Skip to main content
SpringerLink
Log in

Neurologische Manifestationen der ATTR-Amyloidose

Neurological manifestations of ATTR amyloidosis

  • Schwerpunkt: Kardiale Amyloidose
  • Published:
Die Innere Medizin Aims and scope Submit manuscript

Zusammenfassung

Die Transthyretin(ATTR)-Amyloidose ist eine seltene Erkrankung, bei der sich das Protein Transthyretin (TTR) in Form von Amyloidfibrillen in verschiedenen Geweben und Organen ablagert und sekundär zu Funktionsstörungen führt, insbesondere an den peripheren Nerven und am Herzen. Unterschieden wird eine hereditäre von einer sporadischen Form. Die hereditäre Variante wird autosomal-dominant vererbt und tritt in der Regel im jüngeren bis mittleren Lebensalter auf, während die sporadische Form im höheren Lebensalter auftritt und keine bekannte genetische Ursache hat. Typische Zeichen einer hereditären ATTR-Amyloidose (ATTRv, v für Variante) sind eine rasch voranschreitende sensomotorische und autonome Polyneuropathie (PNP), eine kardiale Dysfunktion sowie okuläre und gastrointestinale Symptome. Ein Karpaltunnelsyndrom geht der Manifestation häufig voraus. Für die Behandlung der Patient:innen mit ATTRv-PNP stehen in Deutschland abhängig vom Schweregrad unterschiedliche therapeutische Optionen zur Verfügung (Tafamidis, Patisiran, Inotersen oder Vutrisiran). Bei der sporadischen Variante, der Wildtyp-ATTR-Amyloidose (ATTRwt), stehen meist die Symptome einer progredienten Kardiomyopathie im Vordergrund. Aber auch bei dieser Variante zeigen die Patient:innen in einer neurologischen Mitbeurteilung häufig eine sensible ataktische PNP. Therapeutisch kann der Tetramerstabilisator Tafamidis angewendet werden. Die Behandlung von Patient:innen mit einer ATTR-Amyloidose sollte aufgrund der Komplexität in interdisziplinären auf Amyloidose spezialisierten Zentren erfolgen.

Abstract

Transthyretin amyloidosis (ATTR) is a rare disease in which the protein transthyretin (TTR) is deposited in the form of amyloid fibrils in various tissues and organs and secondarily leads to functional impairment, especially in peripheral nerves and the heart. A differentiation is made between hereditary and sporadic forms. The hereditary variant is inherited in an autosomal dominant manner and usually occurs in the younger to middle-aged, while the sporadic form occurs in older age and has no known genetic cause. Typical signs of hereditary ATTR amyloidosis (ATTRv, v for variant) include a rapidly progressing sensorimotor and autonomic polyneuropathy (PNP), cardiac dysfunction as well as ocular and gastrointestinal symptoms. A carpal tunnel syndrome often precedes the manifestation. Various options (tafamidis, patisiran, inotersen or vutrisiran) are available for the treatment of patients with ATTRv with PNP in Germany, depending on the severity. In the sporadic variant of wild-type ATTR amyloidosis (ATTRwt), symptoms of progressive cardiomyopathy are usually prominent; however, neurological assessment of these patients often also reveals a concomitant sensory ataxic PNP. The tetramer stabilizer tafamidis can be used for treatment. Because of this complex presentation, the management of patients with ATTR amyloidosis should be performed in interdisciplinary centers specialized in amyloidosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abbreviations

ASO:

Antisense-Oligonukleotid

ATTR:

Amyloidogenes Transthyretin

ATTRv:

Variantenassoziierte Transthyretinamyloidose

ATTRwt:

Wildtyp-Transthyretinamyloidose

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

GalNAc:

N‑Acetylgalaktosamin

LFN:

Large-fiber-Neuropathien

mBMI:

Modifizierter Body-Mass-Index

mNIS + 7:

Modifizierter Neuropathy Impairment Score + 7

mRNA:

Messenger-RNA

NIS:

Neuropathy Impairment Score

Norfolk QOL:

Norfolk-Fragebogen zur Lebensqualität

NT-proBNP:

N‑terminales pro-natriuretisches Peptid vom B‑Typ

PNP:

Polyneuropathie

RISC:

„RNA-induced silencing complex“

RNAi:

RNA-Interferenz

SFN:

Small-fiber-Neuropathien

TTR:

Transthyretin

ZNS:

Zentrales Nervensystem

Literatur

  1. Plante-Bordeneuve V, Said G (2011) Familial amyloid polyneuropathy. Lancet Neurol 10(12):1086–1097

    CAS  PubMed  Google Scholar 

  2. Herbert J et al (1986) Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. Neurology 36(7):900–911

    CAS  PubMed  Google Scholar 

  3. Dohrn MF et al (2021) Targeting transthyretin—mechanism-based treatment approaches and future perspectives in hereditary amyloidosis. J Neurochem 156(6):802–818

    CAS  PubMed  Google Scholar 

  4. Weisner B, Roethig HJ (1983) The concentration of prealbumin in cerebrospinal fluid (CSF), indicator of CSF circulation disorders. Eur Neurol 22(2):96–105

    CAS  PubMed  Google Scholar 

  5. Colon W, Kelly JW (1992) Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31(36):8654–8660

    CAS  PubMed  Google Scholar 

  6. Suhr OB, Lundgren E, Westermark P (2017) One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition. J Intern Med 281(4):337–347

    CAS  PubMed  Google Scholar 

  7. Benson MD et al (2018) Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 379(1):22–31

    CAS  PubMed  Google Scholar 

  8. Adams D et al (2018) Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379(1):11–21

    CAS  PubMed  Google Scholar 

  9. Siepen FAD et al (2019) Carpal tunnel syndrome and spinal canal stenosis: harbingers of transthyretin amyloid cardiomyopathy? Clin Res Cardiol 108(12):1324–1330

    Google Scholar 

  10. Mutations in hereditary amyloidosis. http://amyloidosismutations.com/. Zugegriffen: 25. Jan. 2023

  11. Adams D et al (2020) Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. https://doi.org/10.1007/s00415-019-09688-0

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kaku MC et al (2022) Neurological manifestations of hereditary transthyretin amyloidosis: a focus on diagnostic delays. Amyloid. https://doi.org/10.1080/13506129.2022.2046557

    Article  PubMed  Google Scholar 

  13. Dohrn MF et al (2021) Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis. Neurol Res Pract 3(1):57

    PubMed  PubMed Central  Google Scholar 

  14. Tozza S et al (2021) The neuropathy in hereditary transthyretin amyloidosis: A narrative review. J Peripher Nerv Syst 26(2):155–159

    PubMed  PubMed Central  Google Scholar 

  15. Freeman R et al (2022) Cutaneous amyloid is a biomarker in early ATTRv neuropathy and progresses across disease stages. Ann Clin Transl Neurol 9(9):1370–1383

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shields RW Jr (2009) Heart rate variability with deep breathing as a clinical test of cardiovagal function. Cleve Clin J Med 76(Suppl 2):S37–S40

    PubMed  Google Scholar 

  17. Coutinho PM et al (1980) Forty years of experience with type I amyloid neuropathy. Review of 483 cases. Excerpta Medica, Amsterdam

  18. Simmons Z et al (1993) Low diagnostic yield of sural nerve biopsy in patients with peripheral neuropathy and primary amyloidosis. J Neurol Sci 120(1):60–63

    CAS  PubMed  Google Scholar 

  19. Qin Q et al (2021) Current review of leptomeningeal amyloidosis associated with transthyretin mutations. Neurologist 26(5):189–195

    PubMed  PubMed Central  Google Scholar 

  20. Kleefeld F et al (2020) Familial oculo-leptomeningeal transthyretin amyloidosis caused by leu55Arg mutation. J Neuromuscul Dis 7(4):515–519

    PubMed  Google Scholar 

  21. Kleefeld F et al (2022) Same same, but different? The neurological presentation of wildtype transthyretin (ATTRwt) amyloidosis. Amyloid 29(2):92–101

    CAS  PubMed  Google Scholar 

  22. Papagianni A et al (2022) Clinical and apparative investigation of large and small nerve fiber impairment in mixed cohort of ATTR-amyloidosis: impact on patient management and new insights in wild-type. Amyloid 29(1):14–22

    CAS  PubMed  Google Scholar 

  23. Wajnsztajn Yungher F et al (2020) Peripheral neuropathy symptoms in wild type transthyretin amyloidosis. J Peripher Nerv Syst 25(3):265–272

    CAS  PubMed  Google Scholar 

  24. Eldhagen P et al (2020) Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis. J Intern Med. https://doi.org/10.1111/joim.13222

    Article  Google Scholar 

  25. Barroso FA et al (2022) Characteristics of patients with autonomic dysfunction in the transthyretin amyloidosis outcomes survey (THAOS). Amyloid 29(3):175–183

    CAS  PubMed  Google Scholar 

  26. Dohrn MF et al (2020) Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature. J Neurol. https://doi.org/10.1007/s00415-020-09962-6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Maurer MS et al (2018) Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 379(11):1007–1016

    CAS  PubMed  Google Scholar 

  28. Hund E et al (2018) Transthyretin amyloidosis (ATTR amyloidosis): recommendations for the management in Germany and Austria recommendations of the German society of amyloid diseases. Akt Neurol 45(8):605–616

    Google Scholar 

  29. Ioannou A, Fontana M, Gillmore JD (2023) RNA targeting and gene editing strategies for transthyretin amyloidosis. BioDrugs 37(2):127–142

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Coelho T et al (2012) Tafamidis for transthyretin familial amyloid polyneuropathy a randomized, controlled trial. Neurology 79(8):785–792

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Waddington Cruz M et al (2016) Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid 23(3):178–183

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Monteiro C et al (2019) Predictive model of response to tafamidis in hereditary ATTR polyneuropathy. JCI Insight. https://doi.org/10.1172/jci.insight.126526

    Article  PubMed  PubMed Central  Google Scholar 

  33. Merlini G et al (2013) Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res 6(6):1011–1020

    PubMed  PubMed Central  Google Scholar 

  34. Holmgren G et al (1993) Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341(8853):1113–1116

    CAS  PubMed  Google Scholar 

  35. Suhr OB et al (1995) Liver transplantation in familial amyloidotic polyneuropathy. Follow-up of the first 20 Swedish patients. Transplantation 60(9):933–938

    CAS  PubMed  Google Scholar 

  36. Ericzon BG et al (2015) Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation 99(9):1847–1854

    CAS  PubMed  Google Scholar 

  37. Llado L et al (2010) Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation. Liver Transpl 16(12):1386–1392

    PubMed  Google Scholar 

  38. Liepnieks JJ, Benson MD (2007) Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid 14(4):277–282

    CAS  PubMed  Google Scholar 

  39. Liepnieks JJ, Zhang LQ, Benson MD (2010) Progression of transthyretin amyloid neuropathy after liver transplantation. Neurology 75(4):324–327

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Beirao JM et al (2015) Impact of liver transplantation on the natural history of oculopathy in Portuguese patients with transthyretin (V30M) amyloidosis. Amyloid 22(1):31–35

    CAS  PubMed  Google Scholar 

  41. Sekijima Y (2015) Transthyretin-type cerebral amyloid angiopathy: a serious complication in post-transplant patients with familial amyloid polyneuropathy. J Neurol Neurosurg Psychiatry 86(2):124

    PubMed  Google Scholar 

  42. Maia LF et al (2015) CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings. J Neurol Neurosurg Psychiatry 86(2):159–167

    PubMed  Google Scholar 

  43. Ando Y et al (2022) Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid 29(3):143–155

    CAS  PubMed  Google Scholar 

  44. Buxbaum JN (2018) Oligonucleotide drugs for transthyretin amyloidosis. N Engl J Med 379(1):82–85

    PubMed  Google Scholar 

  45. Obici L et al (2020) Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis. Amyloid 27(3):153–162

    CAS  PubMed  Google Scholar 

  46. Solomon SD et al (2019) Effects of Patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation 139(4):431–443

    CAS  PubMed  Google Scholar 

  47. Schmidt HH et al (2022) Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation. Am J Transplant. https://doi.org/10.1111/ajt.17009

  48. Adams D et al (2022) Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. https://doi.org/10.1080/13506129.2022.2091985

  49. HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy. https://classic.clinicaltrials.gov/ct2/show/NCT04153149. Zugegriffen: 30. Juni 2023

  50. Coelho T et al (2020) Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis. J Neurol 267(4):1070–1079

    CAS  PubMed  Google Scholar 

  51. Dasgupta NR et al (2020) Inotersen therapy of transthyretin amyloid cardiomyopathy. Amyloid 27(1):52–58

    CAS  PubMed  Google Scholar 

  52. Coelho T et al (2021) Design and rationale of the global phase 3 NEURO-TTRansform study of antisense oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in hereditary transthyretin-mediated amyloid polyneuropathy. Neurol Ther 10(1):375–389

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Amyloidosis Center Charité Berlin (ACCB), Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland

    Helena F. Pernice &  Katrin Hahn

  2. Klinik für Neurologie mit Experimenteller Neurologie, Charité – Universitätsmedizin Berlin, Berlin, Deutschland

    Helena F. Pernice &  Katrin Hahn

  3. Berlin Institute of Health at Charité (BIH), Universitätsmedizin Berlin, Berlin, Deutschland

    Katrin Hahn

Authors
  1. Helena F. Pernice
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrin Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katrin Hahn.

Ethics declarations

Interessenkonflikt

H.F. Pernice hat Personenförderung, Reisezuschüsse für wissenschaftliche Veranstaltungen und Rednerhonorare durch Alnylam Pharmaceuticals Inc, und persönliche Förderung durch die Deutsche Gesellschaft für Muskelkranke (DGM) GmbH erhalten. K. Hahn hat finanzielle Vergütung für Beratung, Advisory Board Tätigkeiten, Redner-/Kongressbeiträge und Reisezuschüsse für wissenschaftliche Veranstaltungen von Akcea Therapeuticals Inc., Alnylam Pharmaceuticals Inc., Takeda Pharmaceutical Inc., Pfizer Pharmaceuticals Inc. und Swedish Orphan Biovitrum Inc, sowie Forschungsförderung von der Charité (BIH clinical fellow), Alnylam Pharmaceuticals Inc., and Pfizer Pharmaceuticals erhalten.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

Gerd Hasenfuß, Göttingen

Michael Hallek, Köln

Andreas Neubauer, Marburg

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pernice, H.F., Hahn, K. Neurologische Manifestationen der ATTR-Amyloidose. Innere Medizin 64, 848–854 (2023). https://doi.org/10.1007/s00108-023-01570-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00108-023-01570-6

Schlüsselwörter

Keywords

Search

Navigation