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

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

GNPTAB 유전자에서 새로운 돌연변이가 확인된 뮤코지방증 III형 남매

A Case Report of Novel Mutation in GNPTAB in Two Siblings with Mucolipidosis Type III Alpha/beta

  • 김민선 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 박에스더 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 송아리 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 임민지 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 박형두 (성균관대학교 의과대학 삼성서울병원 진단검사의학과) ;
  • 조성윤 (성균관대학교 의과대학 삼성서울병원 소아청소년과) ;
  • 진동규 (성균관대학교 의과대학 삼성서울병원 소아청소년과)
  • Kim, Min-Sun (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Park, Esther (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Song, Ari (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Im, Minji (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Park, Hyung-Doo (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Cho, Sung Yoon (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Jin, Dong-Kyu (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • 발행 : 2018.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

뮤코지방증 III alpha/beta는 GNPTAB 유전자의 돌연변이로 야기되는 점액(Mucolipids) 분해 능력 장애이며 상염색체 열성으로 유전된다. 이는 혈액에서 고농축의 점액을 검사하여 진단되며 유전자 검사를 통해 진단을 확인할 수 있다. 뮤코지방증 III형은 희귀하고 점진적으로 진행하는 대사장애로 증상은 3세 경에 나타나며 성장지연, 관절 경직, 관절통, 골격 이상, 심장 판막 이상, 반복되는 호흡기 감염, 평평한 얼굴과 낮은 콧대의 거친 얼굴, 지적장애 또는 학습 문제를 보인다. 본 증례는 성장 지연과 거친 얼굴을 보이는 4세, 2세 7개월 남매에서 targeted gene panel sequencing으로 [c.2715+1G>A (p.Glu906Leufs*4), c.2544del (p. Glu849Lysfs*22)] 두 개의 변이가 이형 접합체로 발견되어 뮤코지방증 III형을 진단하였으며 c.2544del 은 새로운 돌연변이로 대조군에서 발견되지 않았고 표현형과 연관성 고려 시 pathogenic variant로 해석된다. 이와 같이 GNPTAB 유전자에서 새로운 돌연변이가 확인되어 뮤코지방증 III형 남매 증례를 보고하는 바이다. 본 증례처럼 최근 분자유전학적 기술이 발달함에 따라 조기 진단이 가능해지고 진단 후 Case 1 환자에서와 같이 치료를 위하여 pamidronate 투약 가능하나, 이와 같은 보조적 치료 외에도 조기 진단을 받은 뮤코지방증 환자들을 위한 근본적인 치료법 개발을 위한 노력이 필요하다.

Mucolipidosis type III (pseudo-Hurler polydystrophy) is a mucolipids degrading disorder caused by a mutation in the GNPTAB gene and is inherited by autosomal recessive. It is diagnosed by examining highly concentrated mucolipids in blood and the diagnosis can be confirmed by genetic testing. Mucolipidosis type III is a rare and progressive metabolic disorder. Its initial signs and symptoms usually occur around 3 years of age. Clinical manifestations of the disease include slow growth, joint stiffness, arthralgia, skeletal abnormalities, heart valve abnormalities, recurrent respiratory infection, distinctive facial features, and mild intellectual disability. Here, we are presenting two siblings of mucolipidosis type III, a 4-year-old female and a 2 years and 7 months old male with features of delayed growth and coarse face. The diagnosis was confirmed by [c.2715+1G>A(p.Glu906Leufs*4), c.2544del(p.Glu849Lysfs*22)] mutation in targeted gene panel sequencing. In this case, c.2544del is a heterozygote newly identified mutation in mucolipidosis type III and was not found in the control group including the genome aggregation database. And it is interpreted as a pathogenic variant considering the association with phenotype. Here, we report a Korean mucolipidosis type III patients with novel mutations in GNPTAB gene who have been treated since early childhood. Owing to recent development of molecular genetic techniques, it was possible to make early diagnosis and treatment with pamidronate was initiated appropriately in case 1. In addition to these supportive therapies, efforts must be made to develop fundamental treatment for patients with early diagnosis of mucolipidosis.

키워드

참고문헌

  1. Leroy JG, Cathey SS, Friez MJ. Mucolipidosis III Alpha/Beta. Synonyms: Mucolipidosis IIIA, Pseudo-Hurler Polydystrophy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA): University of Washington, 1993.
  2. Otomo T, Muramatsu T, Yorifuji T, Okuyama T, Nakabayashi H, Fukao T, et al. Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation. J Hum Genet 2009;54:145-51. https://doi.org/10.1038/jhg.2009.3
  3. Leroy JG, Cathey S, Friez MJ. Mucolipidosis II. Gene-Reviews. https://www.ncbi.nlm.nih.gov/books/NBK1828/.
  4. Niwa T, Aida N, Tachibana K, Shinkai M, Ohhama Y, Fujita K, et al. Congenital absence of the portal vein: clinical and radiologic findings. J Comput Assist Tomogr 2002;26:681-6. https://doi.org/10.1097/00004728-200209000-00003
  5. Paik KH, Song SM, Ki CS, Yu HW, Kim JS, Min KH, et al. Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II or type IIIA. Hum Mutat 2005;26:308-14. https://doi.org/10.1002/humu.20205
  6. Mueller OT, Honey NK, Little LE, Miller AL, Shows TB. Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis. J Clin Invest 1983;72:1016-23. https://doi.org/10.1172/JCI111025
  7. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet 2004;12:87-92. https://doi.org/10.1038/sj.ejhg.5201044
  8. Dhingra B, Sharma S, Mishra D, Kumari R, Pandey RM, Aggarwal S. Normal values of liver and spleen size by ultrasonography in Indian children. Indian Pediatr 2010;47:487-92. https://doi.org/10.1007/s13312-010-0090-6
  9. Leroy JG, Demars RI. Mutant enzymatic and cytological phenotypes in cultured human fibroblasts. Science 1967;157:804-6. https://doi.org/10.1126/science.157.3790.804
  10. Yang M, Cho SY, Park HD, Choi R, Kim YE, Kim J, et al. Clinical, biochemical and molecular characterization of Korean patients with mucolipidosis II/III and successful prenatal diagnosis. Orphanet J Rare Dis 2017;12:11. https://doi.org/10.1186/s13023-016-0556-2
  11. Ko AR, Jin DK, Cho SY, Park SW, Przybylska M, Yew NS, et al. AAV8-mediated expression of Nacetylglucosamine-1-phosphate transferase attenuates bone loss in a mouse model of mucolipidosis II. Mol Genet Metab 2016;117:447-55. https://doi.org/10.1016/j.ymgme.2016.02.001
  12. Liu S, Zhang W, Shi H, Yao F, Wei M, Qiu Z. Mutation Analysis of 16 Mucolipidosis II and III Alpha/ Beta Chinese Children Revealed Genotype-Phenotype Correlations. PLoS One 2016;11:e0163204. https://doi.org/10.1371/journal.pone.0163204
  13. Plante M, Claveau S, Lepage P, Lavoie EM, Brunet S, Roquis D, et al. Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population. Clin Genet 2008;73:236-44. https://doi.org/10.1111/j.1399-0004.2007.00954.x
  14. Noble J. Intravemous pamidronate treatment in mucolipidosis II/III. http://www.ismrd.org/__data/assets/pdf_file/0006/10500/IntravenousPamidronateTreatmentInMucolipidosis.pdf.
  15. Pseudo-Hurler Polydystrophy, Mucolipidosis III. https://themedicalbiochemistrypage.org/pseudo-hurlerpolydystrophy.php.
  16. Alegra T, Koppe T, Acosta A, Sarno M, Burin M, Kessler RG, et al. Pitfalls in the prenatal diagnosis of mucolipidosis II alpha/beta: A case report. Meta Gene 2014;2:403-6. https://doi.org/10.1016/j.mgene.2014.03.003