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, phenylalanine (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% of 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.
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, phenylalanine (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% of 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.
Authors: Peter J Dyck; John C Kincaid; P James B Dyck; Vinay Chaudhry; Namita A Goyal; Christina Alves; Hayet Salhi; Janice F Wiesman; Celine Labeyrie; Jessica Robinson-Papp; Márcio Cardoso; Matilde Laura; Katherine Ruzhansky; Andrea Cortese; Thomas H Brannagan; Julie Khoury; Sami Khella; Márcia Waddington-Cruz; João Ferreira; Annabel K Wang; Marcus V Pinto; Samar S Ayache; Merrill D Benson; John L Berk; Teresa Coelho; Michael Polydefkis; Peter Gorevic; David H Adams; Violaine Plante-Bordeneuve; Carol Whelan; Giampaolo Merlini; Stephen Heitner; Brian M Drachman; Isabel Conceição; Christopher J Klein; Morie A Gertz; Elizabeth J Ackermann; Steven G Hughes; Michelle L Mauermann; Rito Bergemann; Karen A Lodermeier; Jenny L Davies; Rickey E Carter; William J Litchy Journal: Muscle Nerve Date: 2017-04-07 Impact factor: 3.217
Authors: Teresa Coelho; Luis F Maia; Ana Martins da Silva; Marcia Waddington Cruz; Violaine Planté-Bordeneuve; Pierre Lozeron; Ole B Suhr; Josep M Campistol; Isabel Maria Conceição; Hartmut H-J Schmidt; Pedro Trigo; Jeffery W Kelly; Richard Labaudinière; Jason Chan; Jeff Packman; Amy Wilson; Donna R Grogan Journal: Neurology Date: 2012-07-25 Impact factor: 9.910
Authors: John L Berk; Ole B Suhr; Laura Obici; Yoshiki Sekijima; Steven R Zeldenrust; Taro Yamashita; Michael A Heneghan; Peter D Gorevic; William J Litchy; Janice F Wiesman; Erik Nordh; Manuel Corato; Alessandro Lozza; Andrea Cortese; Jessica Robinson-Papp; Theodore Colton; Denis V Rybin; Alice B Bisbee; Yukio Ando; Shu-ichi Ikeda; David C Seldin; Giampaolo Merlini; Martha Skinner; Jeffery W Kelly; Peter J Dyck Journal: JAMA Date: 2013-12-25 Impact factor: 56.272
Authors: Jennifer Kollmer; Ernst Hund; Benjamin Hornung; Ute Hegenbart; Stefan O Schönland; Christoph Kimmich; Arnt V Kristen; Jan Purrucker; Christoph Röcken; Sabine Heiland; Martin Bendszus; Mirko Pham Journal: Brain Date: 2014-12-18 Impact factor: 13.501