Inherited Metabolic Disorders Involving the Eye

정재호,Jae Ho, Jung The Korea Society of Inherited Metabolic Disease 2022 대한유전성대사질환학회지 Vol.22 No.2

Inherited metabolic disorders (IMD) are a large group of rare disorders affecting normal biochemical pathways. The ophthalmic involvement can be very varied affecting any part of the eye, including abnormalities of cornea, lens dislocation and cataracts, retina and the optic nerve, and extraocular muscles. Eye disorders can be initial symptoms of some IMD and can be clue for diagnosis of IMD. However, eye disorders can evolve later in the natural history of an already diagnosed metabolic disorder. Awareness of IMDs is important to facilitate early diagnosis and in some cases instigate early treatment if a patient presents with eye involvement suggestive of a metabolic disorder. Ophthalmological interventions are also an important component of the multisystem holistic approach to treating patients with metabolic disorders.

유전성 대사질환의 임상증상과 진단

유한욱,Yoo, Han-Wook 대한유전성대사질환학회 2013 대한유전성대사질환학회지 Vol.13 No.1

Inherited metabolic disorders are individually rare but as a whole, they are nor rare. Since Archibald Garrod introduced a concept of "inborn error of metabolism" or "chemical individuality", more than 600 diseases are currently known, affecting approximately one in 500 newborns cumulatively. They frequently manifest with acute, life-threatening crisis that requires immediate specific intervention or they present with insidious diverse symptoms and signs involving multiple visceral organs or tissues as well as central nervous system, hampering a correct diagnosis. In addition, many pediatricians are not familiar with all diagnostic and therapeutic strategies for diverse inherited metabolic disorders. However, the prognosis of affected children are heavily dependent on rapid and effective treatment. In this lecture, practical guidelines for the specific diagnosis based on diverse clinical features of inherited metabolic disorders will be described. Many sophisticated laboratory tests are available for the confirmatory diagnosis of each disease, which is challenging to general pediatricians with respect to knowledge about biochemical metabolite assay test, enzymatic test and DNA diagnostic tests. Sample collections, indications, methods and interpretation of results in varying laboratory tests will be listed as well.

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.

유아돌연사증후군과 유전성대사질환

윤혜란,Yoon, Hye-Ran 대한유전성대사질환학회 2013 대한유전성대사질환학회지 Vol.13 No.2

Specific genetic conditions may lead to sudden unexpected deaths in infancy, such as inborn errors of fatty acid oxidation and genetic disorders of cardiac ion channels. The disease may present dramatically with severe hypoketotic hypoglycemia, Reye syndrome or sudden death, typically with a peak of frequency around 3-6 month, whilst neonatal sudden death is quite rare. When undetected, approximately 20-25% of infants will die or suffer permanent neurologic impairment as a consequence of the first acute metabolic decompensation. Meanwhile, the advent of newborn screening for metabolic diseases has revealed populations of patients with disorders of fatty acid oxidation (FAO), the most frequent of which is medium chain acyl-CoA dehydrogenase (MCAD) deficiency. Without this screening, affected individuals would likely succumb to sudden infant death syndrome (SIDS). Here we describe an overview of sudden infant death syndrome and inherited metabolic disorder.

Inherited Metabolic Disorders Involving the Nervous System

유지숙,Jeesuk Yu The Korea Society of Inherited Metabolic Disease 2023 대한유전성대사질환학회지 Vol.23 No.2

Inherited metabolic disorders (IMD) are a group of disorders caused by defects in specific biochemical pathways. Up to 85% of IMD display predominantly neurological manifestations by affecting neurodevelopment or causing neurodegeneration. These neurometabolic disorders present with a variety of neurological and non-neurological manifestations. Early diagnosis of IMD is important because some disorders can be treated or improved with specific treatment if detected early. For prompt diagnosis and treatment, it is important to suspect IMD by being familiar with the clinical characteristics, biochemical abnormalities, and characteristic neuroimaging patterns that appear in IMD. Genetic testing, including next-generation sequencing, is also important in diagnosing IMD. During the follow-up of patients with IMD, it is necessary to conduct regular physical and neurological examinations in addition to disease-specific management.

한국에서 탠덤 질량분석기를 이용한 선천성 대사이상질환 신생아 선별검사: 일 개 전문 수탁기관의 경험

조성은,박은정,서동희,이인범,이현주,조대연,오정민 대한진단검사의학회 2015 Laboratory Medicine Online Vol.5 No.4

Background: The purpose of this study is to investigate the positive rates of screening tests for inherited metabolic disorders, set cutoff values, and report the actual status of internal quality controls in LabGenomics Clinical Laboratories by using LC-MS/MS system. Methods: We use Agilent 1260 Infinity HPLC System (Agilent Technologies, USA) for liquid chromatography, and API 2000 (AB Sciex, Canada) for MS/MS system. We set up screening tests for 55 diseases, which include metabolic disorders of 25 amino acids, 16 organic acids, and 14 fatty acids. Results: We determined the analyte cutoff values as 99.9 or 0.1 percentiles in 15,000 newborn samples. The total number of samples tested from January 2012 to September 2014 was 119,948; of these, 6,681 were repeated. Of the repeated samples, 713 were presumed to be positive in the screening tests. Repeat screening with newly obtained dried blood spot specimens was recommended for these 713 samples and 600 specimens were obtained. Thus, the recall rate was 0.5% (600/119,948) for all samples and 84.2% (600/713) for the samples presumed to be positive in the screening tests. About 70 samples, that is, 0.06% of the total samples and 11.7% of the “reobtained” samples, again tested positive; we recommended confirmatory tests for these samples. Conclusions: We have presented data on the status of neonatal screening tests for inherited metabolic disorders using LC-MS/MS, including positive rates and recall rates of screening tests, set up cutoff values and reported the actual status of internal quality controls in a clinical laboratory in Korea. 배경: 랩지노믹스 검사센터는 2012년 1월부터 탠덤 질량분석기를 이용하여 선천성 대사이상질환 신생아 선별검사를 시행해 오고 있다. 이에 본 연구에서는 본 전문 수탁기관에서 시행해 온 탠덤질량분석기를 이용한 선천성 대사이상질환 신생아 선별검사의 양성 결과 빈도와 소환율, 각각의 질환에 대한 기준치 설정 및 정도관리 방법 등의 검사 현황을 소개하고자 한다. 방법: 본 기관에서 액체 크로마토그래피 기기로 Agilent 1260 Infinity HPLC System (Agilent Technologies, USA), MS/MS system으로는 API 2000 (AB Sciex, Canada)을 사용하였다. 본 기관에서 선별하는 질환은 55종이고, 이 중 아미노산 질환이 25종, 유기산 질환이 16종, 지방산 대사질환이 14종이다. 결과: 본 기관에서는 신생아 검체 15,000건을 대상으로 99.9 또는 0.1 percentile을 기준치로 설정하였다. 2012년 1월부터 2014년 9월까지 의뢰된 검사 건수는 총 119,948건이고, 그중 6,681건에서 처음 의뢰된 검체를 이용하여 재검을 시행하였다. 6,681건 중 재검 후에도 여전히 양성 소견을 보이는 713건에 대하여 재채혈을 요구하였고, 그중 600건에서 재채혈 검체를 의뢰받아 소환율은 전체 의뢰 건수 중 0.5% (600/119,948)였고, 선별 재검검사를 위한 재채혈 검체 요구 건수 중 84.2% (600/713)에 해당하였다. 재채혈 검체 600건 중 70건에서 여전히 선별검사 결과 양성 소견을 보여, 확진검사를 의뢰하도록 통보하였고, 이는 전체 검사 의뢰 건수 119,948건 중 0.06%, 재채혈 검체로 실시한 선별 재검검사 건수 600건 중 11.7%에 해당하였다. 결론: 본 연구에서는 본 전문 수탁기관에서 시행해 온 탠덤 질량분석기를 이용한 선천성 대사이상질환 신생아 선별검사의 양성 결과 빈도와 소환율, 각각의 질환에 대한 기준치 설정 및 정도관리 방법 등의 검사 현황을 소개하였다. 이해관계: 저자들은 본 연구와 관련하여 해당 회사와 이해관계가 없음.

Determination of plasma dibasic amino acids following trimethylsilyl–trifluoroacyl derivatization using gas chromatography–mass spectrometry

윤혜란 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.3

A rapid analytical method was developed toquantify dibasic amino acids (ornithine, lysine and arginine)after two-step derivatization procedure with good sensitivityand specificity on human plasma. If early diagnosis has notbeen made, patients with inborn metabolic disorders such asHHH syndrome, Hyperornithinemia and dibasic aminoaciduriarapidly progress to sudden death, physical defect ormental retardation resulting in storage of the toxic materialinto the brain. Therefore, it is necessary to develop theanalytical method for rapid screening and/or correct confirmationdiagnosis. The formation of trimethylsilyl derivativeof the carboxylic (COO–) functional group wasperformed by adding MSTFA. Five lL of methyl orangewas added to the residue until the color changed into yellow. Consecutively, the trifluoroacyl derivative of the amino(–NH2) functional group was produced by adding MBTFA. Specific ions was chosen for quantification with followingions; m/z 166 and m/z 212 for ornithine, m/z 180 and m/z 395for lysine, and m/z 292 and, m/z 519 for arginine. A calibrationcurve showed a linear relationship for the dibasicamino acids spiked to pooled normal plasma showing R2 of0.9955–0.9979 in the range of 0.1–600 ng investigated. Theutility of the method for screening and diagnosis was demonstratedby recovery 80–125 % and reproducibility withRSD (9–17 %) at low, medium and high concentrationfortified to pooled plasma. Collectively, the present studysuggest that this method could be useful for diagnosis, screening, therapeutic monitoring of metabolic disorders ondietary therapy with excellent sensitivity and rapidity.

탠덤매스에의한 체액 중 Globotriaocylceramide(Gb-3)의 측정을 이용한 한국인 고 위험도군에서의 파브리병 스크리닝

윤혜란(Hye-Ran Yoon) 대한약학회 2011 약학회지 Vol.55 No.1

Fabry disease (FD) is an X-linked inborn error of glycoshpingolipid metabolism resulting from mutation in the enzyme α-galactosidase A gene. The disease is an X-linked lipid storage disorder and the lack of α-Gal A causes an intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb-3). Measurement of Gb-3 in plasma has clinical importance for monitoring after enzyme replacement therapy for confirmed FD patients. Using electrospray ionization MS/MS we had developed, a simple, rapid, and highly sensitive analytical method for Gb-3 in plasma was used for the purpose of screening FD among high risk groups in Korean population. To date, no comprehensive results for FD screening have been performed and reported in Korea. We screened 1,100 outpatients from 13 hospitals (including clinics) to assess the incidence of FD among patients in high risk groups. For patients with borderline level amount of Gb-3, we repeated Gb-3 or performing complementary or confirmative assay with α-Gal A activity and DNA mutaion analysis for confirmation diagnosis. Of 1,100 we diagnosed 3 FD with 2 classical type and 1 carrier (0.27%).