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). Ann Neurol 2015;78:901–916
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https://hal.umontpellier.fr/hal-02065312
Contributeur : Mélanie Karli <>
Soumis le : mardi 12 mars 2019 - 15:43:22
Dernière modification le : mercredi 17 juillet 2019 - 02:46:52

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Louise-Laure Mariani, Pierre Lozeron, Marie Théaudin, Zoia Mincheva, Aissatou Signate, et al.. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Annals of Neurology, Wiley, 2015, 78 (6), pp.901-916. ⟨10.1002/ana.24519⟩. ⟨hal-02065312⟩

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