Asymptomatic Carrier Neurologic Assessment: A Tool for Early Detection of Symptomatic Transition in Pathogenic TTR...

Hereditary variant transthyretin amyloidosis (ATTRv) is caused by > 140 pathogenic TTR gene variants. The heterogeneous presentation of ATTRv clinical phenotypes complicates diagnosis and staging of patients. Tools that improve early detection of ATTRv symptoms and signs and identify risk of transition to clinically detectable disease are needed.

A retrospective, multicenter study at amyloid centers in France, Spain, Portugal, and the United Kingdom (December 2023-December 2024) assessed asymptomatic carriers (ACs) and ACs who transitioned to symptomatic disease within the previous 2 years (newly symptomatic carriers [NSCs]). A new 23-question asymptomatic carrier neurologic assessment (ACNA) was developed to screen for the potential transition to clinically detectable ATTRv-polyneuropathy (PN). Question topics spanned sensory, autonomic, and systemic signs and symptoms. Fisher's exact tests were conducted to evaluate the association between each individual question and disease status (i.e., NSC vs. AC). Logistic regression models with a Firth correction were used to estimate odds ratios and corresponding 95% confidence intervals.

The study included 217 carriers (AC, n = 128; NSC, n = 89) with 18 unique transthyretin variants; 166 (76.5%) had p.Val50Met. Of 23 ACNA questions, 17 were significantly associated with transition to symptomatic disease for all patients. The pattern of neurologic signs and symptoms found to be associated with p.Val50Met and other common variants reflected what is known about variant-specific symptomatology. Confounding factors included age, medical center of treatment, and variant type.

The ACNA questionnaire may be a clinically valuable tool to screen ACs for risk of transition to symptomatic ATTRv-PN but requires validation.