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

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

한국인 좌심실 비대증 환자들에서 파브리병 선별검사의 의의

  • 박형두 (성균관의대 삼성서울병원 진단검사의학과) ;
  • 조성윤 (성균관의대 삼성서울병원 소아청소년과) ;
  • 이수연 (성균관의대 삼성서울병원 진단검사의학과) ;
  • 전은석 (성균관의대 삼성서울병원 내과) ;
  • 박승우 (성균관의대 삼성서울병원 내과) ;
  • 이상훈 (성균관의대 삼성서울병원 내과) ;
  • 이상철 (성균관의대 삼성서울병원 내과) ;
  • 최진오 (성균관의대 삼성서울병원 내과) ;
  • 박성지 (성균관의대 삼성서울병원 내과) ;
  • 장성아 (성균관의대 삼성서울병원 내과) ;
  • 김형관 (서울대학교병원 내과) ;
  • 기창석 (성균관의대 삼성서울병원 진단검사의학과) ;
  • 김종원 (성균관의대 삼성서울병원 진단검사의학과) ;
  • 진동규 (성균관의대 삼성서울병원 소아청소년과)
  • 발행 : 2014.12.25
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

목적: 파브리병(Fabry disease)은 alpha-galactosidase A의 결핍으로 인하여 리소좀에 globotriaosylceramide(Gb3)가 축적되어 여러 장기에 이상을 일으키는 질병이다. 본 연구에서는 파브리병의 만성 합병증 중 심장 질환을 주로 보이는 환자들, 그 중에서도 좌심실 비대증을 보이는 한국인 환자들을 대상으로 파브리병의 빈도를 알아보고자 하였다. 방법: 좌심실비대증을 진단받은 환자 257명을 연구대상으로 선정하였고, 남성이 172명(평균 56세, 범위 30-81세), 여성이 84명(평균 66세, 범위 45-85세)이었다. 파브리병 선별을 위하여 고성능액체크로마토그래피-탠덤질량분석기를 이용하여 소변 Gb3 농도를 측정하였다. 확진은 형광분석법에 의한 말초혈액의 alpha-galactosidase A 활성도와 염기서열분석법에 의한 GLA 유전자 돌연변이 유무를 검사하여 이루어졌다. 결과: 소변 Gb3 검사에서 cutoff (25 ug/mmoL creatinine)를 초과하는 환자는 4명이었지만, 최종적으로 추가 검사를 통해 진단된 파브리병 환자는 여성 환자 한 명이었다(1/257명, 0.4%). 확진된 환자는 54.3 ug/mmoL creatinine의 Gb3 농도와 15.5 nmole/hr/mg protein (참고범위, $55.2{\pm}12.7nmole/hr/mg$ protein)의 alpha-galactosidase A 활성도를 보였다. GLA 유전자에서는 c.796G>A (p.D266N) 돌연변이가 이형접합체로 관찰되었다. 추가로 시행한 가족검사에서 환자의 딸은 아직 파브리병의 증상을 보이지 않았지만, 엄마와 같은 GLA 돌연변이(c.796G>A)를 가지고 있었으며, alpha-galactosidaseA 활성도는 42.5 nmole/hr/mg protein, 소변 Gb3 농도는 25.5 ug/mmoL creatinine을 나타냈다. 결론: 한국인 좌심실 비대증을 가진 환자들에서 파브리병의 유병율은 0.4%였다. 유병율이 낮아 보임에도 불구하고, 파브리병 진단 전 환자와 가족 구성원을 발견할 수 있는 장점 덕분에 선별검사의 의의가 있는 것으로 사료된다.

Objectives: Fabry disease (FD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide (Gb3) in tissues due to a deficiency in the enzyme ${\alpha}$-galactosidase A. Hypertrophic cardiomyopathy is one of the chronic complications of FD. We tried to evaluate the prevalence of Fabry disease in the Korean patients with left ventricular hypertrophy (LVH). Methods: A total of 257 patients with LVH were recruited and they were 172 males (mean 56 years, range 30-81 years) and 84 females (mean 66 years, range 45-85 years). Urinary Gb3 was used to screen FD by high performance liquid chromatography-tandem mass spectrometry. Confirmatory tests were done by alpha-galactosidaseA activity using fluorometric assay and by GLA mutation analysis using sequencing. Results: Four patients were screening positive by urinary Gb3 analysis (cutoff, 25 ug/mmol creatinine). But, one female patient was diagnosed with FD confirmed by enzyme analysis in leukocytes as well as by genetic analysis (1/257 patients, 0.4%). She showed 54.3 ug/mmoL creatinine of Gb3 and 15.5 nmole/hr/mg protein (reference range, $55.2{\pm}12.7nmole/hr/mg$ protein) of alphagalactosidase A activity. And she had a heterozygous GLA mutation of c.796G>A (p.D266N). Her daughter was found to be a carrier for FD confirmed by GLA mutation analysis. Asymptomatic carrier showed 25.5ug/mmol creatinine of Gb3 and 42.5 nmole/hr/mg protein (reference range, $55.2{\pm}12.7nmole/hr/mg$ protein) of alpha-galactosidase A activity. Conclusions: The prevalence of FD in Koran patients with LVH was detected as 0.4%. Although the prevalence seems to be low, screening studies are of great importance for detecting hidden cases as well as for identifying other effected family members.

키워드

참고문헌

  1. Clarke JT. Narrative review: Fabry disease. Ann Intern Med 2007;146:425-33. https://doi.org/10.7326/0003-4819-146-6-200703200-00007
  2. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001;38:750-60. https://doi.org/10.1136/jmg.38.11.750
  3. Beer G, Reinecke P, Gabbert HE, Hort W, Kuhn H. Fabry disease in patients with hypertrophic cardiomyopathy (HCM). Z Kardiol 2002;91:992-1002. https://doi.org/10.1007/s00392-002-0870-7
  4. Sokolow M and Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949; 37:161-86. https://doi.org/10.1016/0002-8703(49)90562-1
  5. Casale PN, Devereux RB, Alonso DR, Campo E, Kligfield P. Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings. Circulation 1987;75:565-72. https://doi.org/10.1161/01.CIR.75.3.565
  6. Auray-Blais C, Cyr D, Mills K, Giguere R, Drouin R. Development of a filter paper method potentially applicable to mass and high-risk urinary screenings for Fabry disease. J Inherit Metab Dis 2007;30:106. https://doi.org/10.1007/s10545-006-0444-3
  7. Senechal M and Germain DP. Fabry disease: a functional and anatomical study of cardiac manifestations in 20 hemizygous male patients. Clin Genet 2003;63:46-52.
  8. Mehta A, Clarke JT, Giugliani R, Elliott P, Linhart A, Beck M, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey. J Med Genet 2009;46:548-52. https://doi.org/10.1136/jmg.2008.065904
  9. Linthorst GE, Bouwman MG, Wijburg FA, Aerts JM, Poorthuis BJ, Hollak CE. Screening for Fabry disease in high-risk populations: a systematic review. J Med Genet 2010;47:217-22. https://doi.org/10.1136/jmg.2009.072116
  10. Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 1995;333:288-93. https://doi.org/10.1056/NEJM199508033330504
  11. Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 2005;366:1794-6. https://doi.org/10.1016/S0140-6736(05)67635-0
  12. Lv YL, Wang WM, Pan XX, Wang ZH, Chen N, Ye ZY, et al. A successful screening for Fabry disease in a Chinese dialysis patient population. Clin Genet 2009;76:219-21. https://doi.org/10.1111/j.1399-0004.2009.01166.x
  13. Germain DP, Weidemann F, Abiose A, Patel MR, Cizmarik M, Cole JA, et al. Analysis of left ventricular mass in untreated men and in men treated with agalsidase-beta: data from the Fabry Registry. Genet Med 2013;15:958-65. https://doi.org/10.1038/gim.2013.53
  14. Kruger R, Bruns K, Grunhage S, Rossmann H, Reinke J, Beck M, et al. Determination of globotriaosylceramide in plasma and urine by mass spectrometry. Clin Chem Lab Med 2010;48:189-98.
  15. Paschke E, Fauler G, Winkler H, Schlagenhauf A, Plecko B, Erwa W, et al. Urinary total globotriaosylceramide and isoforms to identify women with Fabry disease: a diagnostic test study. Am J Kidney Dis 2011;57:673-81. https://doi.org/10.1053/j.ajkd.2010.10.046
  16. Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40. https://doi.org/10.1086/504601
  17. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007;9:34-45. https://doi.org/10.1097/GIM.0b013e31802d8321