Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

Abstract

Objective: To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.

Methods: We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.

Results: By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.

Interpretation: Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large-fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing).

Figure 1

Flow chart of patients with familial amyloid polyneuropathy. LateMet30 = Val30Met TTR mutation in patients with late onset (>50 years); PortMet30 = Val30Met mutation in patients of Portuguese origin; Tyr77 = Ser77Tyr TTR mutation; Val107 = Ile107Val TTR mutation.

Figure 2

Survival curves (Kaplan–Meier) of overall survival (A), gait disorders (B), and need for assistance to walk (C) for Ile107Val TTR mutation (Val107), Ser77Tyr TTR mutation (Tyr77), Val30Met TTR mutation in patients with late onset (>50 years; LateMet30), and Val30Met mutation in patients of Portuguese origin (PortMet30) patients, in years after disease onset. Changes in the mean Medical Research Council (MRC) score (best maximum = 5) in the Val107, Tyr77, and LateMet30 groups (D) were compared by 2‐way analysis of variance. ***p < 0.0005 and ****p < 0.0001 significant curve differences and significant MRC score differences.