Journal of Neurology

, Volume 265, Issue 4, pp 976–983 | Cite as

Transthyretin familial amyloid polyneuropathy: an update

Neurological Update

Abstract

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a progressive, fatal, inherited disorder first identified in Portugal and now recognized in all continents. Over the past decade, thanks to the availability of the genetic test, our knowledge on the range of clinical expressions of this disorder has expanded, including different patterns and progression rates of the neuropathy, as well as aspects of the cardiomyopathy, which can be prominent. In the mean time, new tools are being developed to detect earlier TTR amyloid deposition such as cardiac scintigraphy with technetium-labelled pyrophosphate tracers or small nerve fiber alterations from skin biopsies, or using neurophysiological approaches as well as magnetic resonance neurography (MRN). Such refinements, along with an increased awareness of the disease, should reduce the diagnostic delay and facilitate early treatment. In this regard, thanks to a better understanding of the TTR amyloid formation, major advances have been made, allowing for therapeutic developments which are less invasive than liver transplantation (LT). TTR stabilizer drugs are safe and seem to delay the disease progression in some groups of patients. Indeed, positive results have just been released from 2 phase III trials on TTR gene modifiers, namely silencing RNA and antisense oligonucleotide therapies. These recent advances open a new area in the field with the hope that we can safely bring about long-term stabilization of the disease. Furthermore, immunotherapies targeting the amyloid deposits are being explored.

Keywords

Transthyretin amyloidosis Neuropathy Treatment Genetic Gene modifyers therapy 

Abbreviations

ASO

Antisense oligonucleotides

ATTR

Transthyretin amyloidosis

mBMI

Modified body mass index

CSF

Cerebrospinal fluid

CPHPC

(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexa-noyl]pyrrolidine-2 carboxylic acid)]

CIDP

Chronic inflammatory demyelinating polyneuropathy

FAC

Familial amyloid cardiomyopathy

FAP

Familial amyloid polyneuropathy

IENFD

Intra-epidermal nerve fiber density

LT

Liver transplantation

mRNA

Messenger ribonucleic acid

MRN

Magnetic resonance neurography

NIS

Neuropathy Impairment Score

NIS-LL

Neuropathy Impairment Score in Lower Limbs

Norfolk QOL-DN

Norfolk quality of life Diabetic Neuropathy

NSAID

Non-steroidal anti-inflammatory drug

SAE

Serious adverse event

siRNAs

Small interfering RNAs

SAP

Serum amyloid P

TTR

Transthyretin

Notes

Compliance with ethical standards

Conflicts of interest

Support from Ionis, Alnylam, and Eidos therapeutics for participation to advisory boards.

References

  1. 1.
    Andrade C (1952) A peculiar form of peripheral neuropathy; familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75:408–427CrossRefPubMedGoogle Scholar
  2. 2.
    Gertz MA, Benson MD, Dyck PJ et al (2015) Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 66:2451–2466CrossRefPubMedGoogle Scholar
  3. 3.
    Planté-Bordeneuve V, Said G (2011) Familial amyloid polyneuropathy. Lancet Neurol 10:1086–1097CrossRefPubMedGoogle Scholar
  4. 4.
    Kerschen P, Planté-Bordeneuve V (2016) Current and future treatment approaches in transthyretin familial amyloid polyneuropathy. Curr Treat Options Neurol 18(12):53CrossRefPubMedGoogle Scholar
  5. 5.
    Quarta CC, Buxbaum JN, Shah AM et al (2015) The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med 372:21–29CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Liu G, Ni W, Wang H et al (2017) Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds. J Peripher Nerv Syst 22:19–26CrossRefPubMedGoogle Scholar
  7. 7.
    Jacobson DR, Alexander AA, Tagoe C et al (2016) The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Mol Genet Genomic Med 4:548–556CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Alves-Ferreira M, Coelho T, Santos D et al (2017) A trans-acting factor may modify age at onset in familial amyloid polyneuropathy ATTRV30M in Portugal. Mol Neurobiol.  https://doi.org/10.1007/s12035-017-0593-4 PubMedGoogle Scholar
  9. 9.
    Iorio A, De Lillo A, De Angelis F et al (2017) Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. Eur J Hum Genet 25:1055–1060CrossRefPubMedGoogle Scholar
  10. 10.
    Santos D, Coelho T, Alves-Ferreira M et al (2016) Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M). Eur J Hum Genet 24:756–760CrossRefPubMedGoogle Scholar
  11. 11.
    Santos D, Coelho T, Alves-Ferreira M et al (2017) Familial amyloid polyneuropathy in Portugal: new genes modulating age-at-onset. Ann Clin Transl Neurol 4:98–105CrossRefPubMedGoogle Scholar
  12. 12.
    Kurian SM, Novais M, Whisenant T et al (2016) Peripheral blood cell gene expression diagnostic for identifying symptomatic transthyretin amyloidosis patients: male and female specific signatures. Theranostics 6:1792–1809CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Santos D, Santos MJ, Alves-Ferreira M et al (2017) mtDNA copy number associated with age of onset in familial amyloid polyneuropathy. J Neurol Neurosurg Psychiatry.  https://doi.org/10.1136/jnnp-2017-316657 PubMedCentralGoogle Scholar
  14. 14.
    Damy T, Costes B, Hagège AA et al (2016) Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J 37(23):1826–1834CrossRefPubMedGoogle Scholar
  15. 15.
    Loavenbruck AJ, Singer W, Mauermann ML et al (2016) Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox? Ann Neurol 80:401–411CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Carr AS, Pelayo-Negro AL, Evans MR et al (2016) A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. J Neurol Neurosurg Psychiatry 87:620–627CrossRefPubMedGoogle Scholar
  17. 17.
    Mariani L-L, Lozeron P, Théaudin M et al (2015) Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol 78:901–916CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Coelho T, Vinik A, Vinik EJ et al (2017) Clinical measures in transthyretin familial amyloid polyneuropathy. Muscle Nerve 55:323–332CrossRefPubMedGoogle Scholar
  19. 19.
    Dyck PJ, Kincaid JC, Dyck PJB et al (2017) Assessing mNIS+7Ionis and international neurologists’ proficiency in a familial amyloidotic polyneuropathy trial. Muscle Nerve 56:901–911CrossRefPubMedGoogle Scholar
  20. 20.
    Koike H, Ikeda S, Takahashi M et al (2016) Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy. Neurology 87:2220–2229CrossRefPubMedGoogle Scholar
  21. 21.
    Cortese A, Vegezzi E, Lozza A et al (2017) Diagnostic challenges in hereditary transthyretin amyloidosis with polyneuropathy: avoiding misdiagnosis of a treatable hereditary neuropathy. J Neurol Neurosurg Psychiatry 88:457–458CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Plante-Bordeneuve V (2014) Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy. J Neurol 261:1227–1233CrossRefPubMedGoogle Scholar
  23. 23.
    Conceição I, González-Duarte A, Obici L et al (2016) “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst JPNS 21:5–9CrossRefPubMedGoogle Scholar
  24. 24.
    Kollmer J, Hund E, Hornung B et al (2015) In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography. Brain 138:549–562CrossRefPubMedGoogle Scholar
  25. 25.
    Kollmer J, Sahm F, Hegenbart U et al (2017) Sural nerve injury in familial amyloid polyneuropathy: mR neurography vs clinicopathologic tools. Neurology 89:475–484CrossRefPubMedGoogle Scholar
  26. 26.
    Gillmore JD, Maurer MS, Falk RH et al (2016) Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 133:2404–2412CrossRefPubMedGoogle Scholar
  27. 27.
    Ebenezer GJ, Liu Y, Judge DP et al (2017) Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy. Ann Neurol 82:44–56CrossRefPubMedGoogle Scholar
  28. 28.
    Masuda T, Ueda M, Suenaga G et al (2017) Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy. Neurology 88:2192–2197CrossRefPubMedGoogle Scholar
  29. 29.
    Misumi Y, Ueda M, Yamashita T et al (2017) Novel screening for transthyretin amyloidosis by using fat ultrasonography. Ann Neurol 81:604–608CrossRefPubMedGoogle Scholar
  30. 30.
    Castro J, Miranda B, Castro I et al (2016) The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy. Clin Neurophysiol 127:2222–2227CrossRefPubMedGoogle Scholar
  31. 31.
    Carvalho A, Rocha A, Lobato L (2015) Liver transplantation in transthyretin amyloidosis: issues and challenges. Liver Transpl 21:282–292CrossRefPubMedGoogle Scholar
  32. 32.
    Ericzon B-G, Wilczek HE, Larsson M et al (2015) Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation 99:1847–1854CrossRefPubMedGoogle Scholar
  33. 33.
    Maia LF, Magalhães R, Freitas J et al (2015) CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings. J Neurol Neurosurg Psychiatry 86:159–167CrossRefPubMedGoogle Scholar
  34. 34.
    Sekijima Y, Yazaki M, Oguchi K et al (2016) Cerebral amyloid angiopathy in posttransplant patients with hereditary ATTR amyloidosis. Neurology 87:773–781CrossRefPubMedGoogle Scholar
  35. 35.
    Freitas Castro V, Nascimento Alves P, Franco AC et al (2017) Cognitive impairment in liver transplanted patients with transthyretin-related hereditary amyloid polyneuropathy. Amyloid 24:110–114CrossRefPubMedGoogle Scholar
  36. 36.
    Hammarström P, Wiseman RL, Powers ET, Kelly JW (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713–716CrossRefPubMedGoogle Scholar
  37. 37.
    Penchala SC, Connelly S, Wang Y et al (2013) AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci USA 110:9992–9997CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Sekijima Y, Dendle MA, Kelly JW (2006) Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 13:236–249CrossRefPubMedGoogle Scholar
  39. 39.
    Berk JL, Suhr OB, Obici L et al (2013) Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310:2658–2667CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sekijima Y, Tojo K, Morita H et al (2015) Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis. Amyloid 22:79–83CrossRefPubMedGoogle Scholar
  41. 41.
    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 109:9629–9634CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Coelho T, Maia LF, Martins da Silva A et al (2012) Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79:785–792CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Coelho T, Maia LF, da Silva AM et al (2013) Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 260:2802–2814CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Barroso FA, Judge DP, Ebede B et al (2017) Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid 24:194–204CrossRefPubMedGoogle Scholar
  45. 45.
    Waddington Cruz M, Amass L, Keohane D et al (2016) Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid 23:178–183CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cortese A, Vita G, Luigetti M et al (2016) Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area. J Neurol 263:916–924CrossRefPubMedGoogle Scholar
  47. 47.
    Planté-Bordeneuve V, Gorram F, Salhi H et al (2017) Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study. J Neurol 264:268–276CrossRefPubMedGoogle Scholar
  48. 48.
    Maurer MS, Elliott P, Merlini G et al (2017) Design and rationale of the phase 3 ATTR-ACT Clinical Trial (tafamidis in transthyretin cardiomyopathy clinical trial). Circ Heart Fail 10(6).  https://doi.org/10.1161/CIRCHEARTFAILURE.116.003815
  49. 49.
    Benson MD, Kluve-Beckerman B, Zeldenrust SR et al (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33:609–618CrossRefPubMedGoogle Scholar
  50. 50.
    Ackermann EJ, Guo S, Benson MD et al (2016) Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid 23:148–157CrossRefPubMedGoogle Scholar
  51. 51.
    Ionis pharmaceuticals (2017) Phase 3 NEURO-TTR Study of Inotersen (IONIS-TTRRx) Meets Both Primary Endpoints. Press release 2017 May 15th and November 2ndGoogle Scholar
  52. 52.
    Love KT, Mahon KP, Levins CG et al (2010) Lipid-like materials for low-dose, in vivo gene silencing. Proc Natl Acad Sci USA 107:1864–1869CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Coelho T, Adams D, Silva A et al (2013) Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 369:819–829CrossRefPubMedGoogle Scholar
  54. 54.
    Alnylam pharmaceuticals (2017) Apollo-Patisiran phase 3 study: Topline results. Press release, 2017 November 2Google Scholar
  55. 55.
    Bodin K, Ellmerich S, Kahan MC et al (2010) Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 468:93–97CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Richards DB, Cookson LM, Berges AC et al (2015) Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med 373:1106–1114CrossRefPubMedGoogle Scholar
  57. 57.
    De Genst E, Messer A, Dobson CM (2014) Antibodies and protein misfolding: from structural research tools to therapeutic strategies. Biochim Biophys Acta 1844:1907–1919CrossRefPubMedGoogle Scholar
  58. 58.
    Higaki JN, Chakrabartty A, Galant NJ et al (2016) Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin. Amyloid 23:86–97CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Schmidt HH-J, Barroso F, González-Duarte A et al (2016) Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy. Muscle Nerve 54:353–360CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Gorram F, Alarcon F, Perdry H et al (2017) Refine penetrance estimates in the main pathogenic variants of transthyretin hereditary (familial) amyloid polyneuropathy (TTR-FAP) using a new non-parametric approach (NPSE). Amyloid 24:115–116CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Neurology and Amyloid NetworkUniversity Hospital Henri MondorCréteilFrance

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