Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients

J Peripher Nerv Syst. 2011 Jun;16(2):119-29. doi: 10.1111/j.1529-8027.2011.00331.x.


Autosomal-dominant transthyretin (TTR)-related amyloidosis usually manifests in the second to fourth decade with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure. We retrospectively analyzed seventeen probands, including thirteen apparently isolated cases, carrying eight mutations of TTR gene (age of onset = 60.4 ± 13.5 years). Thirteen patients were initially un/misdiagnosed; interval from onset to definite diagnosis was 3.3 ± 2.3 years. Inaugural syndromes were a length-dependent motor-sensory neuropathy in seven cases, a sensory neuropathy in four, an isolated carpal tunnel syndrome in three, a pure dysautonomia in two, and a painful neuropathy in one. Atypical presentations included demyelinating nerve conduction changes with increased cerebrospinal fluid proteins resembling chronic inflammatory demyelinating polyradiculoneuropathy and a predominantly motor involvement resembling a motor neuron disorder. Misleading findings also included amyloid-negative abdominal fat aspirate/biopsy, biclonal gammopathy, and hepatitis C virus (HCV) seropositivity. Sural nerve biopsy detected amyloid deposits in thirteen of fifteen patients, including one case with a previous negative biopsy. TTR-immunohistochemistry was necessary to complete the diagnosis of primary amyloidosis light chain in a patient with biclonal gammopathy. A recurrent p.Phe64Leu mutation manifested in the seventh decade with painful motor-sensory polyneuropathy, dysautonomia, bulbar palsies, and fasciculations. TTR should be tested in a wide clinical spectrum of cryptogenetic, progressive, and motor-sensory neuropathies even manifesting with a very late onset.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyloid Neuropathies, Familial / diagnosis*
  • Amyloid Neuropathies, Familial / genetics*
  • Amyloid Neuropathies, Familial / physiopathology
  • Biopsy
  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Electrophysiology
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Motor Neuron Disease / diagnosis
  • Mutation
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction
  • Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / diagnosis
  • Prealbumin / genetics*
  • Retrospective Studies


  • Prealbumin