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Research paper
Published online: 2020-08-11
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Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis

Monika Gawor, Katarzyna Holcman, Maria Franaszczyk, Marta Lipowska, Piotr Michałek, Anna Teresińska, Zofia T. Bilińska, Paweł Rubiś, Magdalena Kostkiewicz, Wojciech Szot, Piotr Podolec, Jacek Grzybowski
DOI: 10.5603/CJ.a2020.0104
·
Pubmed: 32789836

open access

Ahead of print
Original articles
Published online: 2020-08-11

Abstract

Background: Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland.

Methods: Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed.

Results: In 2017–2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased LV ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke.

Conclusions: According to available research, this is the first time types of TTR mutations and clinical characteristics of Polish patients with cardiac hereditary ATTR have been reported. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population.

Abstract

Background: Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland.

Methods: Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed.

Results: In 2017–2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased LV ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke.

Conclusions: According to available research, this is the first time types of TTR mutations and clinical characteristics of Polish patients with cardiac hereditary ATTR have been reported. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population.

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Keywords

cardiac amyloidosis, hereditary transthyretin amyloidosis, transthyretin amyloidosis, transthyretin cardiomyopathy, transthyretin mutation

About this article
Title

Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis

Journal

Cardiology Journal

Issue

Ahead of print

Article type

Research paper

Published online

2020-08-11

DOI

10.5603/CJ.a2020.0104

Pubmed

32789836

Keywords

cardiac amyloidosis
hereditary transthyretin amyloidosis
transthyretin amyloidosis
transthyretin cardiomyopathy
transthyretin mutation

Authors

Monika Gawor
Katarzyna Holcman
Maria Franaszczyk
Marta Lipowska
Piotr Michałek
Anna Teresińska
Zofia T. Bilińska
Paweł Rubiś
Magdalena Kostkiewicz
Wojciech Szot
Piotr Podolec
Jacek Grzybowski

References (29)
  1. Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019; 73(22): 2872–2891.
  2. Castaño A, Drachman BM, Judge D, et al. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015; 20(2): 163–178.
  3. http://amyloidosismutations.com/mut-attr.php (last accessed December 13th 2019).
  4. Ammirati E, AbouEzzeddine OF. Transthyretin amyloidosis in Western Europe: a snapshot from the THAOS registry and a call for further perspectives. Eur Heart J. 2019 [Epub ahead of print].
  5. Cruz MW, Barroso F, González-Duarte A, et al. The demographic, genetic, and clinical characteristics of Latin American subjects enrolled in the Transthyretin Amyloidosis Outcomes Survey. Amyloid. 2017; 24(sup1): 107–108.
  6. Maurer M, Hanna M, Grogan M, et al. Genotype and Phenotype of Transthyretin Cardiac Amyloidosis. J Am Coll Cardiol. 2016; 68(2): 161–172.
  7. Witteles RM, Bokhari S, Damy T, et al. Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC Heart Fail. 2019; 7(8): 709–716.
  8. Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019; 12(9): e006075.
  9. Holmgren G, Wikström L, Lundgren HE, et al. Discordant penetrance of the trait for familial amyloidotic polyneuropathy in two pairs of monozygotic twins. J Intern Med. 2004; 256(5): 453–456.
  10. Saraiva MJ, Almeida MR, Alves IL, et al. Modulating conformational factors in transthyretin amyloid. Ciba Found Symp. 1996; 199: 47–52; discussion 52.
  11. Szczygieł JA, Wieczorek PZ, Drozd-Sokołowska J, et al. Impaired right ventricular function as a predictor of early mortality in patients with light‑ chain cardiac amyloidosis assessed in a cardiology department. Pol Arch Intern Med. 2017; 127(12): 854–864.
  12. Prochorec-Sobieszek M, Bilińska ZT, Grzybowski J, et al. Cardiac amyloidosis diagnosed by endomyocardial biopsy. Clinical, histopathological, immunohistochemical and ultrastructural studies. Kardiol Pol. 2005; 63(7): 20–35.
  13. Rubiś P, Rudnicka-Sosin L, Jurczyszyn A, et al. The paramount importance of repeated left ventricular endomyocardial biopsy during the diagnosis of restrictive cardiomyopathy due to AL cardiac amyloidosis. Kardiol Pol. 2016; 74(8): 796.
  14. Gawor M, Mazurkiewicz Ł, Milanowska B, et al. Recovery from heart failure in a patient with cardiac amyloidosis treated with autologous stem cell transplantation. Kardiol Pol. 2017; 75(1): 83.
  15. Rajtar-Salwa R, Gębka A, Petkow-Dimitrow P. Non-invasive cardiac imaging methods in transthyretin amyloidosis. Kardiol Pol. 2019; 77(2): 234.
  16. Gillmore JD, Maurer MS, Falk RH. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016; 14: 2404–2412.
  17. Rowczenio D, Quarta CC, Fontana M, et al. Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. Hum Mutat. 2019; 40(1): 90–96.
  18. Maurer M, Hanna M, Grogan M, et al. Genotype and Phenotype of Transthyretin Cardiac Amyloidosis. J Am Coll Cardiol. 2016; 68(2): 161–172.
  19. Chen CH, Huang CW, Lee MJ. A case of familial amyloidotic polyneuropathy with a rare Phe33Leu mutation in the TTR gene. J Formos Med Assoc. 2014; 113(8): 575–576.
  20. Harding J, Skare J, Skinner M. A second transthyretin mutation at position 33 (Leu/Phe) associated with familial amyloidotic polyneuropathy. Biochim Biophys Acta. 1991; 1097(3): 183–186.
  21. Myers TJ, Kyle RA, Jacobson DR. Familial amyloid with a transthyretin leucine 33 mutation presenting with ascites. Am J Hematol. 1998; 59(3): 249–251, doi: 10.1002/(sici)1096-8652(199811)59:3<249::aid-ajh13>3.0.co;2-b.
  22. Csillik A, Pozsonyi Z, Soós K, et al. [Transthyretin familial amyloid polyneuropathy - three Hungarian cases with rare mutations (His88Arg and Phe33Leu)]. Ideggyogy Sz. 2016; 69(7-8): 245–253.
  23. Holmgren G, Hellman U, Jonasson J, et al. A Swedish family with the rare Phe33Leu transthyretin mutation. Amyloid. 2005; 12(3): 189–192.
  24. Leibou L, Frand J, Sadeh M, et al. Clinical and genetic findings in eight Israeli patients with transthyretin-associated familial amyloid polyneuropathy. Isr Med Assoc J. 2012; 14(11): 662–665.
  25. Meng LC, Lyu He, Zhang W, et al. Hereditary transthyretin amyloidosis in eight Chinese families. Chin Med J (Engl). 2015; 128(21): 2902–2905.
  26. Nakamura M, Hamidi Asl K, Benson MD. A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid. 2000; 7(1): 46–50.
  27. Reynolds MM, Veverka KK, Gertz MA, et al. Ocular manifestations of familial transthyretin amyloidosis. Am J Ophthalmol. 2017; 183: 156–162.
  28. Bourque PR, McCurdy AR, Mielniczuk LM, et al. Cardiac amyloidosis phenotype associated with a glu89lys transthyretin mutation. Can J Cardiol. 2017; 33(6): 830.e5–830.e7.
  29. Kristen AV, Maurer MS, Rapezzi C, et al. THAOS investigators. Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One. 2017; 12(4): e0173086.

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