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

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.

The objectives of this study are to describe the phenotypic presentation and report longitudinal assessment, including cardiac imaging of ATTRv G+ family members.

Demographic, electrocardiographic, genetic, and imaging (echocardiography, cardiac technetium-99m pyrophosphate, and magnetic resonance imaging) data were abstracted and analyzed from the electronic health records.

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.

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.