Congenital fibrosis of the extraocular muscles in a Czech family and its molecular genetic cause

Czech version

Authors: Ľ. Ďuďáková ¹; E. Vyhnálková ²; P. Sklenka ³; P. Kuthan ³; P. Diblík ³; P. Lišková ^1,3
Authors‘ workplace: Klinika dětského a dorostového lékařství, 1. LF UK a VFN v Praze ¹; Ústav biologie a lékařské genetiky, Oddělení klinické genetiky, FN Motol, Praha ²; Oční klinika 1. LF UK a VFN v Praze ³
Published in: Cesk Slov Neurol N 2019; 82(5): 561-566
Category: Original Paper
doi: https://doi.org/10.14735/amcsnn2019561

Overview

Aim: Congenital fibrosis of the extraocular muscles (CFEOM) is a rare autosomal dominant disorder characterized by bilateral non-progressive ophthalmoplegia and ptosis. The aim of this study was to identify the molecular genetic cause in a four-generation family with CFEOM and to describe the clinical findings in four affected and one unaffected member.

Patients and methods: All patients underwent an eye examination. Exons 2, 8, 20 and 21 of the KIF21A gene were directly examined by Sanger sequencing in the proband. Sanger sequencing was also used to test for the presence of the detected mutation in other relatives.

Results: Clinical findings were typical in all affected individuals manifesting as ptosis and severely limited vertical and horizontal eye movements with compensatory backward tilt of the head. All patients also had decreased visual acuity attributed to amblyopia and synkinetic eye movements; synergistic convergence on attempted vertical gaze and divergence in the downgaze. A known heterozygous mutation c.2860C>T; p.(Arg954Trp) in KIF21A was identified in all available affected family members with CFEOM. This mutation was not found in a grandson of the proband who had no clinical disease symptoms.

Conclusion: CFEOM is a serious disorder leading to life-long functional and often psychological problems. The molecular genetic cause in patients of Czech origin has been discovered for the first time.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

捷克家庭眼外肌的先天性纤维化及其分子遗传原因

目的：先天性眼外肌纤维化（CFEOM）是一种罕见的常染色体显性遗传疾病，其特征是双侧非进行性眼肌麻痹和上睑下垂。这项研究的目的是确定具有CFEOM的四代家庭的分子遗传原因，并描述四名受影响和一名未受影响的成员的临床发现。

患者和方法：所有患者均接受了眼科检查。通过先证者中的Sanger测序直接检查了KIF21A基因的外显子2、8、20和21。Sanger测序也被用来检测在其他亲属中检测到的突变的存在。

结果：在所有受影响的个体中，典型的临床表现为上睑下垂，垂直和水平眼运动严重受限以及头部向后倾斜。所有患者的视力均因弱视和眼球运动同步而下降;尝试垂直注视和向下注视的协同收敛。已知的杂合突变c.2860C> T;在所有可能患有CFEOM的受影响家庭成员中都发现了KIF21A中的p。（Arg954Trp）。在没有临床疾病症状的先证者的孙子中未发现此突变。

结论：CFEOM是一种严重的疾病，导致终生的功能障碍和心理问题。首次发现捷克籍患者的分子遗传原因。

关键词：先天性眼外肌纤维化–下垂–眼肌麻痹– KIF21A

Keywords:

ptosis – ophthalmoplegia – KIF21A – congenital fibrosis of the extraocular muscles

Sources

1. Sener EC, Lee BA, Turgut B et al. A clinically variant fibrosis syndrome in a Turkish family maps to the CFEOM1 locus on chromosome 12. Arch Ophthalmol 2000; 118(8): 1090–1097. doi: 10.1001/ archopht.118.8.1090.

2. Engle EC, Kunkel LM, Specht LA et al. Mapping a gene for congenital fibrosis of the extraocular muscles to the centromeric region of chromosome 12. Nat Genet 1994; 7(1): 69–73. doi: 10.1038/ ng0594-69.

3. Lim KH, Engle EC, Demer JL. Abnormalities of the oculomotor nerve in congenital fibrosis of the extraocular muscles and congenital oculomotor palsy. Invest Ophthalmol Vis Sci 2007; 48(4): 1601–1606. doi: 10.1167/ iovs.06-0691.

4. Yamada K, Hunter DG, Andrews C et al. A novel KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Marcus Gunn jaw-winking phenomenon. Arch Ophthalmol 2005; 123(9): 1254–1259. doi: 10.1001/ archopht.123.9.1254.

5. Otradovec J. Klinická neurooftalmologie. 1. vyd. Praha: Grada Publishing 2003.

6. Heidary G, Engle EC, Hunter DG. Congenital fibrosis of the extraocular muscles. Semin Ophthalmol 2008; 23(1): 3–8. doi: 10.1080/ 08820530701745181.

7. Engle EC, Goumnerov BC, McKeown CA et al. Oculomotor nerve and muscle abnormalities in congenital fibrosis of the extraocular muscles. Ann Neurol 1997; 41(3): 314–325. doi: 10.1002/ ana.410410306.

8. Miao W, Man F, Wu S et al. Brain abnormalities in congenital fibrosis of the extraocular muscles type 1: a multimodal MRI imaging study. PLoS One 2015; 10(7): e0133473. doi: 10.1371/ journal.pone.0133473.

9. Kim JH, Hwang JM. Hypoplastic oculomotor nerve and absent abducens nerve in congenital fibrosis syndrome and synergistic divergence with magnetic resonance imaging. Ophthalmol 2005; 112(4): 728–732. doi: 10.1016/ j.ophtha.2004.12.006.

10. Reck AC, Manners R, Hatchwell E. Phenotypic heterogeneity may occur in congenital fibrosis of the extraocular muscles. Br J Ophthalmol 1998; 82(6): 676–679. doi: 10.1136/ bjo.82.6.676.

11. Whitman M, Hunter DG, Engle EC. Congenital fibrosis of the extraocular muscles. In: Adam MP, Ardinger HH, Pagon RA et al (eds.). GeneReviews. Seattle: University of Washington 1993.

12. Yamada K, Andrews C, Chan WM et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 2003; 35: 318–321.

13. Nakano M, Yamada K, Fain J et al. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001; 29(3): 315–320. doi: 10.1038/ ng744.

14. Tischfield MA, Baris HN, Wu C et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 2010; 140(1): 74–87. doi: 10.1016/ j.cell.2009.12.011

15. Aubourg P, Krahn M, Bernard R et al. Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3) locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes. J Med Genet 2005; 42(3): 253–259. doi: 10.1136/ jmg.2004.021899.

16. Tukel T, Uzumcu A, Gezer A et al. A new syndrome, congenital extraocular muscle fibrosis with ulnar hand anomalies, maps to chromosome 21qter. J Med Genet 2005; 42(5): 408–415. doi: 10.1136/ jmg.2004.026138.

17. Khan AO, Shinwari J, Omar A et al. Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families. Mol Vis 2011; 17: 218–224.

18. Chan WM, Andrews C, Dragan L et al. Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1. BMC Genet 2007; 8: 26. doi: 10.1186/ 1471-2156-8-26.

19. Ali Z, Xing C, Anwar D et al. A novel de novo KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Mobius syndrome. Mol Vis 2014; 20: 368–375.

20. gnomAD browser. [online]. Available from URL: https:/ / gnomad.broadinstitute.org/ .

21. Národní centrum lékařské genomiky. [online]. Dostupné z URL: https:/ / ncmg.cz/ .

22. Rudolph G, Nentwich M, Hellebrand H et al. KIF21A variant R954W in familial or sporadic cases of CFEOM1. Eur J Ophthalmol 2009; 19(4): 667–674.

23. Li ND, Zhao J, Wang LM et al. R954 mutations in KIF21A gene in Chinese patients with congenital fibrosis of extraocular muscles. Zhonghua Yan Ke Za Zhi 2012; 48(12): 1077–1082.

24. Yang X, Yamada K, Katz B et al. KIF21A mutations in two Chinese families with congenital fibrosis of the extraocular muscles (CFEOM). Mol Vis 2010; 16: 2062–2070.

25. Harley RD, Rodrigues MM, Crawford JS. Congenital fibrosis of the extraocular muscles. Trans Am Ophthalmol Soc 1978; 76: 197–226.

26. Sudiwala S, Knox SM. The emerging role of cranial nerves in shaping craniofacial development. Genesis 2019; 57(1): e23282. doi: 10.1002/ dvg.23282.

27. Desai J, Velo MP, Yamada K et al. Spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Gene Expr Patterns 2012; 12(5–6): 180–188. doi: 10.1016/ j.gep.2012.03.003.

28. Bianchi S, van Riel WE, Kraatz SH et al. Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations. Sci Rep 2016; 6: 30668. doi: 10.1038/ srep30668.

29. Whitman MC, Engle EC. Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance. Hum Mol Genet 2017; 26(R1): R37–R44. doi: 10.1093/ hmg/ ddx168.

30. Magli A, de Berardinis T, D’Esposito F et al. Clinical and surgical data of affected members of a classic CFEOM I family. BMC Ophthalmol 2003; 3: 6.

31. Hlavata L, Dudakova L, Trkova M et al. [Preimplantation genetic diagnosis and monogenic inherited eye diseases]. Cesk Slov Oftalmol 2016; 72(5): 167–171.

32. De Rycke M, Belva F, Goossens V et al. ESHRE PGD Consortium data collection XIII: cycles from January to December 2010 with pregnancy follow-up to October 2011. Hum Reprod 2015; 30(8): 1763–1789. doi: 10.1093/ humrep/ dev122.