Rare transthyretin gene variants (p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys, and p.Phe53Leu): diagnostic pitfalls and clinical characteristics of Polish patients with transthyretin cardiac amyloidosis

Abstract

Introduction: The knowledge about clinical features of Polish patients with hereditary type of transthyretin cardiac amyloidosis (hATTR-CA) is scant.

Objectives: Our aim was to present rare transthyretin (TTR) gene variants and diagnostic difficulties in patients with hATTR-CA.

Patients and methods: In the years 2018-2024, 252 consecutive patients with suspected CA were evaluated, including blood tests, standard 12‑lead electrocardiography, transthoracic echocardiography and 99mtechnetium‑3,3‑diphosphono‑1,2‑propanodicarboxylic acid ([99mTc]Tc‑DPD) scintigraphy. The TTR gene sequencing was performed, if mandatory.

Results: hATTR‑CA was confirmed in 14 patients (including 1 woman). Most of them had pathogenic or likely pathogenic TTR gene variants, which are highly uncommon in the hereditary transthyretin amyloidosis population: p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys, and p.Phe53Leu. Of note, the patients with p.Ala101Val and p.Phe53Cys variants had inconclusive [99mTc]Tc‑DPD scintigraphy results, which may be due to low sensitivity of [99mTc]Tc‑DPD bone scintigraphy to these variants. Cardiac biomarkers did not reflect the intensity of cardiac uptake on [99mTc]Tc‑DPD bone scintigraphy, as 2 patients with intense cardiac uptake of the tracer had normal or borderline levels of high‑sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide. During follow‑up, 4 patients died, and 2 underwent combined heart and liver transplantation.

Conclusions: This study broadens our knowledge regarding genotype‑phenotype correlations of specific TTR variants, widens the spectrum of identified TTR variants in the Polish population, and shows limited value of [99mTc]Tc‑DPD scintigraphy in some patients with hATTR‑CA. In the cases with strong suspicion of ATTR‑CA and inconclusive [99mTc]Tc‑DPD scintigraphy results, genetic testing should be considered.