Neuropathy in Val122Ile Hereditary Transthyretin (ATTR) Amyloidosis: A Multicenter Retrospective Cohort Study

The Val122Ile ATTR Amyloidosis has traditionally been linked to cardiac manifestations. Recent studies suggest that neuropathy may be relevant. In this study, we characterized its peripheral nerve manifestations in depth.

This was a national, multicenter, observational, retrospective study. Patients underwent careful clinical and neurophysiological evaluation. We excluded those with alternative etiologies.

We identified 246 Val122Ile carriers, including 240 heterozygous, 4 homozygous, and 2 compound heterozygous. Gender distribution was similar. Age of onset: 19-89 years, mean 53 ± 17. Self-reported ethnicity: White (26.7%), Black (17.3%), and Mixed (Pardo) (56.0%). Birthplaces spanned all Brazilian regions, mainly the Northeast. Among heterozygotes, 52 of 122 (42.6%) were symptomatic. Carpal tunnel syndrome (CTS) preceded polyneuropathy and/or cardiomyopathy in 69.2%. The most frequent onset manifestations, excluding CTS, were cardiomyopathy (52.9%), neuropathy (37.3%), and mixed phenotype (9.8%). Age of onset: 29-86 years (mean: 64.9 years). During follow-up, 14/27 cardiac patients developed neuropathy, and 8/19 neurologic patients developed cardiomyopathy, significantly increasing the mixed phenotype from 9.8% to 52.9%. Most patients with neuropathy presented with sensory or sensory and motor disease (62.2%), followed by small fiber neuropathy (32.4%), and isolated dysautonomia (5.4%).

Neuropathy is underrecognized in Val122Ile ATTR Amyloidosis, is frequent at disease onset, may be the sole manifestation, and may occur in White persons. CTS frequently preceded neuropathy, usually an axonal polyneuropathy, although atypical patterns were observed. This variant clusters in the Northeast region of Brazil.