Objective:

To evaluate demographics, clinical presentation, diagnostic delay, treatment patterns, genotype-phenotype correlations, and outcomes in patients with hereditary transthyretin-mediated (hATTR) polyneuropathy.

Background:

In hATTR polyneuropathy, pathogenic mutations of the transthyretin (TTR) gene destabilize the protein, leading to systemic amyloid deposition. The disease affects peripheral nerves, the heart, and multiple organ systems, resulting in morbidity and mortality. The rarity and heterogeneous presentation of hATTR polyneuropathy delays recognition; early diagnosis is critical to allow initiation of disease-modifying therapies (DMTs) that may halt or reverse progression.

Design/Methods:

Single-center retrospective chart review of 22 patients with confirmed hATTR polyneuropathy, evaluated between 2018 and 2025. Demographic characteristics, genotypes, clinical presentations, diagnostic pathways, and treatment outcomes were collected. Functional outcomes were assessed using the Polyneuropathy Disability (PND) and Familial Amyloid Polyneuropathy (FAP) scales.

Results:

Among 22 patients (median age 71 years; 14 male, 8 female), the most common mutations were V122I (n=10), V30M (n=6), and Ala117Ser (n=2). Mixed cardiac-neuropathy onset was frequent (13/22). Median diagnostic delay was 48 months, with 41% experiencing delays ≥5 years and 9 patients initially misdiagnosed. Neurologic and autonomic symptoms were common, and 14/18 patients who underwent PYP scintigraphy showed cardiac uptake. All patients received DMTs; 16/22 received gene-silencing therapies (siRNA or ASO) and 6/22 received TTR stabilizers. By PND scores, 60% of patients on gene-silencing therapy improved or stabilized, including 13% with measurable improvement. FAP scores showed similar trends. Patients receiving gene-silencing therapy achieved greater stabilization and improvement compared with those on TTR stabilizers, underscoring the importance of early therapeutic intervention.

Conclusions:

hATTR is frequently misdiagnosed, resulting in diagnostic delays exceeding five years in many cases. Early diagnosis and initiation of DMTs - particularly gene-silencing therapies - are associated with improved or stabilized neurological outcomes. Incorporating genetic testing and family screening into clinical practice is essential for timely detection and treatment.