Deep Phenotyping of F64L Mutation in a Multicentric Cohort of Patisiran-Treated Hereditary Transthyretin Amyloidosis Patients (Patisiranitaly).

BACKGROUND

The F64L variant is among the most frequent TTR mutations in Italy, typically associated with a predominantly neurologic phenotype and limited cardiac involvement.

METHODS

Data from 181 ATTRv patients in the multicenter Patisiranitaly database treated with Patisiran since 2020 were analyzed. Neurologic impairment scores, Norfolk QoL-DN, and cardiac parameters were compared between F64L (n = 56), V30M (n = 37), and non-F64L (n = 125) patients at baseline and during follow-up. Cluster analysis was applied to identify patient subgroups based on these variables.

RESULTS

F64L represented 30.9% of the cohort. Compared to non-F64L patients, F64L patients had a higher prevalence of neurologic onset and neurologic phenotype, a thinner interventricular septum, and lower NT-proBNP levels. Cluster analysis segregated patients into two distinct groups, predominantly reflecting F64L vs. non-F64L status and corresponding neurologic severity. F64L patients showed milder cardiac involvement compared to V30M patients. Longitudinal repeated-measures ANOVA showed stable clinical and instrumental measures.

CONCLUSIONS

F64L is characterized by predominant neurologic involvement and milder cardiac involvement in this Patisiran-treated cohort. Mutation-specific diagnostic and follow-up strategies are essential to capture its natural history and treatment response.