title: Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study.
abstract: OBJECTIVE
  To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP).
  
  
  METHODS
  We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models.
  
  
  RESULTS
  For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p < 0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p < 0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year.
  
  
  CONCLUSIONS
  In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion.
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA. david.adams@bct.aphp.fr.
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Zoia
authors.initials: Z
authors.lastname: Mincheva
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Narupat
authors.initials: N
authors.lastname: Suanprasert
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Pritesh J
authors.initials: PJ
authors.lastname: Gandhi
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Litchy
authors.affiliation: From the National Reference Center for FAP (NNERF) (D.A., Z.M.), APHP, Univ Paris Sud, INSERM Unité 1195, Le Kremlin-Bicêtre, France; Hospital de Santo António (T.C.), Centro Hospitalar do Porto, Portugal; Amyloidosis Research and Treatment Center (L.O., G.M.), Foundation IRCCS Policlinico San Matteo and University of Pavia, Italy; Mayo Clinic (N.S., W.J.L., P.J.D.), Rochester, MN; and Alnylam Pharmaceuticals (B.R.B., J.A.G., P.J.G.), Cambridge, MA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000175:diagnosis* / Q000453:epidemiology* / Q000235:genetics; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011174:Portugal / Q000453:epidemiology; D012720:Severity of Illness Index; D014481:United States / Q000453:epidemiology