Abstract 12278: A Case of Hereditary Transthyretin Amyloidosis Caused by a Rare Mutation

Abstract

Introduction: Transthyretin amyloidosis (ATTR) is an underdiagnosed multisystem disease caused by dissociation of the tetrameric structure, misfolding, and deposition of the protein transthyretin. More than 100 known mutations that decrease the stability of transthyretin have been implicated in hereditary ATTR (ATTRv). Organ tropism and disease progression can vary significantly depending on the specific mutation, though cardiomyopathy and neuropathy are the most common phenotypes (Figure 1b). Reproducibly tracking the pattern of end organ dysfunction in ATTRv caused by novel mutations may help elucidate the mechanism of mutation-specific organ tropism and predict the potential disease course for patients with the same mutation. Case: The index patient is an 86-year-old male with a history of atrial fibrillation, tachy-brady syndrome requiring a pacemaker, orthostatic hypotension, peripheral neuropathy, and left ventricular hypertrophy (interventricular septum 1.4 cm prior to diagnosis) on echocardiogram. The constellation of symptoms raised the clinical suspicion for amyloidosis which was confirmed on endomyocardial biopsy. Given his age, he was presumed to have wild type ATTR by the local team. Upon referral to our center, genetic testing was performed which revealed the missense mutation c.229G>A which results in the amino acid substitution p.Gly77Arg, and has previously only been reported in one patient in Sweden. We initiated family screening and identified multiple family members with the mutation with varying phenotypes including no symptoms, cardiomyopathy, and neuropathy (figure 1a). Discussion: We identified a family with a rare c.229G>A mutation, and report on a mixed cardiomyopathy and neuropathy phenotype. Our report highlights the importance of screening for pathologic genetic variants in all patients with a diagnosis of ATTR given the treatment and prognostic implications for patients and their family members.