controls. SBMA patients may have higher frequency of Brugada syndrome and other electrocardiogram (ECG) abnormalities, which if not detected, can lead to sudden death. There are no reports of cardiomyopathy. However, there are indications that SBMA patients may be more likely to have high blood pressure and elevated total cholesterol and triglycerides. Natural history Progression of muscle weakness is slow, with an approximately 2% decrease in muscle strength by quantitative muscle testing (QMT) per year. The most extensive dataset on disease progression is a study of 223 Japanese patients where milestones in nine activities of daily living (ADL) was observed for up to 20 years. Muscle weakness was first noticed in the lower extremities (71%), upper extremities in (31%), bulbar symptoms (11%), and facial weakness (2%), with some patients observing initial muscle weakness simultaneously in two locations. Hand tremor was noticed first (median age: 33 years), followed by muscular weakness (median = 44 years), need for handrail to ascend stairs (49 years), dysarthria (50 years), dysphagia (54 years), use of a cane (59 years), and wheelchair use (61 years). Twenty-one patients developed pneumonia (median age: 62 years) and 15 of them died (median = 65 years). The most common cause of death in these cases was pneumonia and respiratory failure. There was considerable variation in the age of onset for each milestone, often varying by 25 to 30 years between the 10th to 90th percentile ranges. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that the rate of disease progression does not correlate with CAG-repeat length. The average time interval between muscle weakness and handrail use was 5–6 years, between weakness and cane use was 9–11 years, between weakness and wheelchair use was 12–13 years, and between weakness and death was 10–20 years. Mechanism Molecular mechanism SBMA is caused by a trinucleotide repeat expansion in the first exon of the androgen receptor (AR) gene. The AR gene, located in the X chromosome, contains a CAG repeat that encodes a polyglutamine tract in the androgen receptor protein. The tract normally varies from about 11 to 33 repeats; however, in SBMA patients, the tract contains 38 to 68 CAG repeats. The expanded series of CAG repeats in SBMA results in production of a toxic