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

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

양성 고페닐알라닌혈증 환자에 대한 임상적 고찰과 유전자 분석

Clinical Manifestations and Gene Analysis of Patients with Benign Hyperphenylalaninemia

  • 이정은 (순천향대학교 의과대학 소아과학교실) ;
  • 이정호 (순천향대학교 의과대학 소아과학교실) ;
  • 이동환 (순천향대학교 의과대학 소아과학교실)
  • Lee, Jeongeun (Department of Pediatrics, Soonchunhyang University Hospital) ;
  • Lee, Jeongho (Department of Pediatrics, Soonchunhyang University Hospital) ;
  • Lee, Dong Hwan (Department of Pediatrics, Soonchunhyang University Hospital)
  • 발행 : 2016.08.31
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초록

목적: 본 연구의 목적은 국내 양성 고페닐알라닌혈증의 돌연변이 유전자 분석, 임상 양상, 치료에 대해 조사하는 것이다. 방법: 2010년도 4월부터 2015년도 8월까지, 신생아 선별검사에서 페닐알라닌의 상승으로 본원으로 전원되어 양성 고페닐알라닌혈증으로 진단된 10명의 환자를 대상으로 시행되었다. 조사항목으로는 환자들의 특징 및 임상 양상과 직접 염기서열 분석을 통한 PAH 유전자 돌연변이 형태 분석을 포함하였다. 결과: 10명의 환자들 중 2명은 고페닐알라닌혈증으로 진단된 자녀의 부모였으며, 환자들 중 특이 과거력이나 임상 증상이 있는 경우는 없었다. 혈장 아미노산 분석에서는 페닐알라닌이 1.2 mg/dL부터 4.2 mg/dL까지의 범위로 측정되었다. BH4 부하검사에서는 모든 환자들이 BH4에 무반응이었다. 확진 검사로 시행한 페닐알라닌수산화효소 유전자 분석에서는, 총 20개의 대립유전자들 중에서 11개의 각기 다른 대립유전자형을 확인할 수 있었는데, 이 중 제일 흔한 대립유전자는 R53H (c.158G>A)였다. 뿐만 아니라, 직접염기서열분석 상에서 2가지의 새로운 돌연변이 형태인 V423A (c.1268T>C)와 V51A (c.152T>C)를 발견하였다. 본 연구에 포함된 환자들은 약물을 복용하거나 식사 조절을 하지 않았음에도, 지속적인 외래 추적 관찰 결과 모든 환자들의 페닐알라닌 치는 6 mg/dL 이하로 유지되었으며, 정상적인 신경 인지발달을 하고 있는 것을 확인하였다. 결론: 이 연구는 양성 고페닐알라닌혈증 환자에 대한 분석이며 국내에서 처음으로 시행한 것이다. 모든 양성 고페닐알라닌혈증 환자들은 지속적인 치료 없이도 혈장 페닐알라닌 치를 6 mg/dL 이하로 유지하였고 정상적인 신경 인지발달을 하였다. 그러므로, 돌연변이 검사를 시행하여 양성 고페닐알라닌혈증 환자를 페닐케톤뇨증과 감별함으로써 불필요한 식사 요법이나 약물 투여를 줄여 환자의 삶의 질을 높일 수 있다.

Purpose: This study aimed to analyze genetic mutations, clinical manifestations, and treatment of patients with benign HPA in Korea. Methods: This case series study involved ten HPA patients who were referred to our hospital because of high phenylalanine concentration. We investigated their demographic features, clinical manifestations, and mutations of the PAH gene through direct DNA sequencing. Results: Among ten patients with benign HPA, two pairs of patients were related (father-daughter, mother-daughter relationship) cases, and all of them showed no specific clinical manifestations or notable past history. Their plasma phenylalanine levels ranged between 1.2 and 4.2 mg/dL. In the tetrahydrobiopterin (BH4) loading test, all patients were nonresponsive to BH4. In the confirmation test of PAH mutation analysis, we identified eleven different alleles out of twelve. The most common allele was R53H (c.158G> A). In addition, two novel PAH gene mutations, V423A (c.1268T>C) and V51A (c.152T>C), were identified. Although the patients did not receive any pharmacologic treatment or continuous phenylalanine restriction dietary therapy, their neurocognitive development was normal. Moreover, on serial outpatient follow-up tests, all patients maintained phenylalanine levels below 6 mg/dL. Conclusion: This study is the first in Korea to analyze benign HPA patients. All patients with benign HPA could maintain phenylalanine levels below 6 mg/dL with normal neurocognitive development, without continuous therapy. Therefore, performing mutation analysis and distinguishing benign HPA from phenylketonuria (PKU) are important to help improve life quality in patients with benign HPA by avoiding unnecessary lifelong therapy.

키워드

참고문헌

  1. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. The Lancet 2010;376:1417-27. https://doi.org/10.1016/S0140-6736(10)60961-0
  2. Blau N, Shen N, Carducci C. Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert Review of Molecular Diagnostics 2014;14:655-71. https://doi.org/10.1586/14737159.2014.923760
  3. Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, et al. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab 2014;112:87-122. https://doi.org/10.1016/j.ymgme.2014.02.013
  4. Strisciuglio P, Concolino D. New Strategies for the Treatment of Phenylketonuria (PKU). Metabolites 2014;4:1007-17. https://doi.org/10.3390/metabo4041007
  5. Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, et al. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab 2014;112:87-122. https://doi.org/10.1016/j.ymgme.2014.02.013
  6. Hanley W. Non-PKU mild hyperphenylalaninemia (MHP)-The dilemma. Molecular Genetics and Metabolism 2011;104:23-6. https://doi.org/10.1016/j.ymgme.2011.05.007
  7. Lee DH. Newborn screening of inherited metabolic disease in Korea. Korean Journal of Pediatrics 2006;49:1125-39. https://doi.org/10.3345/kjp.2006.49.11.1125
  8. Blau N, Hennermann JB, Langenbeck U, Lichter- Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Molecular Genetics and Metabolism 2011;104:S2-S9. https://doi.org/10.1016/j.ymgme.2011.08.017
  9. Diamond A. Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought. Acta Paediatrica 1994;83(s407):89-91. https://doi.org/10.1111/j.1651-2227.1994.tb13462.x
  10. Panel NIoHCD. National institutes of health consensus development conference statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 2001;108:972-82. https://doi.org/10.1542/peds.108.4.972
  11. BIOPKU :: International database of patients and mutations causing BH4-responsive HPA/PKU [Internet]. Blau N and Yue W, and Perez B; c2006-2013 [cited 2012 Dec]. Available from: http://www.biopku.org/pah/.
  12. Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genetics in medicine : official journal of the American College of Medical Genetics 2014;16:188-200. https://doi.org/10.1038/gim.2013.157
  13. Burton B, Grange D, Milanowski A, Vockley G, Feillet F, Crombez E, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6Rtetrahydrobiopterin): a phase II, multicentre, openlabel, screening study. Journal of Inherited Metabolic disease 2007;30:700-7. https://doi.org/10.1007/s10545-007-0605-z
  14. Levy HL, Shih VE, Karolkewicz V, French WA, Carr JR, Cass V, et al. Persistent mild hyperphenylalaninemia in the untreated state: a prospective study. New England Journal of Medicine 1971;285:424-9. https://doi.org/10.1056/NEJM197108192850802
  15. Lou Smith M, Saltzman J, Klim P, Hanley WB, Feigenbaum A, Clarke JT. Neuropsychological function in mild hyperphenylalaninemia. American Journal on Mental Retardation 2000;105:69-80. https://doi.org/10.1352/0895-8017(2000)105<0069:NFIMH>2.0.CO;2
  16. Weglage J, Schmidt E, Funders B, Pietsch M, Ullrich K. Sustained attention in untreated non-PKU-hyperphenylalaninemia. Journal of Clinical and Experimental Neuropsychology 1996;18:343-8. https://doi.org/10.1080/01688639608408992
  17. Guldberg P, Rey F, Zschocke J, Romano V, Francois B, Michiels L, et al. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotypebased prediction of metabolic phenotype. The American Journal of Human Genetics 1998;63:71-9. https://doi.org/10.1086/301920