Top

Published in:

Open Access 01-12-2022 | Diseases of the neuromuscular synapses and muscles | Research

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

Authors: A. Muravyev, T. Vershinina, P. Tesner, G. Sjoberg, Yu. Fomicheva, N. Novák Čajbiková, A. Kozyreva, S. Zhuk, E. Mamaeva, S. Tarnovskaya, J. Jornholt, P. Sokolnikova, T. Pervunina, E. Vasichkina, T. Sejersen, A. Kostareva

Published in: Orphanet Journal of Rare Diseases | Issue 1/2022

Abstract

Background

FLNC is one of the few genes associated with all types of cardiomyopathies, but it also underlies neuromuscular phenotype. The combination of concomitant neuromuscular and cardiac involvement is not often observed in filaminopathies and the impact of this on the disease prognosis has hitherto not been analyzed.

Results

Here we provide a detailed clinical, genetic, and structural prediction analysis of distinct FLNC-associated phenotypes based on twelve pediatric cases. They include early-onset restrictive cardiomyopathy (RCM) in association with congenital myopathy. In all patients the initial diagnosis was established during the first year of life and in five out of twelve (41.7%) patients the first symptoms were observed at birth. RCM was present in all patients, often in combination with septal defects. No ventricular arrhythmias were noted in any of the patients presented here. Myopathy was confirmed by neurological examination, electromyography, and morphological studies. Arthrogryposes was diagnosed in six patients and remained clinically meaningful with increasing age in three of them. One patient underwent successful heart transplantation at the age of 18 years and two patients are currently included in the waiting list for heart transplantation. Two died due to congestive heart failure. One patient had ICD instally as primary prevention of SCD. In ten out of twelve patients the disease was associated with missense variants and only in two cases loss of function variants were detected. In half of the described cases, an amino acid substitution A1186V, altering the structure of IgFLNc10, was found.

Conclusions

The present description of twelve cases of early-onset restrictive cardiomyopathy with congenital myopathy and FLNC mutation, underlines a distinct unique phenotype that can be suggested as a separate clinical form of filaminopathies. Amino acid substitution A1186V, which was observed in half of the cases, defines a mutational hotspot for the reported combination of myopathy and cardiomyopathy. Several independent molecular mechanisms of FLNC mutations linked to filamin structure and function can explain the broad spectrum of FLNC-associated phenotypes. Early disease presentation and unfavorable prognosis of heart failure demanding heart transplantation make awareness of this clinical form of filaminopathy of great clinical importance.

Available only for authorised users

Ader F, et al. FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations. Clin Genet. 2019;96:317–29. https://doi.org/10.1111/cge.13594.CrossRefPubMed

Akhtar MM, et al. Association of left ventricular systolic dysfunction among carriers of truncating variants in Filamin C with frequent ventricular arrhythmia and end-stage heart failure. JAMA Cardiol. 2021;6:891–901. https://doi.org/10.1001/jamacardio.2021.1106.CrossRefPubMed

Avila-Smirnow D, et al. Cardiac arrhythmia and late-onset muscle weakness caused by a myofibrillar myopathy with unusual histopathological features due to a novel missense mutation in FLNC. Rev Neurol (Paris). 2016;172:594–606. https://doi.org/10.1016/j.neurol.2016.07.017.CrossRef

Bains S, et al. A novel truncating variant in FLNC-encoded Filamin C may serve as a proarrhythmic genetic substrate for arrhythmogenic bileaflet mitral valve prolapse syndrome. Mayo Clin Proc. 2019;94:906–13. https://doi.org/10.1016/j.mayocp.2018.11.028.CrossRefPubMed

Batonnet-Pichon S, et al. Myofibrillar myopathies: new perspectives from animal models to potential therapeutic approaches. J Neuromuscul Dis. 2017;4:1–15. https://doi.org/10.3233/JND-160203.CrossRefPubMedPubMedCentral

Begay RL, et al. Filamin C truncation mutations are associated with arrhythmogenic dilated cardiomyopathy and changes in the cell-cell adhesion structures. JACC Clin Electrophysiol. 2018;4:504–14. https://doi.org/10.1016/j.jacep.2017.12.003.CrossRefPubMedPubMedCentral

Begay RL, et al. FLNC gene splice mutations cause dilated cardiomyopathy. JACC Basic Transl Sci. 2016;1:344–59. https://doi.org/10.1016/j.jacbts.2016.05.004.CrossRefPubMedPubMedCentral

Brodehl A, et al. Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum Mutat. 2016;37:269–79. https://doi.org/10.1002/humu.22942.CrossRefPubMed

Carvalho AAS, et al. Genetic mutations and demographic, clinical, and morphological aspects of myofibrillar myopathy in a French cohort. Genet Test Mol Biomarkers. 2018;22:374–83. https://doi.org/10.1089/gtmb.2018.0004.CrossRefPubMed

10.

Critchley DR, et al. Talin at a glance. J Cell Sci. 2008;121:1345–7. https://doi.org/10.1242/jcs.018085.CrossRefPubMed

11.

Culic V, et al. Distal arthrogryposis with variable clinical expression caused by TNNI2 mutation. Hum Genome Var. 2016;3:16035. https://doi.org/10.1038/hgv.2016.35.CrossRefPubMedPubMedCentral

12.

Delort F, et al. Alterations of redox dynamics and desmin post-translational modifications in skeletal muscle models of desminopathies. Exp Cell Res. 2019;383:111539. https://doi.org/10.1016/j.yexcr.2019.111539.CrossRefPubMed

13.

Deng H, et al. Exome sequencing of a pedigree reveals S339L mutation in the TLN2 gene as a cause of fifth finger camptodactyly. PLoS ONE. 2016;11:e0155180. https://doi.org/10.1371/journal.pone.0155180.CrossRefPubMedPubMedCentral

14.

Duan BC, et al. Alternating hemiplegia and paroxysmal torticollis caused by SCN4A mutation: a new phenotype? Neurology. 2019;93:673–4. https://doi.org/10.1212/WNL.0000000000008212.CrossRefPubMed

15.

Duff RM, et al. Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. Am J Hum Genet. 2011;88:729–40. https://doi.org/10.1016/j.ajhg.2011.04.021.CrossRefPubMedPubMedCentral

16.

Eden M, et al. Cardiac filaminopathies: illuminating the divergent role of Filamin C mutations in human cardiomyopathy. J Clin Med. 2021. https://doi.org/10.3390/jcm10040577.CrossRefPubMedPubMedCentral

17.

Evangelista T, et al. A heterozygous mutation in the Filamin C gene causes an unusual nemaline myopathy with ring fibers. J Neuropathol Exp Neurol. 2020;79:908–14. https://doi.org/10.1093/jnen/nlaa052.CrossRefPubMed

18.

Furst DO, et al. ilamin C-related myopathies: pathology and mechanisms. Acta Neuropathol. 2013;125:33–46. https://doi.org/10.1007/s00401-012-1054-9.CrossRefPubMed

19.

Guergueltcheva V, et al. Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency. Neurology. 2011;77:2105–14. https://doi.org/10.1212/WNL.0b013e31823dc51e.CrossRefPubMed

20.

Hall CL, et al. Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype. Int J Cardiol. 2020;307:101–8. https://doi.org/10.1016/j.ijcard.2019.09.048.CrossRefPubMed

21.

Jin JY, et al. The novel compound heterozygous mutations of ECEL1 identified in a family with distal arthrogryposis type 5D. Biomed Res Int. 2020;2020:2149342. https://doi.org/10.1155/2020/2149342.CrossRefPubMedPubMedCentral

22.

Jorholt J, et al. Two new cases of hypertrophic cardiomyopathy and skeletal muscle features associated with ALPK3 homozygous and compound heterozygous variants. Genes (Basel). 2020. https://doi.org/10.3390/genes11101201.CrossRef

23.

Kiema T, et al. The molecular basis of filamin binding to integrins and competition with talin. Mol Cell. 2006;21:337–47. https://doi.org/10.1016/j.molcel.2006.01.011.CrossRefPubMed

24.

Kiselev A, et al. De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy. Hum Mutat. 2018. https://doi.org/10.1002/humu.23559.CrossRefPubMed

25.

Kley RA, et al. Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients. Brain. 2007;130:3250–64. https://doi.org/10.1093/brain/awm271.CrossRefPubMed

26.

Kley RA, et al. FLNC-associated myofibrillar myopathy: new clinical, functional, and proteomic data. Neurol Genet. 2021;7:e590. https://doi.org/10.1212/NXG.0000000000000590.CrossRefPubMedPubMedCentral

27.

Kolbel H, et al. First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC. Hum Mutat. 2020;41:1600–14. https://doi.org/10.1002/humu.24062.CrossRefPubMed

28.

Lad Y, et al. Structure of three tandem filamin domains reveals auto-inhibition of ligand binding. EMBO J. 2007;26:3993–4004. https://doi.org/10.1038/sj.emboj.7601827.CrossRefPubMedPubMedCentral

29.

Luan X, et al. A novel heterozygous deletion-insertion mutation (2695–2712 del/GTTTGT ins) in exon 18 of the filamin C gene causes filaminopathy in a large Chinese family. Neuromuscul Disord. 2010;20:390–6. https://doi.org/10.1016/j.nmd.2010.03.009.CrossRefPubMed

30.

Mao Z, et al. Structure and function of Filamin C in the muscle Z-disc. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21082696.CrossRefPubMedPubMedCentral

31.

Miltgen M, et al. Novel heterozygous mutation in ANO3 responsible for craniocervical dystonia. Mov Disord. 2016;31:1251–2. https://doi.org/10.1002/mds.26717.CrossRefPubMed

32.

O’Grady GL, et al. Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. Am J Hum Genet. 2016;99:1086–105. https://doi.org/10.1016/j.ajhg.2016.09.005.CrossRefPubMedPubMedCentral

33.

Ortiz-Genga MF, et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol. 2016;68:2440–51. https://doi.org/10.1016/j.jacc.2016.09.927.CrossRefPubMed

34.

Pires DEV, et al. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 2014;42:W314–9. https://doi.org/10.1093/nar/gku411.CrossRefPubMedPubMedCentral

35.

Previtali SC, et al. Expanding the central nervous system disease spectrum associated with FLNC mutation. Muscle Nerve. 2019;59:E33–7. https://doi.org/10.1002/mus.26443.CrossRefPubMed

36.

Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. https://doi.org/10.1038/gim.2015.30.CrossRefPubMedPubMedCentral

37.

Rojnueangnit K, et al. Identification of gene mutations in primary pediatric cardiomyopathy by whole exome sequencing. Pediatr Cardiol. 2020;41:165–74. https://doi.org/10.1007/s00246-019-02240-x.CrossRefPubMed

38.

Roldan-Sevilla A, et al. Missense mutations in the FLNC gene causing familial restrictive cardiomyopathy. Circ Genom Precis Med. 2019;12:e002388. https://doi.org/10.1161/CIRCGEN.118.002388.CrossRefPubMed

39.

Rossi D, et al. A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy. PLoS ONE. 2017;12:e0186642. https://doi.org/10.1371/journal.pone.0186642.CrossRefPubMedPubMedCentral

40.

Ruparelia AA, et al. Metformin rescues muscle function in BAG3 myofibrillar myopathy models. Autophagy. 2021;17:2494–510. https://doi.org/10.1080/15548627.2020.1833500.CrossRefPubMed

41.

Russo LM, et al. Idiopathic restrictive cardiomyopathy in children. Heart. 2005;91:1199–202. https://doi.org/10.1136/hrt.2004.043869.CrossRefPubMedPubMedCentral

42.

Sammani A, et al. Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta-analysis and systematic review. ESC Heart Fail. 2020;7:1430–41. https://doi.org/10.1002/ehf2.12689.CrossRefPubMedPubMedCentral

43.

Schanzer A, et al. The p.Ala2430Val mutation in filamin C causes a “hypertrophic myofibrillar cardiomyopathy.” J Muscle Res Cell Motil. 2021;42:381–97. https://doi.org/10.1007/s10974-021-09601-1.CrossRefPubMed

44.

Schubert J, et al. Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy. Hum Mutat. 2018;39:2083–96. https://doi.org/10.1002/humu.23661.CrossRefPubMed

45.

Sethi R, et al. A novel structural unit in the N-terminal region of filamins. J Biol Chem. 2014;289:8588–98. https://doi.org/10.1074/jbc.M113.537456.CrossRefPubMedPubMedCentral

46.

Shatunov A, et al. In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy. Eur J Hum Genet. 2009;17:656–63. https://doi.org/10.1038/ejhg.2008.226.CrossRefPubMed

47.

Sievers F, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011;7:539. https://doi.org/10.1038/msb.2011.75.CrossRefPubMedPubMedCentral

48.

Sjekloća L, et al. Crystal structure of human Filamin C domain 23 and small angle scattering model for filamin C 23–24 dimer. J Mol Biol. 2007;368:1011–23. https://doi.org/10.1016/j.jmb.2007.02.018.CrossRefPubMed

49.

Smith DK, et al. Sequence profiles of immunoglobulin and immunoglobulin-like domains. J Mol Biol. 1997;274:530–45. https://doi.org/10.1006/jmbi.1997.1432.CrossRefPubMed

50.

Tasca G, et al. Novel FLNC mutation in a patient with myofibrillar myopathy in combination with late-onset cerebellar ataxia. Muscle Nerve. 2012;46:275–82. https://doi.org/10.1002/mus.23349.CrossRefPubMedPubMedCentral

51.

Theis JL, et al. Genetic association between hypoplastic left heart syndrome and cardiomyopathies. Circ Genom Precis Med. 2021;14:e003126. https://doi.org/10.1161/CIRCGEN.120.003126.CrossRefPubMed

52.

Tucker NR, et al. Novel mutation in FLNC (Filamin C) causes familial restrictive cardiomyopathy. Circ Cardiovasc Genet. 2017;10:50. https://doi.org/10.1161/CIRCGENETICS.117.001780.CrossRef

53.

Valdes-Mas R, et al. Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun. 2014;5:5326. https://doi.org/10.1038/ncomms6326.CrossRefPubMed

54.

van den Bogaart FJ, et al. Widening the spectrum of filamin-C myopathy: predominantly proximal myopathy due to the p.A193T mutation in the actin-binding domain of FLNC. Neuromuscul Disord. 2017;27:73–7. https://doi.org/10.1016/j.nmd.2016.09.017.CrossRefPubMed

55.

Verdonschot JAJ, et al. A mutation update for the FLNC gene in myopathies and cardiomyopathies. Hum Mutat. 2020;41:1091–111. https://doi.org/10.1002/humu.24004.CrossRefPubMedPubMedCentral

56.

Vorgerd M, et al. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. Am J Hum Genet. 2005;77:297–304. https://doi.org/10.1086/431959.CrossRefPubMedPubMedCentral

57.

Wang WB, et al. Identification of a novel pathogenic mutation of the MYH3 gene in a family with distal arthrogryposis type 2B. Mol Med Rep. 2020;21:438–44. https://doi.org/10.3892/mmr.2019.10820.CrossRefPubMed

58.

Waterhouse A, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296–303. https://doi.org/10.1093/nar/gky427.CrossRefPubMedPubMedCentral

59.

Waterhouse AM, et al. Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics. 2009;25:1189–91. https://doi.org/10.1093/bioinformatics/btp033.CrossRefPubMedPubMedCentral

60.

Webber SA, et al. Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: a report from the Pediatric Cardiomyopathy Registry. Circulation. 2012;126:1237–44. https://doi.org/10.1161/CIRCULATIONAHA.112.104638.CrossRefPubMed

61.

Xiao F, et al. Clinical exome sequencing revealed that FLNC variants contribute to the early diagnosis of cardiomyopathies in infant patients. Transl Pediatr. 2020;9:21–33. https://doi.org/10.21037/tp.2019.12.02.CrossRefPubMedPubMedCentral

62.

Zenagui R, et al. A reliable targeted next-generation sequencing strategy for diagnosis of myopathies and muscular dystrophies, especially for the giant titin and nebulin genes. J Mol Diagn. 2018;20:533–49. https://doi.org/10.1016/j.jmoldx.2018.04.001.CrossRefPubMed

63.

Vershinina T, et al. Features of the clinical phenotype of filamine cardiomyopathies with a debut in early childhood. Pediatria. 2020. https://doi.org/10.24110/0031-403X-2020-99-3-88-95.CrossRef

Title: Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood
Authors: A. Muravyev
T. Vershinina
P. Tesner
G. Sjoberg
Yu. Fomicheva
N. Novák Čajbiková
A. Kozyreva
S. Zhuk
E. Mamaeva
S. Tarnovskaya
J. Jornholt
P. Sokolnikova
T. Pervunina
E. Vasichkina
T. Sejersen
A. Kostareva
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Diseases of the neuromuscular synapses and muscles
Cardiomyopathy
Myopathy
Published in: Orphanet Journal of Rare Diseases / Issue 1/2022
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-022-02477-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Potential influences on optimizing long-term musculoskeletal health in children and adolescents with X-linked hypophosphatemia (XLH)

Incidence of Leber hereditary optic neuropathy in 2019 in Japan: a second nationwide questionnaire survey

Systemic amyloidosis journey from diagnosis to outcomes: a twelve-year real-world experience of a single center in a middle-income country

Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders

Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy

One year of COVID-19: infection rates and symptoms in patients with inherited metabolic diseases followed by MetabERN