Journal of The Korean Society of Inherited Metabolic disease (대한유전성대사질환학회지)

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
권호 표지

Molecular Genetic Analysis in Dystroglycanopathy with the Fukuyama Congenital Muscular Dystrophy Phenotype

Fukuyama 선천성 근이영양증에서의 분자유전학적 분석

  • Cha, Lily Myung-Jin (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Shin, Jae Eun (Department of Pathology, Yonsei University College of Medicine) ;
  • Kim, Se Hoon (Department of Pathology, Yonsei University College of Medicine) ;
  • Lee, Min Jung (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Lee, Chul Ho (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Lee, Young-Mock (Department of Pediatrics, Yonsei University College of Medicine)
  • 차명진 (연세대학교 의과대학 세브란스병원 소아청소년과) ;
  • 신재은 (연세대학교 의과대학 세브란스병원 병리학과) ;
  • 김세훈 (연세대학교 의과대학 세브란스병원 병리학과) ;
  • 이민정 (연세대학교 의과대학 세브란스병원 소아청소년과) ;
  • 이철호 (연세대학교 의과대학 세브란스병원 소아청소년과) ;
  • 이영목 (연세대학교 의과대학 세브란스병원 소아청소년과)
  • Published : 2017.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Fukuyama congenital muscular dystrophy (FCMD) is a rare, autosomal-recessive disorder characterized by early-onset hypotonia associated with brain malformations in dystroglycanopathy. Although the wide spectrum of congenital muscular dystrophies causes difficulty in diagnosis, correlating the genotype with the clinical phenotype can help diagnose FCMD. Here, we evaluated the correlation of targeted molecular genetic analysis of FKTN gene mutation with the FCMD phenotype. Methods: This study was conducted retrospectively with 9 subjects. Inclusion criteria included clinical symptoms characterized by early-onset hypotonia with magnetic resonance imaging (MRI) featuring brain malformations. FKTN gene-alteration analysis was performed using various FKTN gene-analysis methods, including sequencing. Results: Among the 9 subjects studied, 4 (44.4%) were male and 5 (55.6%) were female. The median age of onset of the first symptom was 3.1 months. The first symptom was a delayed milestone in 6 cases (66.7%). All 9 subjects (100%) presented with early-onset hypotonia and global delayed development. All subjects presented with cortical malformation in their brain MRIs. Of the 9 subjects, 6 subjects had previously undergone muscle biopsy and 4 cases (4/6; 66.7%) showed dystrophic or myopathic features. Pathogenic mutations causing FCMD were identified in 3 cases. Conclusions: In this study, all 3 subjects with FKTN mutations showed important MRI findings (pachygyria and cerebellar dysplasia). These data suggest that patients with characteristic phenotypes who show pachygyria and cerebellar abnormalities in brain MRIs may have a high probability of being diagnosed with FCMD.

목적: Fukuyama 선천성 근이영양증은 희귀한 열성 유전질환으로 영아 시기에 발병하는 근긴장 저하, 뇌 기형 및 dystroglycanopathy 특징들을 보인다. 선천성 근육병의 넓은 스펙트럼에 여러 질환들이 존재하여 Fukuyama 선천성 근이영양증 진단을 어렵게 하지만, 유전형과 표현형 상관관계를 파악하면 진단을 도울 수 있다. 이 연구에서는 분자유전학 분석을 통해 선정한 FKTN 유전자와 Fukuyama 선천성 근이영증의 표현형의 연관성에 대해 알아보았다. 방법: 이 연구는 후향적으로 9명의 대상자들로 진행하였다. 영아 시기에 발병하는 근긴장 저하의 증상 및 뇌 자기공명영상에서 기형 소견을 보인 환자들을 대상으로 선정하였다. 그리고 FKTN 유전자를 이용한 염기서열 검사를 통해 유전자를 분석하였다. 결과: 9명의 대상자들 중 남성이 4명(44.4%), 여성이 5명(55.5%) 였다. 첫 증상이 발병한 나이의 중간값은 3.1개월였다. 6명(66.7%) 에서 첫 증상이 발달지연으로 나타났다. 모든 환자들은 영아 시기에 근긴장 저하 및 전반적 발달 지연 소견을 보였다. 또한, 모든 환자들은 뇌 자기공명영상에서 뇌 피질 기형 소견을 보였다. 9명의 환자들 중 6명이 근육생검 검사를 실시하였고 그 중 4명(4/6; 66.7%)이 특이 소견을 보였다. Fukuyama 선천성 근이영양증을 일으키는 FKTN 유전자 돌연변이는 3명에서 발견되었다. 결론: 이 연구에서 FKTN 유전자 변이를 보인 3명의 대상자들은 모두 뇌 자기공명영상에서 큰뇌이랑증 및 소뇌 형성장애 소견들을 보였다. 이것을 통해 근육병 증상을 보이면서 뇌 자기공명영상에서 특징적인 소견들을 보일 시 Fukuyama 선천성 근이영양증을 진단할 가능성을 높일 수 있다는 것을 확인하였다.

Keywords

References

  1. Toda T, Kobayashi K, Konoda-Iida E, Sasaki J, Nakamura Y. The Fukuyama congenital muscular dystrophy story. Neuromuscul Disord 2000;10:153-9. https://doi.org/10.1016/S0960-8966(99)00109-1
  2. Fukuyama Y, Kawazura M, Haruna H. A peculiar form of congenital progressive muscular dystrophy: report of fifteen cases. Paediatr Univ Tokyo 1960;4:5-8.
  3. Aida N. Fukuyama congenital muscular dystrophy: a neuroradiologic review. J Magn Reson Imaging 1998;8:317-26. https://doi.org/10.1002/jmri.1880080211
  4. Toda T, Segawa M, Nomura Y, Nonaka I, Masuda K, Ishihara T, et al. Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. Nat Genet 1993;5:283-6. https://doi.org/10.1038/ng1193-283
  5. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388-92. https://doi.org/10.1038/28653
  6. Rahimov R, Kunkel LM. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol 2013;201:499-510. https://doi.org/10.1083/jcb.201212142
  7. Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, et al. Mutations in the fukutinrelated protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin ${\alpha}2$ deficiency and abnormal glycosylation of $\alpha$-dystroglycan. Am J Hum Genet 2001;69:1198-209. https://doi.org/10.1086/324412
  8. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, et al. Mutations in the O-mannosyl transferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71:1033-43. https://doi.org/10.1086/342975
  9. van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Bernabe D, Sabatelli P, Merlini L, et al. POMT2 mutations cause alpha-dystrogylcan hypoglycosylation and Walker-Warburg syndrome. J Med Genet 2005;42:907-12. https://doi.org/10.1136/jmg.2005.031963
  10. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 2001;1:717-24. https://doi.org/10.1016/S1534-5807(01)00070-3
  11. Longman C, Brockington M, Torelli S, Jimenez-Mallebrera C, Kennedy C, Khalil N, et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alphadystroglycan. Hum Mol Genet 2003;12:2853-61. https://doi.org/10.1093/hmg/ddg307
  12. Godfrey C, Foley AR, Clement E, Muntoni F. Dystroglycanopathies: coming into focus. Curr Opin Genet Dev 2011;21:278-85. https://doi.org/10.1016/j.gde.2011.02.001
  13. Kitamura Y, Kondo E, Urano M, Aoki R, Saito K. Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with undiagnosed early-onset neuromuscular disorders. J Hum Genet 2016;61:931-42. https://doi.org/10.1038/jhg.2016.79
  14. Watanabe M, Kobayashi K, Jin F, Park KS, Yamada T, Tokunaga K, et al. Founder SVA retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and Northeast Asia populations. Am J Med Genet A 2005;138:344-8.
  15. Lee J, Lee BL, Lee M, Kim JH, Kim JW, Ki CS. Clinical and genetic analysis of a Korean patient with Fukuyama congenital muscular dystrophy. J Neurol Sci 2009;281:122-4. https://doi.org/10.1016/j.jns.2009.02.373
  16. Lim BC, Ki CS, Kim JW, Cho A, Kim MJ, Hwang H, et al. Fukutin mutations in congenital muscular dystrophies with defective glycosylation of dystroglycan in Korea. Neuromuscul Disord 2010;20:524-30. https://doi.org/10.1016/j.nmd.2010.06.005
  17. Cormand B, Pihko H, Bayes M, Valanne L, Santavuori P, Talim B, et al. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eyebrain disease. Neurology 2001;56:1059-69. https://doi.org/10.1212/WNL.56.8.1059
  18. Vogel H, Zamecnik J. Diagnostic immunohistology of muscle disease. J Neuropathol Exp Neurol 2005;64:181-93. https://doi.org/10.1093/jnen/64.3.181
  19. Hayashi YK, Ogawa M, Tagawa K, Noguchi S, Ishihara T, Nonaka I, et al. Selective deficiency of $\alpha$-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology. 2001;57:115-121. https://doi.org/10.1212/WNL.57.1.115
  20. Lim BC, Lee S, Shin JY, Hwang H, Kim KJ, Hwang YS, et al. Molecular diagnosis of congenital muscular dystrophies with defective glycosylation of alpha-dystroglycan using next-generation sequencing technology. Neuromuscul Disord 2013;23:337-44. https://doi.org/10.1016/j.nmd.2013.01.007
  21. Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, et al. Refining genotype-phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 2007;130:2725-35. https://doi.org/10.1093/brain/awm212
  22. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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;17:405-23. https://doi.org/10.1038/gim.2015.30
  23. Aida N, Tamagawa K, Takada K, Yagishita A, Kobayashi N, Chikumaru K, et al. Brain MR in Fukuyama congenital muscular dystrophy. Brain 2007;17:605-13.