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. 2024 Mar;13(1):117-135.
doi: 10.1007/s40119-023-00344-3. Epub 2023 Dec 20.

Clinical and Genotype Characteristics and Symptom Migration in Patients With Mixed Phenotype Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey

Juan González-Moreno  1 , Angela Dispenzieri  2 , Martha Grogan  3 , Teresa Coelho  4 , Ivailo Tournev  5   6 , Márcia Waddington-Cruz  7 , Jonas Wixner  8 , Igor Diemberger  9   10 , Pablo Garcia-Pavia  11   12 , Doug Chapman  13 , Pritam Gupta  14 , Oliver Glass  13 , Leslie Amass  13 ; THAOS investigators
Collaborators, Affiliations

Clinical and Genotype Characteristics and Symptom Migration in Patients With Mixed Phenotype Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey

Juan González-Moreno et al. Cardiol Ther. 2024 Mar.

Abstract

Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described.

Methods: This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022).

Results: Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1-2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%).

Conclusions: These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis.

Trial registration: ClinicalTrials.gov: NCT00628745.

Keywords: Amyloidosis; Cardiomyopathy; Mixed phenotype; Polyneuropathy; THAOS; Transthyretin.

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Conflict of interest statement

Juan González-Moreno reports speaker fees from Akcea, Alnylam, and Pfizer. Angela Dispenzieri reports research grants from Alnylam, Celgene, Janssen, Millennium, and Pfizer; funding for meeting expenses (travel) from Pfizer; and advisory board fees from Akcea and Intellia. Martha Grogan reports grants and advisory board/consultancy fees paid to her institution from Alnylam, Eidos, Pfizer, and Prothena. Teresa Coelho served as a medical advisor for Pfizer, without honoraria; and reports funding for meeting expenses (travel, accommodation, registration) from Pfizer. Ivailo Tournev reports research funding, honoraria for presentations, and advisory board fees from Alnylam, Pfizer, and Pharma Pro. Márcia Waddington-Cruz reports research funding, consulting fees, and travel support for advisory boards and meetings from FoldRx Pharmaceuticals and Pfizer. Jonas Wixner reports consulting fees and travel support for lectures and advisory boards from Alnylam and Pfizer; and consulting fees from Akcea. Igor Diemberger reports research funding and speaker fees from Daiichi Sankyo and Pfizer (outside scope of present research). Pablo Garcia-Pavia reports speaker fees from Akcea, Alnylam, Eidos, and Pfizer; consulting fees from Alnylam, Akcea, AstraZeneca, Eidos, Neurimmune, and Pfizer; and research/educational support to his institution from Alnylam, Eidos, and Pfizer. Doug Chapman, Pritam Gupta, Oliver Glass, and Leslie Amass are full-time employees of Pfizer and hold stock and/or stock options.

Figures

Fig. 1
Fig. 1
Cumulative incidence of time to reclassification to mixed phenotype according to initial phenotype
Fig. 2
Fig. 2
Summary of symptom categories reported at enrollment in patients with mixed phenotype ATTR amyloidosis overall and by genotype category. ATTR amyloidosis transthyretin amyloidosis, ATTRwt wild-type transthyretin amyloidosis, GI gastrointestinal
Fig. 3
Fig. 3
Distribution of NYHA functional class at enrollment in patients with mixed phenotype A ATTR amyloidosis, B ATTRwt amyloidosis, C V30M ATTRv amyloidosis, and D non-V30M ATTRv amyloidosis. NYHA class is reported only in mixed phenotype patients with HF (n = 719/1185). ATTR amyloidosis transthyretin amyloidosis, ATTRv amyloidosis hereditary transthyretin amyloidosis, ATTRwt amyloidosis wild-type transthyretin amyloidosis, HF heart failure, NYHA New York Heart Association
Fig. 4
Fig. 4
Other clinical and HRQoL characteristics in patients with mixed phenotype ATTR amyloidosis overall and by genotype. Cardiac measures, A LVSWT and B LVEF; neuropathy measure, C derived NIS-LL total score; and HRQoL measures, D EQ-5D-3L derived index and E Norfolk QoL-DN scores are shown. Lines within boxes denote medians; outer limits of boxes denote 10th and 90th percentiles. ATTR amyloidosis transthyretin amyloidosis, ATTRwt amyloidosis wild-type transthyretin amyloidosis, DN diabetic neuropathy, EQ-5D-3L EQ-5D three-level version, HRQoL health-related quality of life, LVEF left ventricular ejection fraction, LVSWT left ventricular septal wall thickness, NIS-LL Neuropathy Impairment Score in the Lower Limbs
Fig. 5
Fig. 5
Distribution of mPND scores in patients with mixed phenotype ATTR amyloidosis overall and by genotype. Denominators are the number of patients with non-missing data. ATTR amyloidosis transthyretin amyloidosis, ATTRwt amyloidosis wild-type transthyretin amyloidosis, mPND modified polyneuropathy disability
See this image and copyright information in PMC

References

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