DISCOVERY: a study examining the prevalence of transthyretin mutations in subjects suspected of having cardiac amyloidosis
Orphanet Journal of Rare Diseases volume 10, Article number: O8 (2015)
Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of either immunoglobulin light-chain (AL) or transthyretin (ATTR) fibrils. Two forms of ATTR CA cause life-threatening cardiomyopathy: an inherited form arising from misfolding of mutated ATTR (familial amyloid cardiomyopathy [FAC]) and a sporadic form caused by wild-type ATTR (senile systemic amyloidosis [SSA]). More than half of over 100 reported ATTR mutations are associated with FAC. The most common mutation in the US is Val122Ile found in 3-4% of African Americans (AA). FAC can be difficult to recognize clinically and is likely under diagnosed. The DISCOVERY study aims to determine the prevalence of TTR mutations and FAC diagnosis in a cohort of patients (pts) with clinical features suggestive of CA.
This is a prospective, multi-center study in adults with two or more of the following eligibility criteria: heart failure signs and symptoms, intraventricular septal thickness (IVS) of >12 mm, LV diastolic dysfunction, low voltage ECG, or history of carpal tunnel disease (CTD). DNA from blood samples is used for sequencing of the TTR gene coding regions by a central lab. Assessments in pts with TTR mutations include cardiac biomarkers, echocardiogram and optional abdominal fat pat aspiration and 6-minute walk test. Descriptive statistics will be utilized.
As of May 2015, 146 pts have been enrolled. At baseline, the mean (Std) age of pts is 64 (13) yrs, 61% are men and 66% are AA. A total of 14 (10%) pts had a Val122Ile mutation and 1 pt had a novel mutation Arg103His. The Gly6Ser polymorphism was found in 8 (5%) pts. The Val122Ile cohort consisted of 40% males with a mean (StD) age of 66 (16). Heart failure signs and symptoms and IVS > 12 mm was reported in 71% and 79% of Val122IIle pts respectively. The majority of pts had NYHA class II (56%) and III (22%) heart failure, 21% had low voltage ECGs and 14% had CTD.
These preliminary data suggest that approximately 10% of pts with clinical and/or radiologic findings suggestive of cardiac amyloidosis have a pathogenic TTR mutation which could potentially lead to a diagnosis of FAC. Additional data on clinical features and tissue diagnosis of FAC in these pts will be presented.
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Akinboboye, O., Ananthasubramaniam, K., Malik, A. et al. DISCOVERY: a study examining the prevalence of transthyretin mutations in subjects suspected of having cardiac amyloidosis. Orphanet J Rare Dis 10 (Suppl 1), O8 (2015). https://doi.org/10.1186/1750-1172-10-S1-O8