title: 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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;
authors.forename: Louise-Laure
authors.initials: LL
authors.lastname: Mariani
authors.affiliation: Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;|French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|Department of Neurophysiology, APHP, Lariboisière Hospital, University Paris-Diderot Sorbonne Paris Cité, INSERM UMR-965, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lozeron
authors.affiliation: Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;|French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|National Institute of Health and Medical Research Unit U1191, Le Kremlin-Bicêtre.
authors.forename: Marie
authors.initials: M
authors.lastname: Théaudin
authors.affiliation: Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;|French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.
authors.forename: Zoia
authors.initials: Z
authors.lastname: Mincheva
authors.affiliation: Department of Neurology, Pierre Zobda-Quitman Hospital, Fort de France.
authors.forename: Aissatou
authors.initials: A
authors.lastname: Signate
authors.affiliation: Reproduction and Child Development Team, Center for Research in Epidemiology and Population Health, Le Kremlin-Bicêtre.|University of Paris-South, Villejuif.|National Institute for Demographic Studies, Paris.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Ducot
authors.affiliation: French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|University Paris-Sud, Paris.|Department of Cardiology, Antoine Béclère Hospital, Clamart.
authors.forename: Vincent
authors.initials: V
authors.lastname: Algalarrondo
authors.affiliation: Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;|National Institute of Health and Medical Research Unit U1191, Le Kremlin-Bicêtre.|University Paris-Sud, Paris.
authors.forename: Christian
authors.initials: C
authors.lastname: Denier
authors.affiliation: French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|Department of Neuropathology, Bicêtre Hospital, Le Kremlin-Bicêtre.
authors.forename: Clovis
authors.initials: C
authors.lastname: Adam
authors.affiliation: Department of Neurology, Raymond Poincaré Hospital, Garches.|University of Versailles Saint-Quentin-en-Yvelines, Versailles.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: Hepatobiliary Center, Paul Brousse Hospital, Villejuif.|National Institute of Health and Medical Research Mixed Unit of Research S785, Villejuif.
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.affiliation: French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|University Paris-Sud, Paris.|Department of Cardiology, Antoine Béclère Hospital, Clamart.
authors.forename: Michel S
authors.initials: MS
authors.lastname: Slama
authors.affiliation: French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|Department of Neuropathology, Bicêtre Hospital, Le Kremlin-Bicêtre.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacroix
authors.affiliation: French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|University Paris-Sud, Paris.|Department of Molecular Biology, Bicêtre Hospital, Le Kremlin-Bicêtre.
authors.forename: Micheline
authors.initials: M
authors.lastname: Misrahi
authors.affiliation: Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;|French National Reference Center for Familial Amyloid Polyneuropathies (NNERf), Le Kremlin-Bicêtre.|National Institute of Health and Medical Research Unit U1191, Le Kremlin-Bicêtre.|University Paris-Sud, Paris.|FILNEMUS, Filière nationale de Santé Maladies Rares Neuromusculaires, Marseille, France.
authors.forename: David
authors.initials: D
authors.lastname: Adams
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000235:genetics; D028227:Amyloid Neuropathies, Familial / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005602:France; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011174:Portugal; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D000682:Amyloid; D011228:Prealbumin; C041120:amyloid prealbumin