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

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
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Somatic Cell Analysis and Cobalamin Responsiveness Study in Ten Korean Patients with Methylmalonic Aciduria

한국 메틸말로닌산혈증 환아 10례에서 Somatic Cell 분석과 cobalamin 반응성 연구

  • Lim, Han Hyuk (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Song, Wung Joo (Korea Genetics Research Center) ;
  • Kim, Gu-Hwan (Medical Genetics Center, Asan Medical Center) ;
  • Watkins, David (Departments of Human Genetics, Medicine, Pediatrics, and Biology, McGill University) ;
  • Rosenblatt, David S. (Departments of Human Genetics, Medicine, Pediatrics, and Biology, McGill University) ;
  • Kim, Yoo-Mi (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Chang, Mea Young (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Kil, Hong Ryang (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Kim, Sook Za (Department of Pediatrics, College of Medicine, Chungnam National University)
  • 임한혁 (충남대학교 의과대학 소아과학교실) ;
  • 송웅주 (한국유전학연구소) ;
  • 김구환 (서울아산병원) ;
  • ;
  • ;
  • 김유미 (충남대학교 의과대학 소아과학교실) ;
  • 장미영 (충남대학교 의과대학 소아과학교실) ;
  • 길홍량 (충남대학교 의과대학 소아과학교실) ;
  • 김숙자 (충남대학교 의과대학 소아과학교실)
  • Published : 2019.04.30
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Abstract

Purpose: Isolated methylmalonic acidemia (MMA) is an autosomal recessive inherited disorder of propionate metabolism. There are two subtypes of MMUT gene defects. $Mut^0$ represents complete loss of methylmalonyl-CoA mutase (MCM) activity while mut- is associated with residual MCM activity, which can be stimulated by hydroxocobalamin (OHCbl) supplementation. The objective of this study is to investigate cobalamin responsiveness and mutations present in Korean MMA population. Methods: We evaluated 10 MMA patients using somatic cell complementation analysis on their fibroblasts to measure MCM activity and vitamin B12 responsiveness for the optimal treatment. MMUT gene was sequenced to identify the MMA mutations. Results: For all patients, the incorporation of $[^{14}C]-propionate$ was low, and there was no response to OHCbl. The incorporation of $[^{14}C]-methyltetrahydrofolate$ and $[^{57}Co]-CNCbl$ fell within the normal range. There was adequate synthesis of methylcobalamin while the synthesis of adenosylcobalamin was low. The complementation analysis showed all patients were $mut^0$. The sequence analysis identified 12 different MMUT mutations, including 2 novel mutations, p.Gln267Ter and p.Ile697Phe, were identified. All the patients in this study had neonatal onset of symptoms, belonged to $mut^0$ complementation class, and as a result, showed no cobalamin responsiveness. Conclusion: No Korean MMA patient showed cobalamin responsiveness.

목적: 코발라민(Cobalamin)과 동반되지 않은 독립형 메틸말론산혈증(methylmalonic acidemia)은 프로피오네이트 대사 질환으로 상염색체 열성으로 유전된다. Methylmalonyl-CoA mutase (MCM)효소발현에 관련된 유전자인 MMUT에는 유전자 결함에는 두 가지 아형이 있다. $Mut^0$은 효소 활성도가 완전히 없는 것이고 Mut-형은 효소활성도가 저하되어 있지만 hydroxocobalamin (OHCbl) 보충으로 잔여효소의 활성도가 증가될 수 있는 형이다. 본 연구의 목적은 한국인 MMA 환아에서 코발라민의 반응성과 돌연변이를 조사하는 것이다. 방법: 최적의 치료를 위해 MCM 활성도와 비타민 $B_{12}$ 반응성을 측정하기 위하여 섬유 아세포의 체세포 보완 분석을 사용하여 10명의 MMA 환자를 평가했다. MMUT 유전자는 MMA 돌연변이의 염기서열을 확인하였다. 결과: $^{14}C-propionate$의 첨가는 OHCbl에 반응이 없는 모든 환자에서 낮게 나타났다. $^{14}C-methyltetrahydrofolate$와 $^{57}Co-cyanocobalamin$의 투여 후 모두 정상범위 내에 있었다. 아데노 실 코발라민의 합성은 낮지 만 메틸 코발라민의 합성은 적절하였다. 보완 분석 결과 모든 환자들은 $mut^0$ 유형이었다. DNA 염기서열분석결과에서 2개의 새로운 돌연변이, p.Gln267Ter 및 p.Ile697Phe를 포함하여 12개의 상이한 MMUT 돌연변이를 확인하였다. 신생아에서 증상이 나타나며 $mut^0$ 형인 MMA 환자 10례 모두에서 코발라민 반응을 보이지 않았다. 결론: 본 연구에서는 모든 한국 MMA 환자에서 코발라민 반응을 시험한 결과 음성이었다.

Keywords

References

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