In the present study, we demonstrated that subjects with SBMA exhibit several forms of ECG abnormalities. The most striking observation in our cohort is that Brugada-type ECG was observed in more than 10% of the subjects with SBMA. Of those, 2 subjects reported symptomatic Brugada syndrome, leading to sudden death. Although sudden death by neuronal loss in the intermediolateral nucleus was reported in amyotrophic lateral sclerosis,24 there are no reports of Brugada syndrome, suggesting that this type of ECG appears to be specific to SBMA.
Brugada syndrome may cause sudden death by ventricular fibrillation at an average age of 41 years, without structural heart problems.14,25 This syndrome may be responsible for 4% to 12% of all sudden deaths, and at least 20% of sudden deaths in patients with structurally normal hearts. Brugada-type ECG is observed frequently in asymptomatic patients.26 Given that the frequency of Brugada-type ECG is reported to be 0.15% to 1.22% in Japanese community-based populations,27,28 our study suggests a very high prevalence of Brugada-type ECGs in SBMA and implies a link between the pathogenesis of the disorders, although we cannot fully exclude the possibility of a chance association of these 2 conditions. In this regard, it is intriguing that SBMA and Brugada syndrome share common clinical features. Both diseases are characterized by male predominance. SBMA affects males exclusively, whereas females with homozygous mutation of the AR gene manifest no neuromuscular phenotype.29 Similarly, Brugada syndrome is known to show a high male predominance (80%–90%).14 The pathologic process of SBMA is dependent on circulating levels of testosterone,5,30–32 and high testosterone levels increase the risk of Brugada syndrome via intensifying ionic current imbalance in the myocardium.33 These commonalities may underlie the high prevalence of Brugada-type ECGs in SBMA. Although another epidemiologic study in 25 European patients with SBMA showed no ECG abnormalities,34 the discrepancy between this and our studies may be attributable to the difference in the sample size and ethnic background. Brugada syndrome is more common in Asian than Caucasian populations,14,25,35 which may contribute to the high occurrence of Brugada-type ECGs in Japanese subjects with SBMA in the present study.
Typical Brugada-type ST elevation (J point elevation) results from an ion current imbalance across cardiac cell membrane, which is induced by the malfunction of cardiac ion channels governing the action potential. Mutations in genes encoding these ion channels or their modulating proteins have been shown to be causative of Brugada syndrome. Among them, mutations in SCN5A, which encodes the [alpha] subunit of cardiac sodium channel, have been reported in 10% to 30% of patients with Brugada syndrome.14 Although much less frequent, several other causative genes have also been identified, including the L-type calcium channel (CACNA1C and CACNB2), glycerol-3-phosphate dehydrogenase 1-like channel, and potassium channels. Recently, a genome-wide association analysis also identified susceptibility loci at SCN5A, SCN10A, and the HEY2 genes for Brugada syndrome.36 Although none of our subjects with Brugada-type ECG had mutations in SCN5A, CACNA1C, or CACNB2, histopathologic and biochemical analyses indicated downregulation of SCN5A gene expression in the myocardium of subjects with SBMA. Given that the mutations in the SCN5A gene are shown to culminate in functional loss of the sodium channels,37 decreased expression of this gene in the myocardium may be associated with the pathogenesis of myocardial involvement in SBMA. Nonneuronal cells, such as hepatocytes and epithelial cells of scrotal skin, show the accumulation of the pathogenic AR, which, at least partially, corresponds to clinical symptoms and findings of SBMA.8 Nuclear accumulation of the pathogenic AR induces transcriptional dysregulation, leading to altered expression of several genes in skeletal muscles, as well as the spinal cord.38,39 Taken together, gene expression abnormalities due to the nuclear accumulation of pathogenic AR may result in myocardial dysfunction in SBMA.
In the present study, we detected no differences in clinical and genetic features between SBMA subjects with and without Brugada-type ECG, but severe hyponatremia in the subject with symptomatic Brugada syndrome (case 2) suggests that patients with SBMA have the potential risk of Brugada syndrome at basal conditions and that certain triggers (such as hyponatremia) may enhance the electrophysiologic deficits in the myocardium and manifest Brugada-type ECGs or fatal ventricular arrhythmias. This hypothesis is consistent with the observation that Brugada ECG patterns may be modulated by numerous factors, including the autonomic nervous system, altered levels of electrolytes, heavy meals, and high body temperature.26 In particular, hypokalemia in conjunction with hyponatremia is reported to precipitate Brugada syndrome, as shown in the present study.40
Although respiratory tract infections due to bulbar palsy are common at advanced stages of SBMA, the cause of death is not determined in a certain population.21 Our results indicate that sudden death due to fatal arrhythmias associated with Brugada syndrome may occur in patients with SBMA. Because subjects with Brugada type 1 ECG are often symptomatic and at a high risk of sudden death, it is important to examine ECGs in patients with SBMA and to carefully manage subjects with Brugada-type ECG abnormalities.
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Neurology. 2014 May 20;82(20):1813-21
Abstracts can be found at
Here is the abstract:
OBJECTIVE: The aim of this study was to clarify myocardial involvement and its clinical implications in subjects with spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease affecting both neuronal and nonneuronal tissues.
Two independent cardiologists evaluated ECGs from a total of 144 consecutive subjects with SBMA. We performed immunohistochemical, immunoblot, and quantitative real-time PCR analyses of autopsied myocardium.
Abnormal ECGs were detected in 70 (48.6%) of 144 subjects. The most frequent findings were ST-segment abnormalities in V1-3 (19.4%), followed by ST-segment abnormalities in V5-6 (18.1%). We detected Brugada-type ECGs in 17 of 28 subjects with ST-segment abnormalities in V1-3. Of those, one subject presented with syncope that required an implantable cardioverter defibrillator and led to eventual sudden death, and another subject also died suddenly. No subjects with Brugada-type ECGs had mutations in SCN5A, CACNA1C, or CACNB2 genes. In autopsied cases, we detected nuclear accumulation of the mutant androgen receptor protein and decreased expression levels of SCN5A in the myocardium.
Subjects with SBMA often show Brugada-type ECG. The accumulation of the pathogenic androgen receptor may have a role in the myocardial involvement in SBMA.
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