Phenotypic Presentation and Longitudinal Characterization of Hereditary ATTRv Amyloidosis in Previously Undiagnosed Family Members

Background: Clinical characteristics, cardiac disease progression, and outcomes of “previously undiagnosed” family members of patients with hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) with pathogenic or likely pathogenic transthyretin (TTR) variants (genotype positive or G+) are unknown despite prognostic and therapeutic implications. Objectives: The objectives of this study are to describe the phenotypic presentation and report longitudinal assessment, including cardiac imaging of ATTRv G+ family members. Methods: Demographic, electrocardiographic, genetic, and imaging (echocardiography, cardiac technetium-99m pyrophosphate, and magnetic resonance imaging) data were abstracted and analyzed from the electronic health records. Results: There were 85 G+ family members, with the most common genotypes being Val50Met (29.4%) and Thr60Ala (28.2%). The mean age was 48.5 ± 11.7 years, 38.8% were male, and 17.9% and 15.5% had a diagnosis of peripheral neuropathy and carpal tunnel syndrome, respectively. The median follow-up was 6.8 years (Q1-Q3: 4.1-9.7), over which 55 patients had follow-up imaging studies. Left ventricular ejection fraction reduction (63 ± 4 to 61 ± 4, P = 0.014) and progressive septal wall thickening (9.4 ± 1.6 to 10.2 ± 2.4, P = 0.037) were observed. There were only 6 (10.9%) patients who developed at least 2 abnormal echocardiographic changes consistent with cardiac disease progression. The risk of developing peripheral neuropathy during follow-up was 25.5% (95% CI: 8.9%-42.1%; P = 0.004), but none were diagnosed with heart failure. Conclusions: Previously undiagnosed ATTRv G+ family members have a greater prevalence and incidence of symptomatic neurological rather than cardiac disease, and the progression of cardiac disease was limited, which has implications for treating these patients preemptively.