Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Genotype and clinical features of Korean patients with methylmalonic aciduria and propionic aciduria

한국인 메틸말로닌산뇨증 및 프로피온산뇨증의 유전자형과 임상 양상

  • Lee, Eun Hye (Department of Pediatrics, Asan Medical Center University of Ulsan College of Medicine) ;
  • Ko, Jung Min (Department of Pediatrics, Asan Medical Center University of Ulsan College of Medicine) ;
  • Kim, Jae-Min (Genome Research Center for Birth Defects and Genetic Disorders) ;
  • Yoo, Han-Wook (Department of Pediatrics, Asan Medical Center University of Ulsan College of Medicine)
  • 이은혜 (울산대학교 의과대학 서울아산병원 소아과학교실) ;
  • 고정민 (울산대학교 의과대학 서울아산병원 소아과학교실) ;
  • 김재민 (보건복지부지정 선천성기형 및 유전질환 유전체연구센터) ;
  • 유한욱 (울산대학교 의과대학 서울아산병원 소아과학교실)
  • Received : 2008.03.03
  • Accepted : 2008.08.05
  • Published : 2008.09.15
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Abstract

Purpose : Methylmalonic aciduria (MMA) and propionic aciduria (PA) are inborn errors in the catabolism of branched-chain amino acids. The study was undertaken to investigate the genotypes and clinical features of Korean patients with MMA and PA. Methods : This study examined 12 patients with MMA and eight with PA. We analyzed various clinical features, laboratory findings, treatments, and neuro-developmental outcomes. Diagnoses were based on the presence of characteristic compounds detected by amino acid analysis in serum and organic acid analysis in urine. Mutation analysis was performed in the genes of MUT, MMAA, MMAB, and MMACHC for MMA and PCCA and PCCB for PA. Results : Among the 20 patients, six patients were diagnosed before one month of age and nine patients were diagnosed after the newborn period. Five patients were diagnosed via a neonatal screening test. Patients with early-onset forms had more severe illness at presentation and generally poor outcomes. A favorable outcome was obtained in 55% patients; most of them were of a late-onset type or diagnosed by neonatal mass screening test without symptoms. Genotypes were confirmed in all patients with MMA. We detected 11 different mutations by MUT gene analysis in 10 patients, and three different mutations in MMACHC genes in two patients. PCCA and PCCB gene mutations were identified in 14 of the 16 alleles, in eight patients with PA. Conclusion : Organic aciduria is a fatal disease; however, better outcomes are expected whenever early diagnosis and prompt management are made possible. Mutation analysis is useful for confirming diagnoses and planning management strategies.

목 적 : 메틸말로닌산뇨증과 프로피오닌산뇨증은 상염색체 열성으로 유전되는 아미노산 대사 이상 질환으로, methylmalonyl-CoA mutase와 propionyl-CoA carboxylse의 결함에 의해 발생하며 최근 유전자형에 대한 연구가 활발히 이루어지고 있다. 저자들은 단일기관에서 경험한 이 질환군의 임상 양상과 유전자형에 대해 조사하고자 하였다. 방 법 : 1993년부터 2007년까지 서울아산병원 소아과에서 유기산뇨증으로 진단된 20례를 대상으로 질병의 종류, 진단시 연령과 임상 양상, 유전자형, 검사 소견, 치료와 예후 등을 후향적으로 분석하였다. 혈장 암모니아, 소변 유기산 분석과 혈장 아미노산을 조사하였고, 유전자분석은 메틸말로닌산뇨증에서는 MUT, MMAA, MMAB 와 MMACHC 유전자를, 프로피오닌산뇨증에서는 PCCA와 PCCB 유전자를 분석하였다. 결 과 : 유기산뇨증으로 진단된 환아는 모두 20명이었으며, 그 중 메틸말로닌산뇨증이 12명(남아 8명, 여아 4명), 프로피오닌산뇨증이 8명(남아 6명, 여아 2명)이었다. 신생아 대사이상 검사로 진단된 환아가 5명이었으며, 6명은 신생아기에 급성 증상으로 발현하였고, 9명은 1개월 이후 발현한 지발형이었다. 신생아기 발현형에서는 6명 중 5명이 구토와 기면을 주증상으로 내원하였으며, 지발형에서는 구토와 기면 이외에도 발달 지연, 보행 장애, 혈소판 감소증 등 다양한 임상 양상을 보였다. 예후로는 메틸말로닌산뇨증 환아 중 2명(17%)이 2세경에 고암모니아혈증과 대사성 산증으로 사망하였으며, 7명(58%)이 정상발달을 보였다. 프로피오닌산뇨증 환아는 1명이 사망하였고, 4명(50%)이 정상 발달을 보이고 있다. 증상의 발현시기에 따라서는 신생아기 발현형에서 6명중에서 2명은 사망, 2명은 정상 발달, 2명은 발달지연을 보이고 있는 것에 비해, 증상 없이 신생아 대사이상 검사로 진단된 환아 중에는 2명(40%)이 정상발달을 보이고 있고, 지발형에서는 7명(63%)이 정상 발달을 보이고 있다. 유전자형은 메틸말로닌산뇨증 전례에서 규명되었으며 10명은 MUT 유전자에서 11종의 서로 다른 돌연변이가 발견되었는데 대부분 nonsense 돌연변이였다. 비타민 B12 반응형 환아 2명에서는 MMACHC 유전자에서 3종의 서로 다른 돌연변이가 발견되었으며 프로피오닌산뇨증에서는 16개 대립유전자 중 14개에서 PCCA와 PCCB 유전자의 돌연변이가 규명되었다. 결 론 : 유기산뇨증은 진단이 지연되면 매우 치명적이나, 조기에 의심하여 진단하고 적절히 치료하면 좋은 예후를 기대할 수 있는 질환이다. 유기산뇨증의 유전자형의 분석은 정확한 진단을 가능하게 할 뿐 아니라 유전상담, 산전 진단 및 표현형의 예측에도 도움이 된다.

Keywords

References

  1. Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet 2006;142:104-12
  2. Fenton WA, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism: the metabolic and molecular bases of inherited disease. New York: McGraw-Hill 2001;2165-93
  3. Dionisi-Vici C, Deodato F, Roschinger W, Rhead W, Wilcken B. Classical organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 2006;29:383-9 https://doi.org/10.1007/s10545-006-0278-z
  4. Horster F, Hoffmann GF. Pathophysiology, diagnosis, and treatment of methylmalonic aciduria; recent advances and new challenges. Pediatr Nephrol 2004;19:1071-4
  5. Lehnert W, Sperl W, Suormala T, Baumgartner ER. Propionic acidaemia: clinical, biochemical and therapeutic aspects. Eur J Pediatr 1994;153:68-80 https://doi.org/10.1007/BF02138781
  6. Hsia YE, Scully KJ, Rosenberg LE. Inherited propionyl-CoA carboxylase deficiency in ketotic hyperglycinemia. J Clin Invest 1971;50:127-30 https://doi.org/10.1172/JCI106466
  7. Gravel RA, Lam KF, Mahuran D, Kronis A. Purification of human liver propionyl-CoA carboxylase by carbon tetrachloride extraction and monomeric avidin affinity chromatography. Arch Biochem Biophys 1980;201:669-73 https://doi.org/10.1016/0003-9861(80)90557-3
  8. Jansen R, Kalousek F, Fenton WA, Rosenberg LE, Ledley FD. Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction. Genomics 1989;4:198-205 https://doi.org/10.1016/0888-7543(89)90300-5
  9. Ledley FD, Lumetta MR, Zoghbi HY, VanTuinen P, Ledbetter SA, Ledbetter DH. Mapping of human methylmalonyl CoA mutase (MUT) locus on chromosome 6. Am J Hum Genet 1988;42:839-46
  10. Nham SU, Wilkemeyer MF, Ledley FD. Structure of the human methylmalonyl-CoA mutase (MUT) locus. Genomics 1990;8:710-6 https://doi.org/10.1016/0888-7543(90)90259-W
  11. Baumgarter ER, Viardot C. Long-term follow-up of 77 patients with isolated methylamalonic acidaemia. J Inherit Metab Dis 1995;18:138-42 https://doi.org/10.1007/BF00711749
  12. Shevell MI, Matiaszuk N, Ledley FD, Rosenblatt DS. Varying neurological phenotypes among mut 0 and mut - patients with methylmalonyl Co A mutase deficiency. Am J Med Genet 1993;45:619-24 https://doi.org/10.1002/ajmg.1320450521
  13. Matsui SM, Mahoney MJ, Rosenberg LE. The natural history of the inherited methylmalonic acidemias. N Engl J Med 1983;308:857-61 https://doi.org/10.1056/NEJM198304143081501
  14. Lerner-Ellis JP, Tirone JC, Pawelek PD, Dore C, Atkinson JL, Watkins D et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 2006;38:93-100 https://doi.org/10.1038/ng1683
  15. Morel CF, Lerner-Ellis JP, Rosenblatt DS. Combined methylmalonic aciduria and homocystinuria (cblC): Phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab 2006;88:315-21 https://doi.org/10.1016/j.ymgme.2006.04.001
  16. Nicolaides P, Leonard J, Surtees R. Neurological outcome of methylmalonic acidaemia. Arch Dis Child 1998;78:508-12 https://doi.org/10.1136/adc.78.6.508
  17. Ogasawara M, Matsubara Y, Mikami H, Narisawa K. Identification of two novel mutations in the methylmalonyl-CoA mutase gene with decreased levels of mutant mRNA in methylmalonic acidemia. Hum Mol Genet 1994;3:867-72 https://doi.org/10.1093/hmg/3.6.867
  18. Kalousek F, Darigo MD, Rosenberg LE. Isolation and characterization of propionyl-CoA carboxylase from normal human liver. Evidence for a protomeric tetramer of nonidentical subunits. J Biol Chem 1980;255:60-5
  19. Campeau E, Desviat LR, Leclerc D, Wu X, Perez B, Ugarte M, Gravel RA. Structure of the PCCA Gene and Distribution of Mutations Causing Propionic Acidemia. Mol Genet Metab 2001;74:238-47 https://doi.org/10.1006/mgme.2001.3210
  20. Perez B, Desviat LR, Rodriquez-Pombo P, Clavero S, Navarrete R, Perez-Cerd C, et al. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Mol Genet Metab 2003;78:59-67 https://doi.org/10.1016/S1096-7192(02)00197-X
  21. Ugarte M, Perez-Cerda C, Rodriguez-Pombo P, Desviat LR, Perez B, Richard E, Muro S, Campeau E, Ohura T, Gravel RA. Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. Hum Mut 1999;14:275-82 https://doi.org/10.1002/(SICI)1098-1004(199910)14:4<275::AID-HUMU1>3.0.CO;2-N
  22. Kim SN, Ryu KH, Lee EH, Kim JS, Hahn SH. Molecular analysis of PCCB gene in Korean patients with propionic acidemia. Mol Genet Metab 2002;77:209-16 https://doi.org/10.1016/S1096-7192(02)00139-7
  23. Ohura T, Narisawa K, Tada K. Propionic acidaemia: Sequence analysis of mutant mRNAs from Japanese beta subunit-deficient patients. J Inherit Metab Dis 1993;16:863-7 https://doi.org/10.1007/BF00714279
  24. Perez-Cerda C, Merinero B, Rodriguez-Pombo P, Perez B, Desviat LR, Muro S et al. Potential relationship between genotype and clinical outcome in propionic acidaemia patients. Eur J Hum Genet 2000;8:187-94 https://doi.org/10.1038/sj.ejhg.5200442
  25. Rutledge SL, Geraghty M, Mroczek E, Rosenblatt D, Kohout E. Tubulointerstitial nephritis in methylmalonic acidemia. Pediatr Nephrol 1993;7:81-2 https://doi.org/10.1007/BF00861581
  26. Baulny HO, Benoist JF, Rigal O, Touati G, Rabier D, Saudubray JM. Methylmalonic and propionic acidaemias: Management and outcome. J Inherit Metab Dis 2005;28:415-23 https://doi.org/10.1007/s10545-005-7056-1
  27. Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G et al. Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J Pediatr 2002;140:321-7 https://doi.org/10.1067/mpd.2002.122394

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