한국 신생아 집단검사의 과거, 현재, 미래

이동환,Lee, Dong Hwan 대한유전성대사질환학회 2014 대한유전성대사질환학회지 Vol.14 No.1

Many inborn errors of metabolism can be completely cured with early detection and early treatment. This is why neonatal screening on inborn errors of metabolism is implemented worldwide. In 1991, the Ministry of Health & Social affairs adopted a nationwide service program for neonatal screening of phenylketonuria, galactosemia, maple syrup urine disease, homocystinuria, histidinemia and congenital hypothyroidism for newborns delivered from low class pregnant women registered in health centers. Government decreased the test items from six to two, PKU and congenital hypothyroidism to increase test numbers with same budget from 1995. 78 laboratories wanted to participate for neonatal screening test in 1999. Government decided to screen six items of PKU, congenital hypothyroidism, maple syrup urine disease, homocystinuria, galactosemia and congenital adrenal hyperplasia from 2006. In 2014, thirteen laboratories are participating. Inter laboratory quality control was started 6 times a year from 1994. In case a patient with an inherited metabolic disease is diagnosed by screening of government program, special milk is provided at government's expense. According to the government project, from 1997 to 2013, 7,080,569 newborns were screened. 144 PKU, 2.451 congenital hypothyroidism were detected. So incidence of PKU is 1/49,170 and congenital hypothyroidism is 1/2,888. The cost benefit of performing screening procedures coupled with treatment has been estimated to be as high as 1.77 times in PKU, 11.11 times in congenital hypothyroidism than cost without screening. By January 2007, many European countries had expanded of their newborn screening programs by inclusion of Tandem mass spectrometry. We are trying to increase the budget to test all newborns for Tandem mass spectrometry from 2016. We are considering four to five central laboratories which cover all newborns and are equipped with tandem mass spectrometer & enzyme immunoassay for TSH, 17OHP & enzyme colorimetric assay for galactose. And I hope to expand test including Wilson disease screening test and lysosomal storage diseases.

Tandem Mass Spectrometry를 이용한 선천성 대사이상질환 선별검사 7년간의 경험

송선미(Sean-Mi Song),윤혜란(Hye-Ran Yoon),이안나(Anna Lee),이경률(Kyoung-Ryul Lee) 대한의학유전학회 2008 대한의학유전학회지 Vol.5 No.1

Purpose : In recent years, many countries have adopted newborn screening programs that use tandem mass spectrometry (MS/MS) to screen and the number of diseases screened has also increased. We began screening for inherited metabolic disorders using MS/MS in April, 2001. Our goal was to determine the overall prevalence of metabolic disorders and to assess the effectiveness of newborn screening by MS/MS in Korea. Methods : From April, 2001 to December, 2007, we screened newborns and high risk groups using MS/MS. Acylcarnitines and amino acids were extracted and butylated and were introduced into the inlet of MS/MS. Confirmatory testing including a repeat newborn screening, and urine organic acid and plasma amino acid analysis were performed on a case-by-case basis. Results : The total number of screened subjects 284,933 which comprised 251,799 neonates and 33,134 high risk subjects. The recall rate was 0.4% (1158 tests) and true positive cases were 117 (0.04%). Confirmed metabolic disorders (newborn/high risk group) were as follows; 78 (25/53) amino acid disorders, 27 (16/11) organic acid disorders, and 12 (5/7) fatty acid oxidation disorders. The estimated prevalence of inherited metabolic diseases in newborns was 1:5,000 and that in the total group was 1:2,000. Conclusion : Newborn screening by MS/MS improved the detection of many inherited metabolic disorders. We therefore propose that all newborns be screened by a MS/MS national program and followed-up using a systemic organization strategy. 목적 : 최근 여러 국가에서 빠르게 탠덤매스 신생아 선천성 대사이상질환 선별 프로그램을 채택하고 있으며 많은 질환들이 검출되고 있다. 본 기관에서는 2001년 4월부터 탠덤매스 선천성 대사이상 질환 신생아 선별 검사를 시작하였다. 연구자들은 한국에서의 탠덤매스 선천성 대사이상질환 검출율 및 탠덤매스 유용성에 대해 평가하고자 하였다. 방법 : 2001년 4월부터 2007년 12월까지 본원에서는 탠덤매스를 이용하여 신생아 및 고위험군에 대해 선별검사를 시행하였다. 검체로부터 아실카르틴과 아미노산을 추출하여 부탄올로 유도체화시킨 후 탠덤매스에 장착하여 분석하였다. 탠덤매스 선별검사 재검, 소변 유기산 및 혈장 아미노산검사 등을 포함한 확진 검사는 개별적으로 시행되었다. 결과 : 총 의뢰건수는 284,933건으로 신생아 251,799건 및 고위험군 33,134건이었다. 소환율은 0.4%(1158건)이었으며, 이들 중 true positive는 117건(0.04%)이었다. 아미노산 대사 이상 질환은 총 78건(25/53), 유기산 대사이상 질환은 총 27건(16/11건) 및 지방산 산화대사이상 질환은 총 12건(5/7건)으로 전체 질환에 대한 검출율은 신생아 1:5,000이었으며 전체군 1:2,000이었다. 결론 : 탠덤매스 신생아 선별검사는 조기 진단 및 치료가 필요한 많은 선천성 대사이상질환의 검출을 용이하게 해주었다. 그러므로, 반드시 모든 신생아들에 대한 국가지원 탠덤매스 선별검사 확대 적용 및 추적관리 시스템이 구축이 필요할 것으로 판단된다.

신생아 난청 선별검사에서 일측성 재검으로 의뢰된 환아의 단기 경과 관찰 결과

이도훈,이정엽,문일하,이병돈,이종대,박무균 대한이비인후과학회 2013 대한이비인후과학회지 두경부외과학 Vol.56 No.12

Background and Objectives Hearing screening is mandatory for newborns. The management of patients who fail hearing screening is important. This study examined the prognosis of patients who had hearing loss detected on the newborn hearing screening. Subjects and Method The results of newborn hearing tests, follow-up hearing tests, and risk factors for hearing loss were analyzed retrospectively in prospectively collected data. Newborn hearing screening testing using an auto auditory brain stem (ABR) response was perfor-med for 1296 newborns from January 2010 to December 2012 at Soonchunhyang University Bucheon Hospital. Follow-up hearing tests using ABR and otoacoustic emissions were perfor-med 6 and 12 months after the newborn hearing screening. Results Of the 1296 newborns who underwent hearing screening tests, 63 were referred and 58 had confirmed hearing loss. The hearing loss was unilateral in 74.2% (43/58). During the 1- year follow-up, about half of the patients showed improved hearing function. Premature birth was related to hearing recovery. Conclusion During the follow-up, some patients with unilateral hearing loss showed recovery. Some premature patients can expect hearing recovery during follow-up testing. Regular follow-up after newborn hearing screening is important to detect hearing changes in this period.

Use of Tandem Mass Spectrometry for Newborn Screening of 6 Lysosomal Storage Disorders in a Korean Population

한민제,전선희,송상훈,박경운,김진규,송정한 대한진단검사의학회 2011 Annals of Laboratory Medicine Vol.31 No.4

Background: We evaluated the performance of multiplex tandem mass spectrometry (MS/MS) in newborn screening for detection of 6 lysosomal storage disorders (LSDs), namely, Niemann-Pick A/B, Krabbe, Gaucher, Fabry, and Pompe diseases and Hurler syndrome. Methods: We revised the conditions and procedures of multiplex enzyme assay for the MS/MS analysis and determined the precision of our enzyme assay and the effects of sample amounts and incubation time on the results. We also measured the degree of correlation between the enzyme activities in the dried blood spots (DBSs) and those in the leukocytes. DBSs of 211 normal newborns and 13 newborns with various LSDs were analyzed using our revised methods. Results: The intra- and inter-assay precisions were 2.9-18.7% and 8.1-18.1%, respectively. The amount of product obtained was proportional to the DBS eluate volume, but a slight flattening was observed in the product vs. sample volume curve at higher sample volumes. For each enzyme assay, the amount of product obtained increased linearly with the incubation period (range, 0-24 hr). Passing and Bablok regression analysis revealed that the enzyme activities in the DBSs and those in the leukocytes were favorably correlated. The enzyme activities measured in the DBSs were consistently lower in patients with LSDs than in normal newborns. Conclusions: The performance of our revised techniques for MS/MS detection and enzyme assays was of the generally acceptable standard. To our knowledge, this is the first report on the use of MS/MS for newborn screening of LSDs in an Asian population. Background: We evaluated the performance of multiplex tandem mass spectrometry (MS/MS) in newborn screening for detection of 6 lysosomal storage disorders (LSDs), namely, Niemann-Pick A/B, Krabbe, Gaucher, Fabry, and Pompe diseases and Hurler syndrome. Methods: We revised the conditions and procedures of multiplex enzyme assay for the MS/MS analysis and determined the precision of our enzyme assay and the effects of sample amounts and incubation time on the results. We also measured the degree of correlation between the enzyme activities in the dried blood spots (DBSs) and those in the leukocytes. DBSs of 211 normal newborns and 13 newborns with various LSDs were analyzed using our revised methods. Results: The intra- and inter-assay precisions were 2.9-18.7% and 8.1-18.1%, respectively. The amount of product obtained was proportional to the DBS eluate volume, but a slight flattening was observed in the product vs. sample volume curve at higher sample volumes. For each enzyme assay, the amount of product obtained increased linearly with the incubation period (range, 0-24 hr). Passing and Bablok regression analysis revealed that the enzyme activities in the DBSs and those in the leukocytes were favorably correlated. The enzyme activities measured in the DBSs were consistently lower in patients with LSDs than in normal newborns. Conclusions: The performance of our revised techniques for MS/MS detection and enzyme assays was of the generally acceptable standard. To our knowledge, this is the first report on the use of MS/MS for newborn screening of LSDs in an Asian population.

신생아 난청과 신생아청각선별검사

박수경 한양대학교 의과대학 2015 Hanyang Medical Reviews Vol.35 No.2

The incidence of bilateral profound hearing loss of newborns is 1 to 2 per 1,000 newborns. It is higher in infants with risk factors for hearing loss. Congenital hearing loss can cause many problems in language, learning, speech development and educational and occupational performance. Most developed countries have conducted the Universal Newborn Hearing Screening (UNHS) with automated otoacoustic emissions (AOAE) or automated auditory brainstem response (AABR). UNHS reduced the average age of identification of permanent hearing loss in infants 6 months or less after birth. This early identification and intervention of hearing loss with amplification and speech therapy optimizes communication during the early critical period of language acquisition and can improve language outcomes in children between 2 and 5 years of age. The aims of this paper are to explain the incidence of newborn hearing loss, the importance of early detection of hearing loss and intervention and newborn hearing screening methods.

차세대 신생아 선별검사에 대한 전망

박경진,김종원 대한진단검사의학회 2015 Laboratory Medicine Online Vol.5 No.4

Newborn screening (NBS) has been effective for detecting asymptomatic newborns with inherited metabolic diseases and has facilitated early clinical intervention, which has resulted in significant decreases in the rates of morbidity and mortality caused by these diseases. The outcome of the NBS program heavily depends on technological advances. Since Dr. Robert Guthrie developed a bacterial inhibition assay to screen for metabolic diseases in the early 1960s, use of the NBS program has spread to many countries. Tandem mass spectrometry (TMS) was a second major technological breakthrough that has allowed screening to be extended to disorders of fatty acid and organic acid metabolism as well as to those of amino acid metabolism, and recently screening has also been expanded to include lysosomal storage diseases. TMS can detect multiple analytes rapidly and simultaneously and is currently applied to nearly 80% of the newborn population in Korea. Next-generation sequencing (NGS) technology could be another major breakthrough to improve the current NBS program. To integrate NGS into the NBS program, various considerations about its analytical validity, clinical validity, clinical utility, and ethical, legal, and social implications should be addressed on the basis of population screening. Here, the authors review population screening criteria, the current status of NBS, and recent advances in NGS. In addition, we discuss the practical and ethical issues, opportunities, and challenges regarding the implementation of NGS in NBS. 신생아 선별검사는 증상이 없는 신생아를 대상으로 질환을 조기에 발견하여 치료함으로써 합병증 및 사망률을 감소시키기 위해 도입된 프로그램이다. 꾸준한 기술적 진보를 통해 신생아 선별검사 프로그램은 공중보건 향상에 크게 기여하였다. 1960년대 초반 R. Guthrie에 의해 세균억제법이 개발된 이후, 프로그램은 여러 나라로 널리 확대 시행되었다. 이후, 탠덤질량분석법이 개발되어 지방산질환 및 유기산질환, 최근에는 리소좀축적질환까지 선별할 수 있게 되었다. 탠덤질량분석법을 이용하면 단시간 내 여러 물질을 동시에 분석할 수 있어, 선별검사 프로그램 향상에 획기적 기여를 하였다. 현재 국내에서는 신생아의 80% 정도에서 탠덤질량분석법을 이용하여 신생아 선별검사를 시행한다. 향후에는 차세대유전체분석법의 적용에 의해 현행 신생아 선별검사 프로그램이 더 향상이 될 것으로 기대된다. 차세대유전체분석법을 신생아 선별검사 프로그램의 일환으로 통합하기 위해서는 분석적 타당성, 임상적 타당성, 임상적 유용성 및 윤리적·법적·사회적 이슈 등을 집단선별검사라는 관점에서 고려하여야 한다. 이에 본 종설에서는 신생아 선별검사의 현황, 집단선별검사 기준, 차세대유전체분석법의 최신 동향을 살펴보고, 차세대유전체분석법을 신생아 선별검사에 적용 시, 고려사항 및 기회 및 해결과제 등에 대해 논의하고자 한다.

A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening

Park, Kyoung-Jin,Park, Seungman,Lee, Eunhee,Park, Jong-Ho,Park, June-Hee,Park, Hyung-Doo,Lee, Soo-Youn,Kim, Jong-Won The Korean Society for Laboratory Medicine 2016 Annals of Laboratory Medicine Vol.36 No.6

<P><B>Background</B></P><P>A newborn screening (NBS) program has been utilized to detect asymptomatic newborns with inherited metabolic diseases (IMDs). There have been some bottlenecks such as false-positives and imprecision in the current NBS tests. To overcome these issues, we developed a multigene panel for IMD testing and investigated the utility of our integrated screening model in a routine NBS environment. We also evaluated the genetic epidemiologic characteristics of IMDs in a Korean population.</P><P><B>Methods</B></P><P>In total, 269 dried blood spots with positive results from current NBS tests were collected from 120,700 consecutive newborns. We screened 97 genes related to NBS in Korea and detected IMDs, using an integrated screening model based on biochemical tests and next-generation sequencing (NGS) called NewbornSeq. Haplotype analysis was conducted to detect founder effects.</P><P><B>Results</B></P><P>The overall positive rate of IMDs was 20%. We identified 10 additional newborns with preventable IMDs that would not have been detected prior to the implementation of our NGS-based platform NewbornSeq. The incidence of IMDs was approximately 1 in 2,235 births. Haplotype analysis demonstrated founder effects in p.Y138X in <I>DUOXA2</I>, p.R885Q in <I>DUOX2</I>, p.Y439C in <I>PCCB</I>, p.R285Pfs<SUP>*</SUP>2 in <I>SLC25A13</I>, and p.R224Q in <I>GALT</I>.</P><P><B>Conclusions</B></P><P>Through a population-based study in the NBS environment, we highlight the screening and epidemiological implications of NGS. The integrated screening model will effectively contribute to public health by enabling faster and more accurate IMD detection through NBS. This study suggested founder mutations as an explanation for recurrent IMD-causing mutations in the Korean population.</P>

Effectiveness of Health Education toward Healthcare Knowledge Improvement about Congenital Hypothyroidism Newborn Screening

Muhammad Faizi,Nur Rochmah,Yuni Hisbiyah,RayiKurnia Perwitasari,WikaYuli Deakandi,Feelin Fatwa Titiharja 대한갑상선학회 2022 International Journal of Thyroidology Vol.15 No.2

Background: The most frequent congenital endocrine disorder in children is congenital hypothyroidism (CH). In Indonesia, CH’s prevalence is greater than the data currently available. However, CH newborn screening has only been carried out in a few locations across Indonesia. Therefore, there is a need to raise primary healthcare practitioners' understanding of the CH Screening Program. Materials and Methods: This study used a pre-posttest design to gauge the healthcare professionals' knowledge of newborn congenital hypothyroid screening. After intervention, a post-test was given. The categorical measures' descriptive statistical analysis results were presented as a mean, median, percentage (%), and frequency (n) distribution table. The improvement in healthcare professionals' understanding of newborn CH screening was evaluated using the Paired Samples test. The cutoff for statistical significance was p<0.05 using SPSS version 20.0. Results: In our study, most of the participants were midwives with a total of 21/53 (39.62%) followed by nurses with 19/53 (35.83%). There was also an increase in the score where previously in the pretest only 1 person got a score above 80, then it increased to half of the participants, namely 49.06% (26/53) who got better scores. months and 37/54 (68.5%). With the Paired Sample test, we prove that there is a significant increase in the participants' scores, and the data obtained is p<0.05, which means that there is an increase in the average data from the pretest to the post-test. Conclusion: There was an improvement in pre-posttest knowledge of healthcare who had been given education about CH newborn screening.

광각 디지털 영상 장치를 이용한 정상 신생아의 안과 선별 검사 결과

박세영,김소영 대한안과학회 2015 대한안과학회지 Vol.56 No.10

Purpose: To present the results of eye screening examinations using RetCam in healthy newborns. Methods: Eye screening examinations were performed using the RetCam wide-field digital imaging system (Clarity Medical System, Pleasanton, CA, USA), as requested by parents, on healthy newborns within a week after birth in an obstetrics and gynecology hospital between June 2012 and September 2014. During the examination, photographs were taken showing red reflex and the fundus. The reading was conducted by a pediatric ophthalmologist. Results: The examinations included a total of 10,023 newborn babies, and abnormalities were discovered in 2,916 patients (29.09%). The most commonly found abnormality was retinal hemorrhage, which was discovered in 2,796 babies (27.89%) and 471 patients showed a large amount of bleeding or macular hemorrhage. In 71 patients (0.7%), ophthalmologic examination was recommended after newborns presented with one of the following conditions: congenital cataracts, retinoblastoma, persistent hyperplastic primary vitreous, vitreous hemorrhaging, persistent pupillary membrane, choroidal nevus or albinism. Due to unclear photographs, 85 eyes of 49 patients (0.48%) could not be read. Conclusions: Ophthalmologic screening using RetCam is a safe, simple and useful technique for discovering ophthalmologic abnormalities. Additionally, when abnormalities are suspected, the role of a pediatric ophthalmologist is increasingly important in helping patients receive appropriate ophthalmologic treatment. Furthermore, retinal hemorrhage, which occurred in the majority of all observed abnormalities, requires further investigation to examine the possibilities of amblyopia in cases with a large amount of bleeding or macula involvement. 목적: 건강한 신생아에서 RetCam을 이용하여 시행한 안과 선별검사의 결과를 보고하고자 한다. 대상과 방법: 2012년 6월부터 2014년 9월까지 쉬즈메디 여성병원 외 8곳의 산부인과 병원에서 출생한 건강한 신생아 중 안과검사를희망한 경우 RetCam wide-field digital imaging system (Clarity Medical System, Pleasanton, CA, USA)을 이용하여 출생 1주 내에검사를 시행하였다. 검사는 적색반사가 보이는 사진과 안저를 촬영하였고, 한 명의 소아안과의사에 의하여 판독이 이루어졌다. 결과: 총 10,023명의 신생아에서 검사가 이루어졌고, 2,916명(29.09%)의 환아에서 이상이 발견되었다. 가장 많은 이상은 망막출혈이었고 2,796명(27.89%)에서 발견되었으며 471명은 출혈의 양이 많거나 황반부 출혈을 동반했다. 71명(0.7%)에서 선천 백내장, 망막모세포종, 일차 유리체 증식증, 유리체 출혈, 동공막 잔존, 맥락막 모반, 백색증 등이 발견되어 안과검사를 권유하였다. 49명 85안(0.48%)은 사진이 선명하지 않아 판독이 불가능하였다. 결론: RetCam을 이용한 신생아의 안과 선별검사는 안전하며 간단하게 안과 이상 유무를 알 수 있는 유용한 검사법이다. 그리고 이상이 의심되는 경우 적절한 안과진료를 받을 수 있도록 하는 소아안과의사의 역할이 점점 중요해질 것으로 생각되며, 이상의 대부분을차지하는 망막출혈의 경우 그 양이 많거나 황반부가 침범될 경우 이후 약시 발생 등의 가능성에 대한 추가 연구가 필요할 것으로 생각된다.

Asymptomatic maternal 3-methylcrotonylglycinuria detected by her unaffected baby's neonatal screening test

Lee, Sun Hee,Hong, Yong Hee The Korean Pediatric Society 2014 Clinical and Experimental Pediatrics (CEP) Vol.57 No.7

3-methylcrotonyl-coenzyme A carboxylase (3MCC) deficiency is an autosomal recessive disorder in which leucine catabolism is hampered, leading to increased urinary excretion of 3-methylcrotonylglycine. In addition, 3-hydroxyisovalerylcarnitine levels increase in the blood, and the elevated levels form the basis of neonatal screening. 3MCC deficiency symptoms are variable, ranging from neonatal onset with severe neurological abnormality to a normal, asymptomatic phenotype. Although 3MCC deficiency was previously considered to be rare, it has been found to be one of the most common metabolic disorders in newborns after the neonatal screening test using tandem mass spectrometry was introduced. Additionally, asymptomatic 3MCC deficient mothers have been identified due to abnormal results of unaffected baby's neonatal screening test. Some of the 3MCC-deficient mothers show symptoms such as fatigue, myopathy, or metabolic crisis with febrile illnesses. In the current study, we identified an asymptomatic 3MCC deficient mother when she showed abnormal results during a neonatal screening test of a healthy infant.