Familial amyloidosis with polyneuropathy associated with TTR Ser50Arg mutation

Abstract

Background: The phenotypic heterogeneity of transthyretin amyloidosis (ATTR) familial polyneuropathy may be linked to the type of mutation and to the environmental factors. A gender difference in relation to the severity of the disease has been suspected. More than 100 different pathogenic variants of hereditary transthyretin (TTR) mutations have been reported. Objective: To describe 32 patients with confirmed TTR Ser50Arg mutation from the same geographical origin. Methods: Seven families with up to four affected generations underwent genetic testing and prospective clinical and laboratory evaluations. Results: The mutation was confirmed in seven patients from different families with clinical symptoms compatible with ATTR amyloidosis, and in 25 (62%) of the 40 direct relatives tested. Of the 32 patients with positive test results, 18 (56%) were men. Only 5 (16%) subjects were disease-free at the time of the genetic test (mean age: 20, range: 18–30-year-old). The rest developed symptoms at a young age, between ages 36 and 41. Symptomatic, histologically positive patients were older than carriers and symptomatic patients without a confirmatory biopsy. The later generation displayed symptoms at a younger age. Initial manifestations in the 27 symptomatic patients were neuropathic in 19 (70%), gastrointestinal in 6 (22%) and autonomic in 1 (4%). Significant differences were demonstrated among genders, where men had a considerably worse outcome. Conclusion: ATTR Ser50Arg mutation was associated with an early onset, an unbalanced male to female ratio, a more aggressive course in males and possibly displayed anticipation.

Keywords::

• Familial amyloidosis
• hereditary amyloidosis
• polyneuropathy
• Ser50Arg mutation

Acknowledgments

The statistic analysis was performed by Dr. González-Duarte MD.

Declaration of Interest: Dr. González-Duarte has an IIR supported by Pfizer Inc. The rest of the authors have nothing to disclose. Dr. Cantú-Brito is a recipient of a NIH grant. The genetic testing was supported by Fold-Rx Pharmaceuticals, later acquired by Pfizer Inc.