Abstract 16455: A Costly Mix-Up: Genotype-Phenotype Mismatch of Hereditary Transthyretin Cardiac Amyloidosis

Introduction: Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative process caused by the extracellular deposition of misfolded amyloid fibrils, resulting in a restrictive cardiomyopathy. Over 100 pathogenic genetic variants are associated with hereditary transthyretin cardiac amyloidosis (hATTR-CM); however, genetic penetrance is unknown. Typical echocardiographic findings include unexplained left ventricular (LV) hypertrophy - specifically concentric LV wall thickness greater than 12mm - and relative apical sparing of longitudinal LV strain. Cardiac MRI shows a characteristic diffuse subendocardial or transmural myocardial delayed gadolinium enhancement (DGE) pattern. Lastly, technetium-99m pyrophosphate scintigraphy (PYP) scan, an emerging sensitive and specific imaging modality, reveals grade 2 or greater myocardial uptake.

Methods: We present a case series of three young patients, two who presented with new-onset, non-ischemic systolic heart failure, and one who presented with LV hypertrophy - suggestive of cardiac amyloidosis. Genetic testing and cardiac imaging with echocardiography, cardiac MRI and/or PYP scan were performed.

Results: Genetic testing for all patients revealed the autosomal dominant and variably penetrant Valine 122 Isoleucine mutation, commonly associated with hATTR-CM. However, imaging for these patients was not suggestive of ATTR-CM. Therefore, they most likely represent silent carriers with alternate etiologies of heart failure.

Discussion: This case series exemplifies several instances of genotype-phenotype mismatch in hATTR-CM. With the increasing use of genetic testing and the variable penetrance of this common pathogenic variant, a thorough evaluation must be conducted to ensure true cardiac infiltration in order to avoid inappropriately initiating the costly transthyretin stabilizer, Tafamidis, or disregarding alternative - potentially reversible - etiologies of heart failure.