Somatic Cell Analysis and Cobalamin Responsiveness Study in Ten Korean Patients with Methylmalonic Aciduria

임한혁,송웅주,김구환,김유미,장미영,길홍량,김숙자,Lim, Han Hyuk,Song, Wung Joo,Kim, Gu-Hwan,Watkins, David,Rosenblatt, David S.,Kim, Yoo-Mi,Chang, Mea Young,Kil, Hong Ryang,Kim, Sook Za The Korean Society of Inherited Metabolic Disease 2019 대한유전성대사질환학회지 Vol.19 No.1

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. 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.

Intervention with Balloon Valvuloplasty followed by Patent Ductus Arteriosus Stent in a Patient with Pulmonary Atresia with Intact Ventricular Septum

임한혁,김영득,장미영,이재환,길홍량,Lim, Han Hyuk,Kim, Young Deuk,Lee, Jae Hwan,Chang, Mea Young,Kil, Hong Ryang The Korean Pediatric Society 2005 Clinical and Experimental Pediatrics (CEP) Vol.48 No.11

Pulmonary atresia with intact ventricular septum (PAIVS) is rare, less than 1% of congenital heart disease. It needs a therapeutic approach according to its individual morphologic feature. Surgical treatment of valvotomy and modified Blalock-Taussig shunt or non-surgical interventional catheter balloon valvuloplasty can be used for mild to moderate hypoplasia of right ventricle. Fontan operation can be considered for less optimum morphological substrate of two ventricular repair. A 3-day-old male neonate was admitted with cyanosis and cardiac murmur. On echocardiogram, he had membranous pulmonary atresia with intact ventricular septum, normal sized tripartite right ventricle, large atrial septal defect with right-to-left shunt, small sized patent ductus arteriosus, and moderate tricuspid regurgitation. He was treated with intravenous continuous infusion of prostaglandin $E_1$ ($PGE_1$) at once. On the third day of hospitalization, Balloon valvuloplasty was performed. After insertion of patent ductus arteriosus stent on the tenth day, $PGE_1$ infusion was discontinued. On the fifteenth day, he was discharged. Now, he is 9 months old and has nearly normal cardiac structure and function with 97% of percutaneous oxygen saturation. 심실중격결손을 동반하지 않은 폐동맥 폐쇄(pulmonary atresia with intact ventricular septum)는 전체 선천적 심장병의 1%를 차지하는 드문 질환으로 형태학적 특성에 따라 다양한 치료적 접근이 필요하다. 이에 저자들은 정상 크기발달의 우심실을 가진 심실중격결손을 동반하지 않은 폐동맥 폐쇄가 있는 신생아에서 풍선판막성형술 후 지속적인 저산소증을 보여 동맥관 스텐트를 이용하여 거의 정상적인 심장구조와 기능으로 호전된 1례를 경험하였기에 보고하는 바이다.

소아 하기도 호흡기 감염에서 항생제 치료 가이드라인으로서의 혈청 procalcitonin의 임상적 유용성

임한혁 ( Han Hyuk Lim ),강혜진 ( Hye Jin Kang ),양은애 ( Eun Ae Yang ),이재호 ( Jae Ho Lee ) 대한소아알레르기호흡기학회(구 대한소아알레르기 및 호흡기학회) 2012 소아알레르기 및 호흡기학회지 Vol.22 No.1

Purpose: Procalcitonin (PCT), a precursor of calcitonin, has been described as a biomarker of bacterial infection and inflammation. This study was performed to evaluate the clinical usefulness of PCT levels and to reduce the unnecessary usage of antibiotics in children with lower respiratory tract infection (RTI). Methods: Eighty-eight children, with lower RTI, under the age of 5 years, who were admitted to Chungnam National University Hospital, between May 2010 and December 2010, were enrolled. White blood cell counts, erythrocyte sedimentation rate, C-reactive protein, and PCT were measured. Blood and sputum cultures were performed to identify the causative bacteria and reverse transcription-polymerase chain reaction for the viruses. Clinical features were reviewed, retrospectively. Results: The mean participant age was 1.9±1.5 years. The cut-off value for serum PCT levels, which was derived from the receiver-operator characteristic curve, was 0.11·ng/mL. In 29 patients (33.0%) with low PCT levels (<0.11 ng/mL), antibiotic therapy showed no benefit for clinical and laboratory findings. However, in 59 patients (67.1%) with high PCT levels (≥0.11 ng/mL), hospitalization (P=0.005) and fever (P=0.054) exhibited a shorter duration, after antibiotic therapy. Conclusion: A single initial serum PCT levels (≥0.11 ng/mL) may be clinically useful to give a guideline for antibiotic treatment in children with lower respiratory tract infection and to reduce the unnecessary usage of antibiotics.

Transcatheter Closure of a Residual Shunt after Surgical Repair of Traumatic Ventricular Septal Defect

정희정,임한혁,유재현,이재환,길홍량,Jeong, Hee Jeong,Lim, Han Hyuk,Yu, Jae Hyun,Lee, Jae Hwan,Kil, Hong Ryang The Korean Pediatric Society 2005 Clinical and Experimental Pediatrics (CEP) Vol.48 No.10

The traumatic ventricular septal defect (VSD) is a rare but potentially life threatening complication of chest wall injury. The traumatic VSD occurs in up to 4.5% of penetrating cardiac trauma. Most of the patients are usually operated on because of heart failure and/or significant left-to-right shunt. The feasibility of surgical repair under cardiopulmonary bypass may be affected by coexisting pulmonary, cerebral or other vascular injuries. Transcatheter closure of VSD is being considered as an alternative therapeutic modality to surgery in order to avoid the potential risk of cardiopulmonary bypass. We report a patient who underwent a successful transcatheter closure of VSD with an $Amplatzer^{(R)}$ VSD occluder. The patient had a residual VSD with significant left-to-right shunt after surgical repair of post-traumatic VSD using cardiopulmonary bypass. 흉부 관통상에 의해 심실중격결손이 동반된 대부분의 환자들은 내원 시 활력징후가 불안정하여 심폐소생술 및 응급 개흉술을 시행받게 되는데, 이러한 경우 심장과 흉부 손상의 위치 및 정도에 대한 자세한 검사가 이루어지지 않은 상태이므로 발견되지 않았거나 잔존하는 이상 소견들이 수술 후 검사에서 발견될 수 있고 이에 대한 재수술을 필요로 하는 경우도 있다. 심실중격결손의 심도자술을 통한 폐쇄는 수술을 대처할 수 있는 방법으로서, 특히 수술 후 잔존하는 단락의 경우 이차 수술의 위험을 피할 수 있다. 저자들은 흉부 자상에 의한 심실벽의 열창 및 심실중격결손을 수술적 방법으로 봉합한 후 잔존하는 심실중격결손을 기구($Amplatzer^{(R)}$ VSD occluder)를 이용한 중재적 심도자술로 치료한 증례를 문헌 고찰과 함께 보고한다. 심도자술 6개월 후 시행한 심초음파검사에서 잔존하는 심실 좌우 단락은 없었고, 심실 크기와 기능도 정상이었고, 현재 상태는 양호하여 정상적으로 학교생활을 하고 있다.

신생아 대사질환 선별검사에서 발견된 갈락토스혈증의 감별진단

최성윤,송웅주,임한혁,길홍량,김숙자,Choi, Sung Yoon,Song, Woong Ju,Lim, Han Hyuk,Kil, Hong Ryang,Kim, Sook Za 대한유전성대사질환학회 2013 대한유전성대사질환학회지 Vol.13 No.2

Purpose: We retrospectively investigated individuals who hadbeen identified by neonatal screening as potential galactosemia patients to determine the etiology of galactosemia. Methods: One hundred fifty-three patients referred to Korea Genetics Research Center due to high galactose level detected by neonatal screening test between February 2005 and May 2013 were examined. Galactose and galactose-1-phosphate levels were measured by using a fluoro metric microplate reader. Lactose free diet was initiated immediately after confirmed by urine Clinitest. If reducing sugar was negative, we employed abdominal sonogram and echocardiogram to check for possible porto-systemic shunt. Results: Fifteen patients were diagnosed with galactosemia. One patient had galactokinase (GALK) deficiency; four had UDP galactose-4-epimerase (GALE) deficiency; two had citrin deficiency; and four had porto-systemic shunt. Two had unknown causes of galactosemia. Conclusion: In addition to genetic defects of GALT, GALK and GALE, citrin deficiency or porto-systemic shunt could also cause galactosemia. It is crucial to carry out differential diagnosis to determine the cause of galactosemia.

소아 폐렴 환자에서 혈중 procalcitonin을 이용한 항생제 사용 결정과 임상적 결과의 비교 분석

안세진 ( Se Jin An ),배성필 ( Sung Phil Bae ),박준수 ( Joon Soo Park ),최영진 ( Young Jin Choi ),임한혁 ( Han Hyuk Lim ),이재호 ( Jae Ho Lee ) 대한천식알레르기학회 2016 Allergy Asthma & Respiratory Disease Vol.4 No.1

Purpose: It is difficult to differentiate between viral and bacterial pneumonia in children and to decide antibiotic therapy. Study was conducted to investigate the clinical usefulness of antibiotic therapy based on procalcitonin (PCT) in children diagnosed with viral pneumonia. Methods: This study included 108 patients diagnosed with viral pneumonia. Patient’s age, fever duration, hospital stay, and treatment progress were noted, and laboratory study including PCT levels were tested. In addition, Polymerase chain reaction was done to test for viruses. Patients were divided into PCT and non-PCT groups according to PCT level. And their clinical patterns, treatment outcome, antibiotic use, severity of complications were compared. Results: The number of patients with respiratory syncytial virus (RSV) was 35 and 50, rhinovirus was 5 and 10 in PCT and non-PCT groups, respectively. Fever duration was longer by 2.5 days in PCT group than in the non-PCT group (P<0.001), but there was no difference in the duration of hospital stay (P=0.191). White blood cell and absolute neutrophil count levels were higher in the PCT group (P=0.013 and P<0.001, respectively). Use of antibiotic therapy was performed in group was on 22% and 90% of patients in the PCT and non-PCT groups, respectively showing a significant reduction in the frequency of antibiotic therapy in PCT group, without a significant difference in treatment outcome, despite more severe clinical signs (P<0.001). Conclusion: Antibiotic therapy based on serum PCT levels in children admitted for pneumonia can reduce the frequency of antibiotic therapy in viral pneumonia, without causing significantly different treatment outcome or complications.