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Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy

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Abstract

Familial amyloid polyneuropathy (FAP) is a progressive systemic autosomal dominant disease caused by pathogenic mutations in the transthyretin (TTR) gene. We studied clinical, electrophysiological, histopathological, and genetic characteristics in 15 (13 late-onset and two early-onset) patients belonging to 14 families with polyneuropathy and mutations in TTR. In comparison, we analysed the features of nine unrelated patients with an idiopathic polyneuropathy, in whom TTR mutations have been excluded. Disease occurrence was familial in 36 % of the patients with TTR-associated polyneuropathy and the late-onset type was observed in 86 % (mean age at onset 65.5 years). Clinically, all late-onset TTR-mutant patients presented with distal weakness, pansensory loss, absence of deep tendon reflexes, and sensorimotor hand involvement. Afferent-ataxic gait was present in 92 % leading to wheelchair dependence in 60 % after a mean duration of 4.6 years. Autonomic involvement was observed in 60 %, and ankle edema in 92 %. The sensorimotor polyneuropathy was from an axonal type in 82 %, demyelinating or mixed type in 9 % each. Compared to the TTR-unmutated idiopathic polyneuropathy patients, we identified rapid progression, early ambulatory loss, and autonomic disturbances, associated with a severe polyneuropathy as red flags for TTR–FAP. In 18 % of the late-onset TTR-FAP patients, no amyloid was found in nerve biopsies. Further diagnostic pitfalls were unspecific electrophysiology, and coincident diabetes mellitus (23 %) or monoclonal gammopathy (7 %). We conclude that a rapid disease course, severely ataxic gait, hand involvement, and autonomic dysfunction are diagnostic hallmarks of late-onset TTR–FAP. Genetic analysis should be performed even when amyloid deposits are lacking or when polyneuropathy-causing comorbidities are concomitant.

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References

  1. Andrade C (1952) A peculiar form of peripheral neuropathy. Brain 75:408–427

    Article  CAS  PubMed  Google Scholar 

  2. Schönland SO, Hegenbart U, Bochtler T et al (2012) Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. Blood 119:488–493

    Article  PubMed  Google Scholar 

  3. Sommer C, Schröder JM (1989) Amyloid neuropathy: immunocytochemical localization of intra- and extracellular immunoglobulin light chains. Acta Neuropathol 79:190–199

    Article  CAS  PubMed  Google Scholar 

  4. Linke RP (2012) On typing amyloidosis using immunohistochemistry. Detailed illustrations, review and a note on mass spectrometry. Prog Histochem Cytochem 47:61–132

    Article  PubMed  Google Scholar 

  5. Liz MA, Mar FM, Franquinho F, Sousa MM (2010) Aboard transthyretin: from transport to cleavage. IUBMB Life 62:429–435

    CAS  PubMed  Google Scholar 

  6. Costa PP, Figueira AS, Bravo FR (1978) Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci USA 75:4499–4503

    Article  CAS  PubMed  Google Scholar 

  7. Cardoso I, Goldsbury CS, Müller SA et al (2002) Transthyretin fibrillogenesis entails the assembly of monomers: a molecular model for in vitro assembled transthyretin amyloid-like fibrils. J Mol Biol 317:683–695

    Article  CAS  PubMed  Google Scholar 

  8. Quintas A, Vaz DC, Cardoso I, Saraiva MJ, Brito RMM (2001) Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants. J Biol Chem 276:27207–27213

    Article  CAS  PubMed  Google Scholar 

  9. Planté-Bordeneuve V, Said G (2011) Familial amyloid polyneuropathy. Lancet Neurol 10:1086–1097

    Article  PubMed  Google Scholar 

  10. Conceiçao I, De Carvalho M (2007) Clinical variability in type I familial amyloid polyneuropathy (Val30 Met): comparison between late- and early-onset cases in Portugal. Muscle Nerve 35:116–118

    Article  PubMed  Google Scholar 

  11. Hund E, Linke RP, Willig F, Grau A (2001) Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment. Neurology 56:431–435

    Article  CAS  PubMed  Google Scholar 

  12. Westermark P, Sletten K, Johansson B, Cornwell GG (1990) Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 87:2843–2845

    Article  CAS  PubMed  Google Scholar 

  13. Bulawa CE, Connelly S, DeVit M et al (2012) Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci USA 109:9629–9634

    Article  CAS  PubMed  Google Scholar 

  14. Coelho T, Maia L, da Martins Silva A (2010) Tafamidis (Fx-1006A): a first-in-class disease-modifying therapy for transthyretin familial amyloid polyneuropathy. Amyloid 17:75–76

    Article  Google Scholar 

  15. Said G, Grippon S, Kirkpatrick P (2012) Tafamidis. Nat Rev Drug Discov 11:185–186

    Article  CAS  PubMed  Google Scholar 

  16. Holmgren G, Steen L, Ekstedt J et al (1991) Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 40:242–246

    Article  CAS  PubMed  Google Scholar 

  17. Holmgren G, Steen L, Suhr O et al (1993) Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341:1113–1116

    Article  CAS  PubMed  Google Scholar 

  18. Dubowitz V, Sewry C (2007) Histological and histochemical stains and reactions. Muscle biopsy a practical approach. Elsevier, Philadelphia, pp 3–39

    Google Scholar 

  19. Schröder JM, Hoheneck M, Weis J, Deist H (1985) Ethylene oxide polyneuropathy: clinical follow-up study with morphometric and electron microscopic findings in a sural nerve biopsy. J Neurol 232:83–90

    Article  PubMed  Google Scholar 

  20. Weis J, Brandner S, Lammens M, Sommer C, Vallat J-M (2012) Processing of nerve biopsies: a practical guide for neuropathologists. Clin Neuropathol 31:7–23

    Article  PubMed  Google Scholar 

  21. Benson MD, Kincaid JC (2007) The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 36:411–423

    Article  CAS  PubMed  Google Scholar 

  22. Jacobson DR, Pastore RD, Yaghoubian R et al (1997) Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 336:466–473

    Article  CAS  PubMed  Google Scholar 

  23. Mathis S, Magy L, Diallo L, Boukhris S, Vallat JM (2012) Amyloid neuropathy mimicking chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 45:26–31

    Article  PubMed  Google Scholar 

  24. Cappellari M, Cavallaro T, Ferrarini M et al (2011) Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients. J Peripher Nerv Syst 16:119–129

    Article  PubMed  Google Scholar 

  25. Palaninathan SK, Mohamedmohaideen NN, Snee WC, Kelly JW, Sacchettini JC (2008) Structural insight into pH-induced conformational changes within the native human transthyretin tetramer. J Mol Biol 382:1157–1167

    Article  CAS  PubMed  Google Scholar 

  26. Wilkinson-White LE, Easterbrook-Smith SB (2007) Characterization of the binding of Cu(II) and Zn(II) to transthyretin: effects on amyloid formation. Biochemistry 46:9123–9132

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Q, Kelly JW (2005) Cys-10 mixed disulfide modifications exacerbate transthyretin familial variant amyloidogenicity: a likely explanation for variable clinical expression of amyloidosis and the lack of pathology in C10S/V30M transgenic mice? Biochemistry 44:9079–9085

    Article  CAS  PubMed  Google Scholar 

  28. Almeida MR, Alves IL, Terazaki H, Ando Y, Saraiva MJ (2000) Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119 M. Biochem Biophys Res Commun 270:1024–1028

    Article  CAS  PubMed  Google Scholar 

  29. Hammarström P, Jiang X, Hurshman Babbes AR, Powers ET, Kelly JW (2002) Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci USA 99:16427–16432

    Article  PubMed  Google Scholar 

  30. Hurshman Babbes AR, Powers ET, Kelly JW (2008) Quantification of the thermodynamically linked quaternary and tertiary structural stabilities of transthyretin and its disease-associated variants: the relationship between stability and amyloidosis. Biochemistry 47:6969–6984

    Article  CAS  PubMed  Google Scholar 

  31. Soares ML, Coelho T, Sousa A et al (2005) Susceptibility and modifier genes in Portuguese transthyretin V30 M amyloid polyneuropathy: complexity in a single-gene disease. Hum Mol Genet 14:543–553

    Article  CAS  PubMed  Google Scholar 

  32. Sousa MM, Du Y, Fernandes R, Guimarães A, Stern D, Saraiva MJ (2001) Familial amyloid polyneuropathy: receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways. J Neurosci 21:7576–7586

    CAS  PubMed  Google Scholar 

  33. Sousa MM, Saraiva MJ (2003) Neurodegeneration in familial amyloid polyneuropathy: from pathology to molecular signaling. Prog Neurobiol 71:385–400

    Article  CAS  PubMed  Google Scholar 

  34. Koike H (2002) Type I (transthyretin met30) familial amyloid polyneuropathy in japan: early- vs late-onset form. Arch Neurol 59:1771–1776

    Article  PubMed  Google Scholar 

  35. Koike H, Sobue G (2012) Late-onset familial amyloid polyneuropathy in Japan. Amyloid 19:55–57

    Article  CAS  PubMed  Google Scholar 

  36. Koike H, Misu K, Sugiura M et al (2004) Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy. Neurology 63:129–138

    Article  CAS  PubMed  Google Scholar 

  37. Koike H, Ando Y, Ueda M et al (2009) Distinct characteristics of amyloid deposits in early- and late-onset transthyretin Val30Met familial amyloid polyneuropathy. J Neurol Sci 287:178–184

    Article  CAS  PubMed  Google Scholar 

  38. Monteiro FA, Sousa MM, Cardoso I, do Amaral JB, Guimarães A, Saraiva MJ (2006) Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy. J Neurochem 97:151–161

    Article  CAS  PubMed  Google Scholar 

  39. Monteiro FA, Cardoso I, Sousa MM, Saraiva MJ (2006) In vitro inhibition of transthyretin aggregate-induced cytotoxicity by full and peptide derived forms of the soluble receptor for advanced glycation end products (RAGE). FEBS Lett 580:3451–3456

    Article  CAS  PubMed  Google Scholar 

  40. Sousa MM, Yan SD, Stern D, Saraiva MJ (2000) Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation. Lab Invest 80:1101–1110

    Article  CAS  PubMed  Google Scholar 

  41. Sousa MM, Fernandes R, Palha JA, Taboada A, Vieira P, Saraiva MJ (2002) Evidence for early cytotoxic aggregates in transgenic mice for human transthyretin Leu55Pro. Am J Pathol 161:1935–1948

    Article  CAS  PubMed  Google Scholar 

  42. Stern D, Du Yan S, Fang Yan S, Marie Schmidt A (2002) Receptor for advanced glycation end products: a multiligand receptor magnifying cell stress in diverse pathologic settings. Adv Drug Deliv Rev 54:1615–1625

    Article  CAS  PubMed  Google Scholar 

  43. Kodaira M, Sekijima Y, Tojo K et al (2008) Non-senile wild-type transthyretin systemic amyloidosis presenting as bilateral carpal tunnel syndrome. J Peripher Nerv Syst 13:148–150

    Article  PubMed  Google Scholar 

  44. Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J (2006) Seeking confidence in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. Blood 107:3489–3491

    Article  CAS  PubMed  Google Scholar 

  45. Suhr OB, Ericzon B-G (2012) Selection of hereditary transthyretin amyloid patients for liver transplantation: the Swedish experience. Amyloid 19:78–80

    Article  PubMed  Google Scholar 

  46. Koike H, Kawagashira Y, Iijima M et al (2008) Electrophysiological features of late-onset transthyretin Met30 familial amyloid polyneuropathy unrelated to endemic foci. J Neurol 255:1526–1533

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank the personnel of the Department of Neurology and the Institute of Neuropathology at the University Hospital Aachen (Germany), and particularly Astrid Knischewski and Hannelore Mader, for their technical assistance, and Prof Klaus Altland for valuable information. We are grateful to the patients and their families for their participation in our study.

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The authors declare that they have no conflicts of interest.

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Correspondence to Kristl G. Claeys.

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Dohrn, M.F., Röcken, C., De Bleecker, J.L. et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol 260, 3093–3108 (2013). https://doi.org/10.1007/s00415-013-7124-7

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  • DOI: https://doi.org/10.1007/s00415-013-7124-7

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