunit of the cardiac sodium channel [12]. Theses mutations are associated with dysfunction the of sodium channel. It is also thought that other mutations may exist involving ion channels in the heart, which may produce similar phenotypes and are likely to be implicated in other families. Identifying these mutations may be an aid in risk stratification and medical decision-making regarding which patients should receive implantable defibrillators. Of particular interest is the possible connection between Brugada syndrome and sudden cardiac death in athletes and as a possible cause of Sudden Infant Death Syndrome (SIDS). There is little evidence to support the role of Brugada syndrome in sudden cardiac death in the pediatric population. However, it is suggested that Brugada syndrome may cause sudden death in children even in the first months of life where it may be misdiagnosed as SIDS. A paper by Priori et al provides evidence for the argument that Brugada syndrome may be a possible cause of SIDS [13]. In this paper, the authors describe a case of a 14-month old child taken to the emergency department after losing consciousness. An ECG revealed ventricular fibrillation. During monitoring in the intensive care unit ECG changes transiently showed ST-segment elevation in precordial leads and a diagnosis of Brugada Syndrome was suspected. Review of the family history showed that two sisters of the child died suddenly at early ages, with one dying at 2-months, which were diagnosed as SIDS, and the second at 3 years of age. Similarly, the 3-year-old girl arrived at the emergency department in ventricular fibrillation. Subsequent cardiac evaluation did not show the presence of any structural heart disease and the ECG was normal. The patient remained in post anoxic coma for 7 months before dying from a lethal arrhythmia. Also of interest, cardiac arrest and sudden death occurred in two of the child's brothers aged 12-months and 12-months old. Both parents of children had unremarkable personal clinical history, normal echocardiogram, ECG, and Holter recording. Family history of the mother showed that one of her brothers died unexpectedly at age 14 months and her half-sister had a child who died suddenly at age 12 months after repeated unexplained episodes of cyanosis. Given the clinical history of the child and the significant family history, Brugada syndrome was suspected as the cause of sudden death in the family. After reaching this conclusion, the family was provided genetic counseling, and informed consent to do genetic analysis in the family was obtained. DNA extracted from peripheral blood of living family members was screened for mutations in the cardiac sodium-channel gene. A single based-pair substitution was identified leading to an amino acid change located in the intracellular segment linking domain I to domain II of the sodium channel protein. The researchers showed that the mutation was present in both parents, and also in one asymptomatic sibling. The mutation was not identified in any of the 500 age matched controls. They concluded that familial sudden death in this family was caused by a variant of Brugada syndrome with severe manifestation in early childhood. They also report incomplete penetrance, where a parent with a normal ECG may still carry and transmit the mutation, which has been reported in Brugada syndrome and can be seen in this family, where three gene carriers were completely asymptomatic with normal ECG's [14]. Given this, Brugada syndrome should be considered as a cause of unexplained sudden cardiac death in children.
