Restrictive cardiomyopathy: difficulties desminopathy diagnostics

The article provides a brief overview of the problems of diagnostics and etiological verification of restrictive cardiomyopathy (RCMP). Multiple causes lead to the restrictive phenotype of intracardiac hemodynamics and diastolic dysfunction of the heart: infiltrative (amyloidosis, sarcoidosis, elastoma, metabolic syndrome, tumor metastasis to the myocardium); endomyocardial (tropical endomyocardial fibrosis, hypereosinophilic syndrome, carcinoid, radiation damage); accumulation diseases (hemochromatosis, Pompe and Gaucher diseases, Fabry disease). RKMP is also characteristic for desminopathy — so-called desmin storage disease. This is a disease caused by mutations in the desmin gene (DES) that determine the development of cardiomyopathy or myofibrillar myopathy, and in some cases cause a combined phenotype of the disease. Desmin belongs to the group of intermediate filaments that maintain the structural and functional integrity of myofibrils. Mutations in DES lead to disruption of the assembly of filaments and a change in the myofibrillar cell lattice, which contributes to an increased vulnerability of myocytes to mechanical stress. The article presents a clinical case of familial desminopathy associated with a new missense R118P mutation of DES gene, characterized by dominant cardiac RCMP phenotype and subclinical manifestations of myofibrillar myopathy.

1. McKenna WJ, Maron BJ, Thiene G. Classification, Epidemiology, and Global Burden of Cardiomyopathies. Circulation research. 2017;121:722-30. doi: 10.1161/CIRCRESAHA.117.309711.

2. Towbin J. Inherited cardiomyopathies. Circ J. 2014;78:2347-56. doi:10.1253/circj.CJ-14-0893.

3. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24:214-20. doi:10.1097/HCO.0b013e32832a1d2e.

4. Teekakirikul P, Kelly MA, Rehm HL, et al. Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era. J Mol Diagnostics. 2013;15:158-67. doi:10.1016/j.jmoldx.2012.09.00.

5. Ho CY, Charron P, Richard P, et al. Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovasc Res. 2015;105:397-408. doi:101093/cvr/cvv025.

6. Burke MA, Cook SA, Seidman JG, et al. Clinical and mechanistic insights into the genetics of cardiomyopathy. J Am Coll Cardiol. 2016;68:2871-86. doi:10.1016/j.jacc.2016.08.079.

7. Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of dilated cardiomyopathy. Eur Heart J. 2015;36:1123-35. doi:10.1093/eurheartj/ehu301.

8. Kostareva A, Kiselev A, Gudkova A, et al. Genetic spectrum of idiopathic restrictive cardiomyopathy uncovered by next-generation sequencing. PLoS One. 2016;11:e0163362. doi:10.1371/journal.pone.0163362.

9. Gallego-Delgado M, Delgado JF, Brossa-Loidi V, et al. Idiopathic restrictive cardiomyopathy is primarily a genetic disease. J Am Coll Cardiol. 2016;67:3021-3. doi:10.1016/j.jacc.2016.04.024.

10. Walsh R, Thomson KL, Ware JS, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genetics in medicine: official journal of the American College of Medical Genetics. 2017;19:192-203. doi:101038/gim.2016.90.

11. Brodehl A, Dieding M, Biere N, et al. Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect. Journal of molecular and cellular cardiology. 2016;91:207-14. doi: 101016/j.yjmcc.2015.12.015.

12. Harada H, Hayashi T, Nishi H, et al. Phenotypic expression of a novel desmin gene mutation: hypertrophic cardiomyopathy followed by systemic myopathy. Journal of human genetics. 2018;63:249-54. doi:10.1038/s10038-017-0383-x.

13. Ojrzynska N, Bilinska ZT, Franaszczyk M, et al. Restrictive cardiomyopathy due to novel desmin gene mutation. Kardiologia polska. 2017;75:723. doi:10.5603/KP.2017.0129.

14. Klauke B, Kossmann S, Gaertner A, et al. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Human molecular genetics. 2010;19:4595-607. doi:10.1093/hmg/ddq387.

15. Schirmer I, Dieding M, Klauke B, et al. A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy. Mol Genet Genomic Med. 2018;6(2):288-93. doi:10.1002/mgg3.358.

16. Cetin N, Balci-Hayta B, Gundesli H, et al. A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies. Journal of medical genetics. 2013;50:437-43. doi:10.1136/jmedgenet-2012-101487.

17. Goldman RD, Cleland MM, Murthy SN, et al. Inroads into the structure and function of intermediate filament networks. J Struct Biol. 2012;177:14-23. doi: 101016/j.jsb.2011.11.017

18. Hnia K, Ramspacher C, Vermot J, Laporte J. Desmin in muscle and associated diseases: beyond the structural function. Cell and tissue research. 2015;360:591-608. doi :101007/s00441-014-2016-4.

19. Charrier EE, Asnacios A, Milloud R, et al. Desmin Mutation in the C-Terminal Domain Impairs Traction Force Generation in Myoblasts. Biophys J. 2016;110:470-80. doi: 10.1016/j.bpj.2015.11.3518.

20. Clemen CS, Herrmann H, Strelkov SV, Schroder R. Desminopathies: pathology and mechanisms. Acta Neuropathol. 2013;125:47-75. doi:101007/s00401-012-1057-6.

21. Brodehl A, Ferrier RA, Hamilton SJ, et al. Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum Mutat. 2016;37:269-79. doi:10.1002/humu.22942.

22. Ploski R, Rydzanicz M, Ksiazczyk TM, et al. Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy. Am J Med Genet A. 2016;170:3241-8. doi:10.1002/ajmg.a.37860.

23. Wu W, Lu CX, Wang YN, et al. Novel phenotype-genotype correlations of restrictive cardiomyopathy with myosin-binding protein C (MYBPC3) gene mutations tested by next-generation sequencing. J Am Heart Assoc. 2015;4:001879. doi:10.1161/JAHA.115.001879.

24. Вайханская Т. Г. Диабетическая кардиомиопатия: два клинических фенотипа — рестриктивный и дилатационный. Механизмы патогенеза, диагностические критерии и лечение. Кардиология в Беларуси. 2015;42:121-39.

25. Arbustini Е, Narula N, Tavazzi L, et al. The MOGE(S) Classification of Cardiomyopathy for Clinicians. JACC. 2014; 6 4:304-18. doi:101016/j.jacc.2014.05.027

26. McLendon PM, Robbins J. Desmin-related cardiomyopathy: an unfolding story. American journal of physiology. Heart and circulatory physiology. 2011;301:H1220-8. doi :101152/ ajpheart.00601.2011.

27. Arbustini E, Morbini P. Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits. JACC. 1998;31(3):645-53. doi:10.1016/S0735-1097(98)00026-6.

28. Arbustini E, Pasotti M, Pilotto A, et al. Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects. European journal of heart failure. 2006;8:477-83. doi:10.1016/j.ejheart.2005.11.003.

29. Spaendonck-Zwarts KY van, Hessem L van, Jongbloed JD, et al. Desmin-related myopathy. Clin Genet. 2011;80:354-66. doi:10.1111/j.1399-0004.2010.01512.x.

30. Patel DM, Green KJ. Desmosomes in the heart: a review of clinical and mechanistic analyses. Cell communication & adhesion. 2014;21:109-28. doi:10.3109/15419061.2014.906533.

31. Capetanaki Y, Papathanasiou S, Diokmetzidou A, et al. Desmin related disease: a matter of cell survival failure. Current opinion in cell biology. 2015;32:113-20. doi:101016/j.ceb.2015.01.004.

32. Charron P, Arad M, Arbustini E, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31:2715-26. doi:10.1093/eurheartj/ehq271.

33. Brodehl A, Gaertner-Rommel A, Milting H. Molecular insights into cardiomyopathies associated with desmin (DES) mutations. Biophysical Reviews. 2018;10:983-1006. doi:10.1007/s12551-018-0429-0.