Diagnosis and management of mixed-phenotype hereditary-transthyretin amyloidosis: A case-based, Canadian perspective

Published: Mar 10, 2025

Abstract

Hereditary amyloid transthyretin variant (ATTRv) amyloidosis is a rare, life-threatening disease, characterized by the deposition of aggregated transthyretin (TTR) protein in multiple organs and tissues. Diagnosis is often delayed due to its heterogeneity in presentation, which includes a wide range of cardiac and/or neurological symptoms. Thus, awareness of ATTRv amyloidosis across multiple specialties is needed for early diagnosis and management. This paper provides a review surrounding the diagnosis and management of mixed phenotype ATTRv amyloidosis, addressed through three clinical questions. This paper discusses: 1) the need for patients with ATTRv amyloidosis to be screened for mixed cardiac and neurologic phenotypes through early multidisciplinary referral; 2) the therapeutic landscape for ATTRv amyloidosis in Canada with emphasis on the need for prompt therapy selection and initiation, based on multidisciplinary collaboration; and 3) how disease can be monitored pre- and post-treatment. Case studies are provided to illustrate how available evidence impacts practice.

Introduction

Amyloid transthyretin amyloidosis is a debilitating and life-threatening disease caused by the misfolding and aggregation of mutated transthyretin (TTR) protein, which deposits in multiple organs and tissues leading to progressive damage and dysfunction (Figure 1). It can occur sporadically with aggregation of wild-type protein (typically presenting as cardiomyopathy in patients over 60 years of age) or it can be associated with mutations in the TTR gene, inherited in an autosomal dominant manner (hereditary or ATTR variant [ATTRv] amyloidosis).¹

Authors

Nowell Fine MD, Anique Ducharme MD, Genevieve Matte MD, Michelle Mezei MD, Vera Bril MD, Diego Delgado MD, MSc