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BACKGROUND The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known. AIM To investigate the association between NUDT15 polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels. METHODS This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship between NUDT15 polymorphisms and 6-TGN levels were analysed. RESULTS Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolisers respectively (P

AIMS: This study explores the effects of various genetic polymorphisms in candidate genes on thiopurine metabolism and toxicity in adult patients with Crohn's disease in Korea. METHODS: A total of 131 adult patients with Crohn's disease receiving thiopurine treatment were included. The TPMT and NUDT15 genes and an additional 116 genetic polymorphisms (in 40 genes and 3 intergenic locations) were screened for genotyping. Among the polymorphisms screened, 91 genetic polymorphisms (in 34 genes and 3 intergenic locations) in addition to TPMT and NUDT15 genotypes were included for statistical analyses to investigate their effects on thiopurine metabolites and adverse outcomes (leukopenia, hepatotoxicity, gastrointestinal intolerance, skin rash and alopecia). RESULTS: The median duration of thiopurine treatment was 47.0 months (range 6.0–153.4 months). Patient sex, maintenance dose of thiopurine, and use of anti‐tumour necrosis factor agents were associated with thiopurine metabolite concentrations (P < .05). In the univariate analysis, the TPMT genotype was associated with 6‐thioguanine level (P < .05), although the significance of this did not remain in multivariate analysis. Genetic polymorphisms in the ATIC (rs3821353 and rs16853834), IMPDH2 (rs11706052) and ITPA (rs6139036) genes were associated with thiopurine metabolism (P < .05). Genetic polymorphisms in the ABCC5 (rs8180093) and NUDT15 genotypes were associated with leukopenia (P < .05). CONCLUSION: The results of this study may help clinicians to understand the effects of other various polymorphisms in addition to TPMT and NUDP15 in thiopurine metabolism for management of Crohn's disease patients.

Background Combined methylmalonic acidemia and homocystinuria is a rare inherited disorder of intracellular cobalamin metabolism caused by biallelic variants in one of the following genes: MMACHC (cblC), MMADHC (cblD), LMBRD1 (cblF), ABCD4 (cblJ), THAP11 (cblX‐like), and ZNF143 (cblX‐like), or a hemizygous variant in HCFC1 (cblX). Prenatal diagnosis of combined methylmalonic acidemia with homocystinuria is crucial for high‐risk couples since the disorder can be life‐threatening for offspring. We would like to describe two infant deaths both of which are likely attributable to cblC despite not having a genetic confirmation, and subsequent pregnancy and prenatal genetic testing. Methods Parental clinical exome sequencing and targeted Sanger sequencing of MMACHC gene in amniotic fluid was performed to check the carrier status of the fetus. Results Parental clinical exome sequencing revealed a heterozygous pathogenic variant [NM_015506.2:c.217C>T (p.Arg73*)] in the MMACHC gene of the mother and [NM_015506.2:c.609G>A (p.Trp203*)] in the MMACHC gene of the father. Targeted Sanger sequencing of MMACHC gene in amniotic fluid revealed that the fetus carried only one nonsense variant [NM_015506.2:c.609G>A (p.Trp203*)], which was inherited from the father. The mother delivered a healthy baby and the neonate did not show any symptoms or signs of combined methylmalonic acidemia and homocystinuria after birth. Conclusion We present a case of prenatal diagnosis with parental exome sequencing, which successfully diagnosed the carrier status of the fetus and parents in a combined methylmalonic acidemia and homocystinuria family., Figure shows the Sanger sequencing analysis of the family with methylmalonic acidemia and homocystinuria cobalamin C type. We did successfuly prenatal diagnosis of combined methylmalonic acidemia and homocystinuria cobalamin C type using clinical exome sequencing and targeted gene analysis.

Purpose The current status of therapeutic drug monitoring (TDM) assay utilization by clinical laboratories in South Korea remains little known. We investigated the TDM status of five antibiotics known for nephrotoxicity (vancomycin, amikacin, gentamicin, tobramycin, and teicoplanin) for the improvement of TDM in South Korea among patients with infectious diseases using a cross-sectional nationwide survey. Patients and methods We developed an online questionnaire and collected responses using a user-friendly web-based platform. The survey included questions about laboratory characteristics, implementation and operation of drug assays, implementation and operation of TDM consulting services, patient needs, and barriers to providing better TDM service including expectations and concerns about other platform-based drug assays. Results Among a total of 235 clinical laboratories, 112 (47.7%) responded, and 62 of the responding laboratories (55.4%) possessed drug assay facilities. Only 41.2% to 58.1% of respondents were providing TDM consulting services for each antibiotic. Respondents indicated that there are unmet needs regarding drug assays and TDM consultation as well as barriers to TDM utilization including high operating costs, lack of knowledge about TDM, lack of user-friendly software, lack of medical and laboratory information systems that can access patient information critical for TDM dose calculation, and reimbursement issues. Conclusion This study, the first nationwide survey addressing these questions, showed that there are barriers against the utilization of TDM in South Korea. These barriers may be addressed by improving drug assays and TDM consulting services with the goals of new analytical method development, better interpretation of results, consultation services, and quality control.

Background Screening for congenital adrenal hyperplasia (CAH) using immunoassays for 17α-hydroxyprogesterone generates many false-positive results. We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for simultaneous quantification of nine steroid hormones in dried blood spot (DBS) samples, and established reference intervals for these hormones. Methods We examined our method for linearity, precision, accuracy, extraction recovery, and matrix effects and determined the reference intervals of cortisol, 17α-hydroxyproges-terone, 11-deoxycortisol, 21-deoxycortisol, androstenedione, corticosterone, 11-deoxycorticosterone, testosterone, and progesterone in 1,146 DBS samples (from 272 preterm and 874 full-term neonates). Immunoassay and LC-MS/MS methods were compared for 17α-hydroxyprogesterone. Fourteen additional samples were tested to validate the clinical applicability of the LC-MS/MS method. Results The linearity range was 2.8–828.0 nmol/L for cortisol and 0.9–40.0 nmol/L for the other steroids (R2>0.99). Intra-day and inter-day precision CVs were 2.52–12.26% and 3.53–17.12%, respectively. Accuracy was 80.81–99.94%, and extraction recovery and matrix effects were 88.0–125.4% and 61.7–74.2%, respectively. There was a negative bias, with higher values measured by immunoassay compared with LC-MS/MS (r=0.8104, P

Background The aim of this study was to investigate the seroprevalence of cytomegalovirus (CMV) infection using the serologic status of CMV IgG and IgM antibodies in Korean women of childbearing age. Methods We retrospectively reviewed CMV IgG and IgM test results from Korean women aged 15–49 years who underwent testing between January 2009 and December 2019. Seroprevalence of CMV IgG and IgM by year and age was investigated. Results The study period was 11 years, and among 6837 samples tested, 95.8% were CMV IgG–positive. The seropositivity in women aged 15‐

The gold standard for the laboratory diagnosis of central precocious puberty is based on the measurement of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation. We sought to investigate the laboratory data for GnRH stimulation testing using samples collected from Korean children at different time points. Sampling times were at the basal time point (0) and 15, 30, 45, 60, 90, and 120 min after GnRH stimulation. Pubertal response was defined as occurring when the peak LH concentration was 5 IU/L or more and rose to at least 2 times the basal LH concentration after GnRH stimulation. During the study period, 19,990 test results from 1958 Korean children (1841 females aged 1.3&ndash, 8.9 years and 117 males aged 7.3&ndash, 9.9 years) were obtained. Among the 1958 children, 1232 (62.9%) showed pubertal responses. The receiver operating characteristic curve that demonstrated the greatest area under the curve (AUC) among all examined time points was 45 min after GnRH stimulation in males (AUC 0.982, 95% CI 0.938&ndash, 0.998) and 60 min in females (AUC 0.975, 95% CI 0.967&ndash, 0.981). The combination of 45 min and 60 min showed the greatest AUC (0.996, 95% confidence interval 0.991&ndash, 0.998), with a sensitivity level of 99.1% and a specificity of 100% for all children. The results of this study provide a possibility for a reduction in sampling time points (45 min and 60 min) to identify the presence of a pubertal response after GnRH stimulation in Korean children.

BACKGROUND Little is known about the reference interval of serum folate concentration if using recently re-standardized assays traceable to the World Health Organization (WHO) international standard reference 03/178 in a Korean population. This study aimed to investigate serum folate levels in Korean subjects without macrocytic anemia or increased homocysteine, for the assessment of folate deficiency. METHODS We retrospectively reviewed data from Korean adults whose hemoglobin, mean corpuscular volume, and serum total homocysteine values were within reference limits. RESULTS The median (interquartile range) serum folate level was 7.8 (5.4 - 12.6) ng/mL in men and 10.2 (6.9 - 15.6) ng/mL in women. The reference interval for serum folate (2.5th and 97.5th percentiles) ranged from 2.9 to 38.0 ng/ mL. From among 723 Korean adults, the lower limit of reference intervals of serum folate for folate deficiency, defined as the 2.5th percentile, was 2.9 ng/mL. The prevalence of folate deficiency was higher in men (6.5%) than in women (1.2%, p < 0.05) when a cutoff value of 3.0 ng/mL was applied. Using the cutoff value of 4 ng/mL for folate deficiency, which is in accordance with the instructions from the manufacturer of the new assay and the WHO 2012 guideline for homocysteine as a metabolic indicator before assay standardization, about 5% of subjects were reclassified as folate deficient. CONCLUSIONS Our study suggests that any change of reference limits using a re-standardized assay needs to be verified in clinical laboratories.

Background Current guidelines pertaining to diagnosing macrocytic anemia in association with vitamin B12 and folate deficiency recommend that vitamin B12, folate, homocysteine, and methylmalonic acid assays should be assessed concurrently due to their close relationship in metabolism. We aimed to investigate the completion of these assays in local clinics and hospitals without in‐house clinical laboratories in Korea. Methods We retrospectively reviewed data from the laboratory information system between September 25, 2017, and June 30, 2019, to investigate usage rates of vitamin B12, folate, homocysteine, and methylmalonic acid assays in patients with macrocytic anemia. Results During the study period, 14 894 Korean adults among 109 524 (13.6%) total hemoglobin‐tested subjects underwent concurrent erythrocyte mean corpuscular volume (MCV) tests. Among these 14,894 adults, 265 (1.2%) from 94 local clinics or hospitals without in‐house clinical laboratories in Korea had macrocytic anemia. Furthermore, among these 265 adults, only one woman underwent serum vitamin B12 and folate assay and one man underwent serum homocysteine testing during the study period. No patients among the 265 individuals with macrocytic anemia received erythrocyte folate or methylmalonic acid testing (with either serum, plasma, random urine, or 24‐hour collected urine). Conclusions The results of this study provide basic information regarding utilization rates of assays in association with vitamin B12 and folate deficiency. Making more data available is expected to improve rates of testing in patients with macrocytic anemia in local clinics and hospitals without in‐house clinical laboratories in Korea.

Numerous studies have shown that vitamins reduce the risk of cancers, but the relationship between serum vitamin levels and breast cancer is still controversial. In this study, we evaluated serum levels of vitamins in Korean patients with benign breast disease or breast cancer and investigated their associations with clinical and laboratory parameters. Concentrations of vitamin A, D, and E, together with homocysteine and methylmalonic acid as biomarkers of vitamin B12 deficiency, were measured by high-performance liquid chromatography (HPLC) or liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the serum of 104 breast cancer patients, 62 benign breast disease patients, and 75 healthy Korean females. We further assessed possible associations between vitamin levels and breast cancer subtypes, the presence of lymph node metastasis, and tumor stages. Serum concentrations of vitamins A and E were significantly lower in breast cancer patients and in benign breast disease patients than in healthy controls. Severe vitamin D deficiency was more prevalent in breast cancer patients than in healthy controls. Vitamin D level was significantly lower in breast cancer patients with estrogen receptor-negative or triple-negative subtypes than in those with other subtypes. Further research with a larger study population is required to elucidate the role of vitamins in breast cancer.

IgG consists of four subclasses: IgG1, IgG2, IgG3, and IgG4. Changes in the serum concentration of each subclass reflect different clinical situations, and quantification of each subclass is important to assess patients' clinical states. Herein, we evaluated the analytical performance of the SPAPLUS turbidimetric analyzer (The Binding Site, Birmingham, UK) for IgG subclass. Precision, linearity, comparison with the BNII system (Siemens Healthineers, Erlangen, Germany), and reference interval were assessed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. The repeatability and within-laboratory precision were within 5% for all IgG subclasses. The coefficient of determination (R

Purpose We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). Materials and methods Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. Results A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p l 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p l 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p l 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. Conclusion NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

BACKGROUND We retrospectively investigated soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratios and screen-positive rates according to cutoff values for preeclampsia risk assessment based on the number of fetuses. METHODS sFlt-1/PlGF ratios < 38.0 and < 53.0 were defined as low risk of preeclampsia (screen negative) for singleton and twin pregnancies, respectively. RESULTS During the study period, 442 test results from 403 pregnant women (374 with singleton and 29 twin pregnancies) from 32 local clinics and hospitals were analyzed. The overall rate of positive preeclampsia screening was 25.1% and this rate was higher when gestational age was ≥ 34 weeks than when it was < 34 weeks (58.7% vs. 18.6%, p < 0.05). Among 34 women with follow-up results, a change in interpretation category was observed during the follow-up period at ≥ 4.8 weeks for singleton and ≥ 1.6 weeks for twin pregnancies, respectively. CONCLUSIONS This study may help to understand the sFlt-1/PlGF ratio in pregnant Korean women.

Background Hepatitis B virus (HBV) infection remains a global concern with different epidemiologies due to several factors including migration, vaccination policies, and new antiviral treatment regimens. It is important to understand the characteristics of a patient population, including the prevalence of diseases, and to assess test utilization to understand and evaluate the clinical performance of laboratory tests and to improve the quality of clinical laboratories. Materials and methods In this study, we evaluated serologic and virologic laboratory tests including hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B envelope antigen (HBeAg), hepatitis B envelope antibody, and HBV DNA in Korean adults who were exposed to HBV. Results During the 1‐year study period, we obtained 22 750 specimens from 17 523 adult Korean patients (>18.0 years; 9894 males and 7629 females) with a median age of 50.1 years (interquartile range, 42.2‐58.2 years). Among them, five serologic and virologic laboratory tests were performed for 1340 (5.9%) specimens from 1172 adult Korean patients (>18.0 years; 647 males and 525 females) with a median age of 46.8 years (range, 19.0‐84.5 years). The prevalence of serologic and virologic tests indicating several clinical situations was evaluated. The correlation coefficient between HBV DNA and HBeAg was ρ = 0.85 (P

Vitamins are known to be associated with immunity and nutrition. Moreover, vitamin deficiency can affect host immunity to various infectious diseases, including tuberculosis. Although patients with tuberculosis often have vitamin D deficiency, little is known about the levels of other vitamins. Here, we aimed to investigate the status of vitamins A, BWe performed a case-control study to investigate the serum vitamin concentrations in 152 patients with tuberculosis and 137 control subjects. The concentrations of vitamin A, vitamin D, vitamin E, homocysteine, and methylmalonic acid were measured using high-performance liquid chromatography (HPLC) or HPLC-tandem mass spectrometry. Patient demographic data and other biochemical parameters were also analyzed.The serum concentrations of vitamins A, D, and E were significantly lower in patients with tuberculosis than in control subjects (1.4 vs. 2.0 μmol/L, P 0.001; 10.6 vs. 19.3 ng/mL, P 0.001; and 22.8 vs. 30.6 μmol/L, P 0.001, respectively). In contrast, the methylmalonic acid levels were higher in patients with tuberculosis (134.9 vs. 110.8 nmol/L, P 0.001). The prevalences of vitamin deficiencies were significantly higher in patients with tuberculosis. Moreover, multiple vitamin deficiencies were only observed in patients with tuberculosis (22.4% of all patients with tuberculosis vs. 0% of all control subjects). Positive correlations among vitamin A, D, and E concentrations were observed (vitamins A and D, r = 0.395; vitamins D and E, r = 0.342; and vitamins A and E, r = 0.427, P 0.001). Body mass index, total cholesterol, low-density lipoprotein, iron, and total iron-binding capacity all showed positive correlations with vitamin A, D, and E concentrations.Vitamin deficiencies are common in patients with tuberculosis. Further research investigating the clinical importance of vitamin and nutritional status in patients with tuberculosis is needed.

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

The aim of this study was to evaluate serum cytokines and natural antimicrobial peptide profiles in pulmonary tuberculosis, and compare them with levels in controls without tuberculosis, to explore the associations between these biomarkers and response to antituberculosis treatment. Serum levels of 10 biomarkers were measured using a Luminex bead array platform. Tuberculosis biosignatures were identified from the discovery cohort (n=148) and were validated in the independent cohort (n=148). Association between biosignatures and clinical outcome was investigated with negative conversion in follow-up sputum culture after 2months of treatment. Serum concentrations of eotaxin, MIP-1α, sIL-2Rα, and lipocalin 2 were significantly different between pulmonary tuberculosis patients and controls (P0.05). Serum concentrations of eotaxin and sIL-2Rα were higher in pulmonary tuberculosis patients than in controls, while those of MIP-1α and lipocalin 2 were lower (P0.05). Eotaxin concentrations were significantly higher in good responders to treatment (P0.05), indicating this immunomolecule may serve as a positive predictor for therapy response in pulmonary tuberculosis. The magnitude serum eotaxin, MIP-1α, sIL-2Rα, and lipocalin 2 are important indicators for pulmonary tuberculosis. These biomarkers alone or combinatorial detections have potential applicability in monitoring tuberculosis patients during antituberculosis treatment.Cytokines and endogenous antimicrobial peptides represent an important part of immune system and the identification of a pattern of differentially expressed those biomarkers (a "biosignature") could help to differentiate tuberculosis infection from the non-infected state which might eventually assist case identification and accelerate access to treatment. In this direction, cytokine analysis including multiple serum biomarkers to evaluate biosignatures of pulmonary tuberculosis would provide basic knowledge to aid understanding of the pathophysiology of tuberculosis infection and for the development of future diagnostic methods, treatments, and monitoring for pulmonary tuberculosis.

The relationships between serum levels of trace elements and breast cancer remain relatively unknown. In this study, we investigate serum levels of seven trace elements in Korean breast cancer patients compared to controls without breast cancer. Serum trace element levels were determined using inductively coupled plasma mass spectrometry in Korean breast cancer patients before initiation of breast cancer treatment. Korean females without breast cancer served as a control group. Trace element levels were measured in the discovery cohort (n = 287) and were validated in an independent cohort (n = 142). We further investigated possible associations between trace element levels and the presence of lymph node metastasis, distant metastasis, or triple-negative breast cancer among breast cancer patients in subgroup analyses. Serum manganese and molybdenum levels were significantly higher (p &lt, 0.05) in breast cancer patients than in controls. Serum copper levels were significantly higher in breast cancer patients with distant metastasis, while selenium levels were significantly lower. Other trace elements were neither significantly different between breast cancer patients and controls nor between subgroups of breast cancer patients. Our study provides insights about the potential roles and impacts of trace elements through an assessment of the associations between trace elements and breast cancer.

Background Several molecular assays have been developed to detect the BRAF V600E mutation in fine needle aspirates (FNAs) for the diagnosis of papillary thyroid cancer. Using a multiplex PCR technique, we evaluated the Anyplex BRAF V600E Real-time Detection (Anyplex) assay and compared its efficacy with that of the Seeplex BRAF V600E ACE Detection (Seeplex) method. Methods We tested 258 consecutive FNA specimens using the Seeplex and Anyplex assays. Any conflicting results between the two assays were confirmed by using mutant enrichment with 3'-modified oligonucleotide (MEMO) sequencing. The limits of detection (LODs) and reproducibility for each assay were evaluated with serially diluted DNA from a BRAF V600E-positive cell line. Results The BRAF V600E mutation was detected in 36.4% (94/258) FNA specimens by either the Seeplex or Anyplex assay. Results for the two assays showed 93.4% (241/258) agreement, with a kappa value of 0.861 (95% confidence interval, 0.798-0.923). Of the eight specimens that were BRAF V600E-positive by the Anyplex assay but not by the Seeplex assay, five were found to be BRAF V600E-positive by MEMO sequencing. The mutation detection rate of the Seeplex and Anyplex assays was 79.0% and 84.0%, respectively, in the FNA specimens diagnosed as malignant (n=81). The LOD as determined by probit analysis was 0.046% (95% confidence interval, 0.019-0.532%). Conclusions The Anyplex assay performed better than the Seeplex assay with respect to the detection of the BRAF V600E mutation.

Deficiencies in essential trace elements are associated with impaired immunity in tuberculosis infection. However, the trace element concentrations in the serum of Korean patients with tuberculosis have not yet been investigated. This study aimed to compare the serum trace element concentrations of Korean adult patients with tuberculosis with noninfected controls and to assess the impact of serum trace element concentration on clinical outcome after antituberculosis treatment. The serum concentrations of four trace elements in 141 consecutively recruited patients with tuberculosis and 79 controls were analyzed by inductively coupled plasma-mass spectrometry. Demographic characteristics were also analyzed. Serum cobalt and copper concentrations were significantly higher in patients with tuberculosis compared with controls, while zinc and selenium concentrations were significantly lower (p &lt, 0.01). Moreover, serum selenium and zinc concentrations were positively correlated (ρ = 0.41, p &lt, 0.05). A high serum copper concentration was associated with a worse clinical outcome, as assessed after one month of antituberculosis therapy. Specifically, culture-positive patients had higher serum copper concentrations than culture-negative patients (p &lt, 0.05). Patients with tuberculosis had altered serum trace element concentrations. Further research is needed to elucidate the roles of individual trace elements and to determine their clinical impact on patients with tuberculosis.

CYP21A2 mutation analysis of congenital adrenal hyperplasia (CAH) is challenging because of the genomic presence of a homologous CYP21A2 pseudogene and the significant incidence of pseudogene conversion and large deletions. The objective of this study was to accurately analyze the CYP21A2 genotype in Korean CAH patients using a combination of complementary methods. Long-range PCR and restriction fragment length polymorphism analyses were performed to confirm valid amplification of CYP21A2 and to detect large gene conversions and deletions before direct sequencing. Multiple ligation-dependent probe amplification (MLPA) analysis was conducted concurrently in 14 CAH-suspected patients and six family members of three patients. We identified 27 CYP21A2 mutant alleles in 14 CAH-suspected patients. The c.293-13A>G (or c.293-13C>G) was the most common mutation, and p.Ile173Asn was the second, identified in 25% and 17.9% of alleles, respectively. A novel frame-shift mutation of c.492delA (p.Glu 164Aspfs*24) was detected. Large deletions were detected by MLPA in 10.7% of the alleles. Mutation studies of the six familial members for three of the patients aided in the identification of haplotypes. In summary, we successfully identified CYP21A2 mutations using both long-range PCR and sequencing and dosage analyses. Our data correspond relatively well with the previously reported mutation spectrum analysis.

We investigated the vitamin D status of Korean women during pregnancy and assessed the effects of vitamin D deficiency on two pregnancy outcomes, preterm births and the births of small for gestational age. We measured the serum 25-hydroxyvitamin D levels in 220 pregnant Korean women who were recruited prospectively and compared these levels with those of 500 healthy non-pregnant women. We analyzed vitamin D status according to patient demographics, season, and obstetrical characteristics, moreover, we also assessed pregnancy outcomes. The overall prevalence of vitamin D deficiency(&lt, 20 ng/mL) in pregnant women and healthy non-pregnant women was 77.3% and 79.2%, respectively, and the prevalence of severe vitamin D deficiency (&lt, 10 ng/mL) was 28.6% and 7.2%, respectively (p &lt, 0.05). Vitamin D deficiency was more prevalent in the winter (100%) than in the summer (45.5%) in pregnant Korean women. A higher risk of vitamin D deficiency was observed in the first trimester than in the third trimester (adjusted OR 4.3, p &lt, 0.05). No significant association was observed between vitamin D deficiency and any of the pregnancy outcomes examined. Further research focusing on the long-term consequences of vitamin D deficiency during pregnancy in Korean women is warranted.

Background Rare inherited metabolic diseases with neurological and gastrointestinal manifestations can be misdiagnosed as other diseases or remain as disorders with indeterminate etiologies. This study aims to provide evidence to recommend the utility of whole exome sequencing in clinical diagnosis of a rare inherited metabolic disease. Methods and results A 4-month-old female baby visited an outpatient clinic due to poor weight gain, repeated seizure-like episodes, developmental delay, and unexplained hepatomegaly with abnormal liver function test results. Although liver biopsy revealed moderate fibrosis with a suggested diagnosis of glycogen storage disease (GSD), no mutations were identified either by single gene approach for GSD ( G6PC and GAA ) or by next generation sequencing panels for GSD (including 21 genes). Whole exome sequencing of the patient revealed compound heterozygous mutations of PMM2 : c.580C > T (p.Arg194*) and c.713G > C (p.Arg238Pro) which mutations were associated with congenital disorder of glycosylation Ia (CDG-Ia: PMM2-CDG). Conclusions We successfully applied exome sequencing to diagnose the first reported Korean patient with CDG-Ia, which was misdiagnosed as GSD. Whole exome sequencing may prove to be the preferred strategy for analysis of clinical features that do not readily suggest a specific diagnosis, such as those observed in inherited metabolic diseases, including CDG.

BACKGROUND The accurate interpretation of sequence variation is critical for successful molecular diagnoses. It is also fundamental to the accurate diagnosis and treatment of phenylketonuria (PKU). This study aims to evaluate the significance of the c.158G>A (p.Arg53His) variant in the PAH gene, which was previously reported to be a pathogenic mutation that results in decreased phenylalanine hydroxylase enzyme activity in hyperphenylalaninemia (HPA) patients. METHODS Seven unrelated Korean patients with HPA genotyped with the c.158G>A variant were included in this study. The variant c.158G>A was classified by the standards and guidelines for the interpretation of sequence variants by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. RESULTS By both directly collecting genetic data and comprehensively reviewing the existing literature, we found that this variant is more appropriately classified as "Likely benign" rather than pathogenic. The allele's frequency is 2.57% in the general Korean population, which was greater than expected for phenylketonuria. This variant was observed to be homozygous in healthy subjects and was also observed in cis with other pathogenic variants. It is common in East Asian populations (especially in Koreans) compared to Western populations. There is a possibility that it causes decreased enzyme activity without leading to the full pathology of phenylketonuria. CONCLUSIONS This study expands our understanding of the consequences of variation in PAH and its relationship to HPA.

ObjectivesThe aim of this study was to investigate the immunity against rubella using the serological status of rubella-specific IgG antibodies (antirubella IgG) in Korean women of childbearing age (15–49 years).DesignRetrospective cross-sectional study.SettingPopulation-based cross-sectional study in South Korea.ParticipantsBetween January 2010 and December 2017, test results from Korean women aged 15–49 years who had visited an obstetric private clinic (nationwide institutions) and had requested rubella-specific IgG antibody tests from Green Cross Laboratories were obtained from the laboratory information system.ResultsBetween 2010 and 2017, antirubella IgG test results from 328 426 Korean women aged 15–49 years who had visited private obstetric clinics (1438 institutions nationwide) were retrospectively analysed by tested year, age, cohort and geographic regions. Over the 8-year study period, the rate of unimmunised women ranged from 7.8% to 9.7%. Multivariable-adjusted logistic regression models showed that the odds of being immune to rubella (positive and equivocal results of antirubella IgG test) were lower in 2017 compared with 2010, in women in their 40s, in a pre-catch-up cohort and in women living in Incheon, Busan, South Gyeongsang, North and South Jeolla and Jeju provinces (pConclusionsIn consideration of the factors associated with prevalence of women unimmunised to rubella, future public health efforts should be focused on catch-up activities. The results of this study could be used to strengthen disease control and prevent rubella, including a nationwide immunisation programme.

Since there are limited data on the incidence and clinical findings of central nervous system (CNS) infection by three α-herpesviruses including human herpes simplex virus 1 (HSV-1), HSV-2 and varicella-zoster virus (VZV) in Korea, a retrospective analysis of clinical data and polymerase chain reaction (PCR) results was performed in patients who presented with suspicion of acute viral meningitis and/or encephalitis at the emergency department of a tertiary referral hospital in Seoul, Korea. During the 3-year study period, a total of 224 cerebrospinal fluid (CSF) samples from 224 patients were examined. Among the 224 patients, 135 (60.3%) patients were identified as having aseptic meningitis (n = 70, 51.9%), encephalitis (n = 41, 30.4%) or meningoencephalitis (n = 24, 17.8%) at discharge. Twenty-four (17.8%) patients were identified as having VZV meningitis (n = 16, 11.9%), VZV meningoencephalitis (n = 2, 1.5%), HSV-2 meningitis (n = 4, 3.0%), or HSV-1 encephalitis (n = 2, 1.5%). Of the 24 patients infected with the three herpesviruses, immunocompromised patients accounted for 33.3% (n = 8). Skin rashes were observed in half (n = 9) of the patients with VZV, and none with HSV-1 or HSV-2. One patient with VZV meningitis and four patients with brain parenchymal involvement had neurologic sequelae. In conclusion, three herpesviruses are important causative agents of CNS infectious disease with significant morbidity in adults, regardless of the immunologic status. Therefore, CSF should be examined for HSV-1, HSV-2, and VZV using sensitive diagnostic methods in all cases of adult patients with clinical manifestations of CNS disease in order to identify the correct etiology and to determine appropriate therapy. J. Med. Virol. 86:957–962, 2014. © 2014 Wiley Periodicals, Inc.

This study aimed to investigate serum methylmalonic acid (MMA) and homocysteine levels and to assess their effects on pregnancy and neonatal outcomes. Serum MMA and homocysteine levels in 278 pregnant Korean women, determined by liquid chromatography–tandem mass spectrometry in each trimester, were compared with those of previous studies in other ethnic groups. We investigated the association between MMA and homocysteine status with pregnancy and neonatal events: gestational diabetes, preeclampsia, gestational age at delivery, preterm birth, small for gestational age, neonatal birth weight, and congenital abnormalities. The median (range) MMA level was 0.142 (0.063–0.446) µmol/L and homocysteine level was 10.6 (4.4–38.0) µmol/L in pregnant women. MMA levels were significantly higher in the third trimester than during other trimesters (p < 0.05), while homocysteine levels were not. No significant association was observed between MMA or homocysteine levels and any of the maternal or neonatal outcomes examined. Future studies are needed to assess the associations among maternal serum concentrations of MMA and homocysteine, and maternal and neonatal outcomes.

BACKGROUND Molecular techniques are fundamental for establishing an accurate diagnosis and therapeutic approach of glycogen storage diseases (GSDs). We aimed to evaluate SLC37A4 mutation spectrum in Korean GSD Ib patients. METHODS Nine Korean patients from eight unrelated families with GSD Ib were included. SLC37A4 mutations were detected in all patients with direct sequencing using a PCR method and/or whole-exome sequencing. A comprehensive review of previously reported SLC37A4 mutations was also conducted. RESULTS Nine different pathogenic SLC37A4 mutations were identified in the nine patients with GSD Ib. Among them, four novel mutations were identified: c.148G>A (pGly50Arg), c.320G>A (p.Trp107*), c.412T>C (p.Trp138Arg), and c.818G>A (p.Gly273Asp). The most common mutation type was missense mutations (66.7%, 6/9), followed by nonsense mutations (22.2%, 2/9) and small deletion mutations (11.1%, 1/9). The most common mutation identified in the Korean population was c.443C>T (p.Ala148Val), which comprised 39.9% (7/18) of all tested alleles. This mutation has not been reported in GSD Ib patients in other ethnic populations. CONCLUSIONS This study expands knowledge of the SLC37A4 mutation spectrum in Korean patients with GSD Ib.

Background Mucolipidosis types II and III (ML II/III) are autosomal recessive disorders caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. We investigated the molecular genetic characteristics of the GNPTAB gene, which codes for the alpha/beta subunits of a phosphotransferase, in Korean ML II/III patients. We included prenatal tests and evaluated the spectrum of mutations in East Asian populations with ML II/III through a literature review. Methods Seven patients from six families were enrolled in the study including two prenatal tests using chorionic villi samples. A diagnosis of ML II/III was made based on clinical findings and increases in serum lysosomal enzyme levels. PCR and direct sequencing were performed to identify GNPTAB mutations. Results We found 14 mutant alleles including seven known mutations of c.2189delT (p.Leu730fs*7), c.1090C > T (p.Arg364*), c.2681G > A (p.Trp894*), c.3565C > T (p.Arg1189*), c.310C > T (p.Gln104*), c.1071G > A (p.Trp357*) and c.2574_2575delGA (p.Asn859Glnfs*2). Four were novel variants of unknown significance: c.992A > G (p.Tyr331Cys), c.2666 T > A (p.Leu889*), c.637-6 T > G (p.Thr213Phefs*11), and c.471_472delTT (p.Tyr158Serfs*8). Family studies revealed the probands to be compound heterozygotes. The fetuses carried the same GNPTAB mutations as the mucolipidosis II/III probands in the prenatal diagnosis. Conclusions We identified GNPTAB mutations in all patients with ML II/III, but did not identify a hot spot in Korean patients. We successfully performed prenatal diagnosis using molecular investigation.

Background: Molecular diagnosis of glycogen storage diseases (GSDs) is important to enable accurate diagnoses and make appropriate therapeutic plans. The aim of this study was to evaluate the PHKA2 mutation spectrum in Korean patients with GSD type IX. Methods: Thirteen Korean patients were tested for PHKA2 mutations using direct sequencing and a multiplex polymerase chain reaction method. A comprehensive review of the literature on previously reported PHKA2 mutations in other ethnic populations was conducted for comparison. Results: Among 13 patients tested, six unrelated male patients with GSD IX aged 2 to 6 years at the first diagnostic work-up for hepatomegaly with elevated aspartate transaminase (AST) and alanine transaminase (ALT) were found to have PHKA2 mutations. These patients had different PHKA2 mutations: five were known mutations (c.537 + 5G > A, c.884G > A [p.Arg295His], c.3210_3212delGAG [p.Arg1072del], exon 8 deletion, and exons 27-33 deletion) and one was a novel mutation (exons 18-33 deletion). Notably, the most common type of mutation was gross deletion, in contrast to other ethnic populations in which the most common mutation type was sequence variant. Conclusions: This study expands our knowledge of the PHKA2 mutation spectrum of GSD IX. Considering the PHKA2 mutation spectrum in Korean patients with GSD IX, molecular diagnostic methods for deletions should be conducted in conjunction with direct sequence analysis to enable accurate molecular diagnosis of this disease in the Korean population.

Candida famata is a commensal yeast found in natural substrates and various types of cheese [1]. It is a rare cause of candidiasis and has been described in human infections, including bloodstream infections [2]. Results of commercial microbial identification systems based on biochemical tests, available for C. famata identification, are not accurate [3, 4]. Here, we describe three candidiasis cases that were misidentified as C. famata by the Vitek 2 system (bioMerieux, Marcyl'Etoile, France). This study was approved by our Institutional Review Board. In case 1, an extremely low-birth-weight male infant was delivered at 23 weeks and 3 days of gestation. On postnatal day 49, desaturations, neutropenia, and elevated C-reactive protein level were observed. Peripheral blood and central line (C-line) tip cultures grew C. famata, with low discrimination from C. parapsilosis. The infant was treated with fluconazole, and blood cultures obtained 1 week later were negative. In case 2, a 41-yr-old woman had T-cell lymphoma with leptomeningeal seeding. She was undergoing chemotherapy with an Ommaya reservoir in place, and neutropenic fever developed. Meropenem, vancomycin, and caspofungin were empirically administered. Blood cultures obtained from a C-line and peripheral blood were positive for C. lusitaniae. Five days after treatment, blood cultures were negative; however, C. lusitaniae rebounded 2 days later and was identified in the cerebrospinal fluid. At this point, caspofungin was replaced by liposomal amphotericin B (AmB). Owing to persistent fevers, fluconazole was added to the treatment regimen, and a subsequent blood culture grew C. famata. Finally, owing to probable invasive pulmonary aspergillosis, voriconazole alone was administered. The patient died 2 days after the initiation of this treatment. In case 3, a 68-yr-old woman was hospitalized for treatment of a prosthetic joint infection following a total left knee arthroplasty in 2010. She was treated unsuccessfully with several surgical and antibiotic therapies. In July 2013, C. parapsilosis was isolated from the joint fluid, and the patient subsequently underwent open debridement and insertion of an antibiotic-loaded cement spacer in February 2014. Owing to ongoing pain, her joint fluid was cultured the following month, which tested positive for C. famata, and fluconazole treatment was initiated. Because of the discrepancy within these results or low discrimination between species, sequence analyses of the internal transcribed spacer (ITS) and D1/D2 regions of the rRNA gene were performed to identify C. famata isolates [5]. In cases 1, 2, and 3, C. parapsilosis, C. lusitaniae, and C. parapsilosis were identified, respectively (Table 1), with no isolate being identified as C. famata. Table 1 Three cases of candidiasis misidentified as Candida famata by the Vitek2 system Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based identification of clinically relevant yeasts has proven to be superior to identification by phenotypic identification systems [4]. Thus, we subjected the isolates from cases 1 and 2 to MALDI-TOF MS (Bruker Biotyper, Bruker Daltonik, Bremen, Germany). The results were consistent with those obtained by sequencing; however, based on the manufacturer's breakpoints, the identification confidence score (1.70) allowed for only a genus-level identification in both cases [4]. In recent molecular identification studies, phenotypic methods initially identified isolates as C. famata, including strains of C. guilliermondii, C. lusitaniae, C. parapsilosis, and C. palmioleophila [1, 3]. Moreover, the ARTEMIS and SENTRY surveillance programs that identified 53 isolates as C. famata were disproven when sequencing analysis was performed by Castanheira et al. [4], suggesting that phenotypic identification of C. famata is almost certainly incorrect. The results of these studies are consistent with those of the three cases presented herein. Therefore, it is possible that, in the absence of confirmatory assays (e.g., sequencing), previous case reports may have misdiagnosed C. famata infection. To date, six such cases have been reported in Korea (Table 2), and the data presented here suggest the possibility of misidentification. Table 2 Case reports of Candida famata infections in Korea General antifungal susceptibility patterns of C. famata, C. parapsilosis, and C. lusitaniae are different. C. famata exhibits good susceptibility to AmB but reduced susceptibility to echinocandins and azoles. Therefore, liposomal AmB is recommended as the initial therapy [2]. C. parapsilosis is highly susceptible to most antifungal agents, but exhibits higher minimal inhibitory concentrations to echinocandins. C. lusitaniae is usually susceptible to azoles and echinocandins; however, it rapidly acquires resistance to AmB in vitro. Therefore, although misidentification of C. famata in our cases did not have a significant impact on the patients' treatment, this could have led to misinterpretation of antifungal susceptibility and incorrect selection of the initial antifungal agent. In conclusion, it is important to be aware of the potential misidentification of C. famata by commercial systems. For more accurate identification of these isolates, sequencing analysis of ITS and D1/D2 may be helpful.

Inv(11)(p15q22)/NUP98-DDX10 rearrangement is a rare but recurrent chromosomal translocation associated with myeloid malignancies. Structural chromosomal rearrangements of the nucleoporin 98 gene (NUP98) at 11p15.4 produce NUP98 fusions with the DDX10 DEAD (Asp-Glu-Ala-Asp) box polypeptide 10 (DDX10) gene on chromosome 11q22 [1]. To date, only 15 such cases, except the present case, with de novo or therapy-related myeloid disorders have been reported [1, 2, 3, 4, 5, 6, 7, 8]. Three NUP98-DDX10 fusion isoforms, types I, II, and III, have been reported. The type I fusion, which fuses NUP98 exon 12 ({"type":"entrez-nucleotide","attrs":{"text":"NM_139131.1","term_id":"21264368","term_text":"NM_139131.1"}}NM_139131.1) with DDX10 exon 6 ({"type":"entrez-nucleotide","attrs":{"text":"NM_004398.2","term_id":"13514830","term_text":"NM_004398.2"}}NM_004398.2), has been reported in 2 adult therapy-related AML patients [1, 8]. The type II fusion, which fuses NUP98 exon 14 with DDX10 exon 7, has been reported in 12 cases. The type III fusion, which fuses NUP98 exon 15 and DDX10 exon 7, has been reported in 1 adult de novo AML patient with a concurrent case of type II fusion [7]. Herein we report a de novo childhood AML patient with inv(11)(p15q22)/NUP98-DDX10 rearrangement for the first time in Korea. A 4-yr-old boy presented with petechiae and easy bruising. His complete blood count revealed the following: Hb, 7.7 g/dL; leukocyte count, 7.64×109/L (absolute neutrophil count, 0.32×109/L); and platelets, 42×109/L. Additional analysis of the peripheral blood revealed 15% myeloblasts and leukoerythroblastic features. The bone marrow (BM) study showed 55% blasts with dysplastic erythropoiesis and megakaryopoiesis, suggesting AML with myelodysplasia-related changes. The estimated cellularity of the BM section was variable at 10-100% (overall 50%). Flow cytometry revealed that the blasts were positive for CD13, CD33, CD64, CD11c, CD117, cMPO, HLA-DR, and CD34 (CD64 and CD34 were weakly expressed). Chromosomal analysis performed on a short-term culture of BM cells using the Giemsa banding technique revealed that the patient's karyotype was 46,XY,inv(11)(p15q22)[19]/46,XY[1] (Fig. 1). FISH analysis with probes for EGR1 (5q-), D7S522 (7q-), TP53/CEP17 [i(17q)/t(17p)], and MLL [t(11q23)] (Vysis, Downers Grove, IL, USA) showed no cytogenetic abnormalities. The HemaVision (DNA Technology, Aarhus, Denmark) screen was negative for all detectable fusion transcripts. Mutation analyses for NPM1 and internal tandem duplications of FLT3 and CEBPA were negative. One microgram of total RNA was reverse transcribed for reverse transcription (RT)-PCR experiments for further evaluation of cytogenetic abnormalities. The NUP98-DDX10 fusion transcript was detected by using previously described primers [1], and sequence analysis revealed an in-frame fusion between NUP98 nucleotide 1907 (exon 14) and DDX10 nucleotide 914 (exon 7), which presented as a type II fusion (Fig. 1). After the patient received induction chemotherapy, follow-up BM examination and cytogenetic analyses showed no residual leukemic cells with the 46,XY karyotype [20]. The patient tolerated a 4-month follow-up period of consolidation chemotherapy quite well. Fig. 1 Karyotyping, reverse transcription (RT)-PCR, and sequence analyses of the NUP98-DDX10 fusion transcripts in the present case. (A) Giemsa-band karyotype with 400-band resolution showing inv(11)(p15q22). (B) RNA samples from the patient's leukemic cells ... Among the 29 NUP98 fusion partners and their fusion transcripts, the NUP98-DDX10 rearrangement, which encodes proteins that contain a coiled-coil domain that is thought to function in the oligomerization of proteins, has been reported to increase the proliferation and self-renewal of primary human CD34+ cells and disrupt their erythroid and myeloid differentiation [9, 10]. Among the 16 reported NUP98-DDX10-positive cases including the present case, 8 were children and 8 were adults. Nine of them were de novo (7 AML, 1 MDS, 1 accelerated phase of CML) and 6 were therapy-related cases (3 AML, 2 MDS, and 1 chronic myelomonocytic leukemia) [1, 2, 3, 4, 5, 6, 7]. For the remaining 1 case, the information whether the case was therapy-related or not was not available [8]. Male predominance was observed (12/16 cases). Although the prognostic implications of the NUP98/DDX10 rearrangement have not been clearly identified, nucleoporin-associated malignancies tend to occur at a younger age and have a poor outcome [2, 3, 4, 6, 7, 8]. The majority of reported cases showed evidence of monocytic differentiation: AML-M4 and AML-M5, according the French-American-British classification, and chronic myelomonocytic leukemia (CMML) [1, 2, 3, 5, 6, 7]. Although this patient's leukemic cells were not morphologically monocytic, flow cytometry showed that they were positive for monocytic markers (CD64 and CD11c). Cytogenetically, the reported NUP98-DDX10 fusions were derived from diverse rearrangements of chromosome 11 [i.e., inv(11) (14 cases), insertion (1 case), or reciprocal translocation (1 case)]. Among the 3 NUP98-DDX10 fusion isoforms derived from alternative splicing, all reported childhood AML patients had type II isoforms. Although alternative splicing mechanisms have been suggested to play different roles in leukemogenesis involving other NUP98 fusions, the mechanism and impact of nonrandom breakpoint localization within NUP98 fused with DDX10 are yet to be clarified [6, 7]. Considering its possible cryptic nature, identifying the NUP98-DDX10 rearrangement could contribute to expanding its use as a marker for minimal residual disease and future therapeutic approaches [6]. Here, we describe a de novo childhood AML patient with NUP98-DDX10 rearrangement (type II fusion) and inv(11)(p15q22) as the sole karyotypic abnormality, comparable to previous studies. Due to its possible association with adverse clinical outcomes, further studies are required to explore the implications of this karyotypic abnormality.

Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 μmol/L; reference range, 11.2-48.2 μmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 μmol/L; reference range, 131-710 μmol/L) and glutamine (5,777 μmol/L; reference range, 376-709 μmol/L), whereas that of citrulline was decreased (2 μmol/L; reference range, 10-45 μmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.

This prospective study sought to investigate serum levels of trace elements (cobalt, copper, zinc, and selenium) and to assess their effects on pregnancy and neonatal outcomes. Serum levels of trace elements in 245 Korean pregnant women (median gestational age at delivery was 39 + 4 weeks and interquartile range was 38 + 4–40 + 1 weeks) were compared with those of 527 general adults and those of previous studies in other ethnic groups. Pregnancy and neonatal outcomes including gestational diabetes, preeclampsia, neonatal birth weight, and congenital abnormalities were assessed. The median serum trace element concentrations of all pregnant women were: cobalt: 0.39 μg/L (interquartile range, IQR 0.29–0.53), copper: 165.0 μg/dL (IQR 144.0–187.0), zinc: 57.0 μg/dL (IQR 50.0–64.0), and selenium: 94.0 μg/L (IQR 87.0–101.0). Serum cobalt and copper concentrations were higher in pregnant women than in the general population, whereas zinc and selenium levels were lower (p < 0.01). Concentrations of all four trace elements varied significantly during the three trimesters (p < 0.05), and seasonal variation was found in copper, zinc, and selenium, but was not observed for cobalt. The prevalence of preeclampsia was significantly lower with high copper (p = 0.03). Trace element levels varied by pregnancy trimester and season, and alteration in copper status during pregnancy might influence pregnancy outcomes such as preeclampsia.

Jin Ah Jung,1 Tae-Eun Kim,2 Hyun Lee,3 Byeong-Ho Jeong,3 Hye Yun Park,3 Kyeongman Jeon,3 O Jung Kwon,3 Jae-Wook Ko,4 Rihwa Choi,5 Hye-In Woo,6 Won-Jung Koh,3 Soo-Youn Lee4,5 1Department of Clinical Pharmacology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Korea; 2Department of Clinical Pharmacology, Konkuk University Medical Center, 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, 4Department of Clinical Pharmacology and Therapeutics, 5Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School ofMedicine, Seoul, Korea; 6Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea Background/aim: Isoniazid (INH) is an essential component of first-line anti-tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study.Methods: A total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0–6.0mg/L. This dosing algorithm was then used for newly enrolled 53 patients.Results: Serum concentrations of INH were significantly lower in the rapid-acetylators than in the slow-acetylators (2.55mg/L vs 6.78mg/L, median, P

We describe 3 children with urinary tract abnormalities and large numbers of Streptococcus pneumoniae in their urine, along with a brief review of previously reported cases. These findings strongly suggest that S. pneumoniae is a uropathogen, especially in children with urinary tract abnormalities.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. It is caused by mutations in the PKD1 and PKD2 genes, and manifests as progressive cyst growth and renal enlargement, resulting in renal failure. Although there have been a few studies on the frequency and spectrum of mutations in PKD1 and PKD2 in Korean patients with ADPKD, only exons 36–46, excluding the duplicated region, were analyzed, which makes it difficult to determine accurate mutation frequencies and mutation spectra. Methods We performed sequence analysis of 20 consecutive unrelated ADPKD patients using long-range polymerase chain reaction (PCR) to avoid pseudogene amplification, followed by exon-specific PCR and sequencing of the all exons of these two genes. Multiplex ligation-dependent probe amplification was performed in patients in whom pathogenic mutations in PKD1 or PKD2 were not identified by LR-PCR and direct sequencing to detect large genomic rearrangements. Results All patients met the diagnostic criteria of ADPKD, and pathogenic mutations were found in 18 patients (90.0%), comprising 15 mutations in PKD1 and three in PKD2. Among 10 novel mutations, eight mutations were found in the PKD1 gene while two mutations were found in the PKD2 gene. Eight of 14 PKD1 mutations (57.1%) were located in the duplicated region. Conclusions This study expands the spectra of mutations in the PKD1 and PKD2 genes and shows that the mutation frequencies of these genes in Korean ADPKD patients are similar to those reported in other ethnicities. Sequence analysis, including analysis of the duplicated region, is essential for molecular diagnosis of ADPKD.

Background: Classic galactosemia (OMIM #230400) is an autosomal recessive metabolic disorder caused by a deficiency of the galactose-1-phosphate uridyltransferase (GALT, EC2.7.7.12) protein due to mutations in the GALT gene. The aim of this study was to provide a comprehensive and updated mutation spectrum of GALT in a Korean population. Methods: Thirteen unrelated patients screened positive for galactosemia in a newborn screening program were included in this study. They showed a reduced GALT enzyme activity in red blood cells. Direct sequencing of the GALT gene and in silico analyses were done to evaluate the impact of novel variations upon GALT enzyme activity. We also reviewed previous reports for GALT mutations in Koreans. Results: We identified six novel likely pathogenic variations including three missense (p.Ala101Asp, p.Tyr165His, and p.Pro257Thr), one small deletion/insertion [c. 826_827delinsAA (p.Ala276Asn)], one frameshift (p.Asn96Serfs*5), and one splicing (c.378-1G > C) likely pathogenic variations. The most frequent variation was the Duarte variant (c.940A > G, 35.3%), followed by c.507G > C (p.Gln169His, 9.6%), among 34 Korean patients. Other mutations were widely scattered. None of the eight common mutations used for targeted mutation analysis in Western countries including p.Gln188Arg, p.Ser135Leu, p.Lys285Asn, p.Leu195Pro, p.Tyr209Cys, p.Phe171Ser, c.253-2A > G, and a 5 kb deletion, had been found in Koreans until this study. Conclusions: Considering the mutation spectrum in Koreans, direct sequence analysis of entire GALT exons is recommended for accurate diagnosis. The mutations responsible for GALT deficiency in the Korean population were clearly different from those of other populations.

Purpose The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients. Methods The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy. Findings A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7–77 mg/wk). Estimated dose and actual maintenance dose correlated well overall ( r range, 0.52–0.73). Mean absolute error (MAE) of the 16 algorithms ranged from –1.2 to –20.1 mg/wk. The percentage of patients whose estimated dose fell within 20% of the actual dose ranged from 1.0% to 49%. All algorithms showed poor accuracy with increased MAE in a higher dose range. Performance of the dosing algorithms was worse in patients with VKORC1 1173TC or CC than in total ( r range, 0.38–0.61 vs 0.52–0.73; MAE range, –2.6 to –28.0 mg/wk vs –1.2 to –20.1 mg/wk). Implications The algorithms had comparable prediction abilities but showed limited accuracy depending on ethnicity, warfarin dose, and VKORC1 genotype. Further studies are needed to develop genotype-guided warfarin dosing algorithms with greater accuracy in the Korean population.