Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy

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Abstract
Objective: To investigate the genotypic-phenotypic variations in a series of patients with familial amyloid polyneuropathy (FAP). Background: Progress in molecular genetics has led to the identification of point mutations in the transthyretin (TTR) gene in FAP-a dominantly inherited neuropathy with a fatal outcome. These findings have modified the management of patients with small-fiber neuropathy and allow genetic counseling. Methods: We performed a clinical and molecular genetic study with screening of the TTR gene mutations and associated haplotypes in 65 patients from 29 unrelated families of French ancestry. Results: We detected nine heterozygous point mutations segregating with FAP. Fourteen families (48%) carried the common methionine (Met) 30 substitution. Seven kindreds (24%) had previously unreported TTR variants, namely asparagine 35, serine (Ser) 91, phenylanine (Phe) 77, and Ser 116. At least two different haplotypes were associated with each of the following: Met 30, Phe 77, and valine 107, suggesting that multiple founders occurred for each variant. Only 35% the index patients had affected relatives. Other patients had a sporadic presentation. All progressed to a severe sensorimotor and autonomic neuropathy with frequent cardiac involvement (80%). On average, a late age at onset (54.3 ± 13.3 years) and a disease duration shorter than 10 years were observed for virtually all variants. Conclusion: The heterogeneity of the TTR variants, the late age at onset, and the short duration of the disease found in our patients contrast with the presentation of FAP in Portugal. These findings must be taken into account in the management of both patients and asymptomatic carriers.