Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Márcia Waddington-Cruz, Jonas Wixner, Leslie Amass, Jan Kiszko, Doug Chapman, Yukio Ando, THAOS investigators, Fabio Adrian Barroso, Marcelo Rugiero, Johan Van Cleemput, Ivaylo Tarnev, Theodoros Kyriakides, Arnt Kristen, Hartmut Schmidt, Felix Darstein, Burkhard Gess, Josep Maria Campistol Plana, Juan Gonzalez Moreno, Jose Gonzalez Costello, Pablo Garcia Pavia, Roberto Fernandéz Torrón, Francisco Munoz Beamud, Violaine Planté-Bordeneuve, David Adams, Olivier Lairez, Claudio Rapezzi, Giampaolo Merlini, Marco Luigetti, Yoshiki Sekijima, Taro Yamashita, Sonoko Misawa, Soon Chai Low, Hans Nienhuis, Teresa Coelho, Isabel Conceição, Rayomand Press, Yesim Parman, Mathew Maurer, Stephen Gottlieb, Annabel Wang, Brian Drachman, Angela Dispenzieri, Sasa Zivkovic, Daniel Lenihan, Márcia Waddington-Cruz, Jonas Wixner, Leslie Amass, Jan Kiszko, Doug Chapman, Yukio Ando, THAOS investigators, Fabio Adrian Barroso, Marcelo Rugiero, Johan Van Cleemput, Ivaylo Tarnev, Theodoros Kyriakides, Arnt Kristen, Hartmut Schmidt, Felix Darstein, Burkhard Gess, Josep Maria Campistol Plana, Juan Gonzalez Moreno, Jose Gonzalez Costello, Pablo Garcia Pavia, Roberto Fernandéz Torrón, Francisco Munoz Beamud, Violaine Planté-Bordeneuve, David Adams, Olivier Lairez, Claudio Rapezzi, Giampaolo Merlini, Marco Luigetti, Yoshiki Sekijima, Taro Yamashita, Sonoko Misawa, Soon Chai Low, Hans Nienhuis, Teresa Coelho, Isabel Conceição, Rayomand Press, Yesim Parman, Mathew Maurer, Stephen Gottlieb, Annabel Wang, Brian Drachman, Angela Dispenzieri, Sasa Zivkovic, Daniel Lenihan

Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.

Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).

Results: Of 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).

Conclusion: In THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.

Trial registration: ClinicalTrials.gov NCT00628745.

Keywords: ATTRv amyloidosis; Cardiac; Disease onset; Neurologic.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Illustration of incidence of late- and early-onset ATTRv Val30Met amyloidosis in different countries in THAOS. Countries with more late-onset disease than early-onset disease are marked in dark blue; countries with more early-onset than late-onset disease are marked in light blue. Countries contributing ≤ 5 patients with Val30Met not shown. Belgium: late-onset n = 1, early-onset n = 0; Bulgaria: late-onset n = 5, early-onset n = 0; Cyprus: late-onset n = 0, early-onset n = 1; Malaysia: late-onset n = 2, early-onset n = 0; the Netherlands: late-onset n = 3, early-onset n = 2; Turkey: late-onset n = 1, early-onset n = 0
Fig. 2
Fig. 2
Electrocardiographic (ECG) (a) and echocardiographic (b, c) findings at enrollment in patients with late- and early-onset ATTRv Val30Met amyloidosis. LV left ventricular

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