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Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher C

Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating inflammatory disorder of the central nervous system. It is characterized by encephalopathy, multifocal neurological deficits, and typical magnetic resonance imaging findings of widespread demyelinating lesions, predominantly involving the white matter of the brain and spinal cord. ADEM mainly affects children and is commonly associated with preceding viral and bacterial infections, and, rarely, vaccinations. Despite substantial advances in the understanding of the association of myelin oligodendrocyte glycoprotein antibody with recurrent forms of ADEM or other demyelinating conditions, specific etiologic agents or biological markers have not been identified. Therefore, the diagnosis of ADEM is still based on clinical and radiological findings and the exclusion of other conditions mimicking ADEM. However, a prompt diagnosis and adequate treatment are crucial because diagnostic delays or inappropriate treatment may lead to unwanted neurological sequelae in some children. There is no standardized treatment protocol for ADEM, but the use of corticosteroids, intravenous immunoglobulin, and plasmapheresis has been associated with good clinical outcomes. Adequate treatment has reportedly resulted in favorable outcomes, with full or almost full recovery in most children with ADEM, although some children may develop neurological sequelae, such as cognitive impairment and motor deficits. Further studies are needed to identify biological clues and optimal treatment protocols to minimize the incidence of neurological sequelae.

Objectives Prolactin (PRL) stimulates the mammary glands development; however, it also inhibits gonadotropin-releasing hormone (GnRH) secretion. We evaluated the relationship between PRL levels and puberty in girls with precocious breast development. Methods This study included 244 girls with breast development < 8 years of age. Patients were categorized as central precocious puberty (CPP) [peak luteinizing hormone (LH) levels ≥ 5 IU/L after GnRH stimulation] versus non-CPP (NPP) group. High PRL was defined as serum PRL > 17.9 ng/mL. Results High PRL was more common in NPP than in CPP group (17.6 vs. 8.1%, p=0.025), although mean PRL levels did not differ. In NPP group, the high PRL group had lower peak LH/follicle-stimulating hormone (FSH) ratio, and later LH peak time after GnRH stimulation than normal PRL group (all p Conclusions Girls with NPP showed higher proportion of high PRL than CPP group. High PRL group showed more features of prepubertal response in NPP group, and associated with decreased odds for CPP, suggesting the possibility of PRL role on breast development while suppressing hypothalamic–pituitary–gonadal axis activation in NPP girls.

Background There is limited comprehensive evidence on the potential association between early menarche and subsequent health outcomes. Aim To evaluate the existing evidence for the association of early menarche with later health outcomes and assesse the strength and validity of the evidence for these associations. Design Umbrella review. Methods We searched PubMed, Web of Science, Embase, CINAHL, Cochrane Database of Systematic Reviews and Google Scholar, and manually screened retrieved references to find systematic reviews and meta-analyses from inception to July 2021. Early menarche was defined by taking into account ethnicity and birth year, and the outcomes were long-term consequences in adulthood. Results Thirteen reviews encompassing 283 original articles and over 6.8 million participants from 39 countries across 5 continents were included. In categorical outcomes, early menarche was associated with metabolic syndrome (n = 37 543 pooled adjusted relative risk [aRR] 1.56, 95% confidence interval (CI) 1.33, 1.83; high certainty [Hi]), endometrial cancer (n = 874 188, aRR 1.40, 95% CI 1.17, 1.68; Hi), type 2 diabetes mellitus/impaired glucose tolerance (n = 1 185 444, aRR 1.30, 95% CI 1.19, 1.42; Hi), breast cancer (n = 103 574, aRR 1.19, 95% CI 1.06, 1.33; Hi), death from all causes (n = 152 747, aRR 1.11, 95% CI 1.03, 1.19; Hi), obesity (n = 54 006, aRR 1.68, 95% CI 1.53, 1.84; moderate certainty [Mod]), gestational diabetes mellitus (n = 48 535, aRR 1.32, 95% CI 1.09, 1.58; Mod), hypertension (n = 1 682 689, aRR 1.24, 95% CI 1.20, 1.29; Mod), endometriosis (n = 885 390, aRR 1.22, 95% CI 1.09, 1.37; Mod), ovarian cancer (n = 1 022 451, aRR 1.17, 95% CI 1.04, 1.31; Mod) and asthma (n = 22 859, aRR 1.31, 95% CI 1.09, 1.57; low certainty [Lo]). For continuous outcomes, early menarche was associated with increased body mass index (BMI) in adults ≥40 years of age (n = 121 943, adjusted pooled standardized mean difference [aSMD] 0.30, 95% CI 0.28, 0.32; Mod), BMI in adults Conclusion We found varied levels of evidence for the association between early menarche and the development of subsequent health problems. Our results recommend that physicians should pay attention to these associations, as early menarche can be a potential indicator of metabolic disorders and female-specific cancer and cause death in women.

The aim of this study was to establish the physiologically based pharmacokinetic (PBPK) model of flurbiprofen related to CYP2C9 genetic polymorphism and describe the pharmacokinetics of flurbiprofen in different CYP2C9 genotypes. PK-Sim® software was used for the model development and validation. A total of 16 clinical pharmacokinetic data for flurbiprofen in different CYP2C9 genotypes, dose regimens, and age groups were used for the PBPK modeling. Turnover number (k

Development and validation of a decision tree model (DTM) for prediction of mental health status in Korean caregivers of children with glaucoma.Cross-sectional study.Caregivers of children younger than 18 years with diagnosed primary childhood glaucoma (n = 42), secondary childhood glaucoma (n = 51), and glaucoma suspect (GS; n = 36) were prospectively enrolled at Seoul National University Children's Hospital, Seoul, Korea. The participants completed 2 questionnaires, the 9-item Patient Health Questionnaire (PHQ-9) and the 7-item Generalized Anxiety Disorder (GAD-7) Assessment. A DTM analysis for discrimination of those with moderate-to-severe depressive (PHQ-9 score ≥10) and anxiety (GAD-7 score ≥11) symptoms was performed with recursive partitioning algorithms based on the obtained clinical, demographic, and socioeconomic data.The mean PHQ-9 and GAD-7 scores did not significantly differ among the 3 groups (P = .823 for PHQ-9 score; P = .730 for GAD-7 score). The DTM's balanced accuracies were 0.875 (95% CI = 0.778-0.972) for the PHQ-9 score and 0.880 (95% CI = 0.800-0.960) for theGAD-7 score. The DTM of the PHQ-9 revealed that in caregivers of children with glaucoma, depressive symptoms should be strongly suspected when (1) the child has undergone more than 2 glaucoma surgeries; or (2) the visual acuity (VA, converted to logarithm of minimum angle of resolution [logMAR]) in the better eye is worse than 0.4 if the child has had only 1 or no surgery.Evaluation of the number of glaucoma surgeries and VA in the better eye can be a useful decision support tool in predicting mental illness in caregivers of children with glaucoma.

The rates, patterns and associated factors for false-positive classification of deviation maps by Cirrus optical coherence tomography (OCT) have been reported. However, research on OCT layer-by-layer deviation maps is lacking. We aimed to determine the rates and associated factors for false-positive classification of segmented macular layers and retinal nerve fiber layer (RNFL) deviation maps of Spectralis OCT, and to identify false-positive patterns on segmented macular layers deviation maps. 118 healthy eyes of 118 normal participants who had undergone Spectralis OCT imaging were included. False-positive classification was determined by the area and location of yellow or red color-coded regions on the deviation map. The false-positive rates on the deviation maps were the highest on the ganglion cell layer map, followed by the inner plexiform layer, retinal layer, and RNFL maps. More myopic/less hyperopic refractive error was a factor significantly associated with higher false-positive classification on the RNFL deviation map, and three false-positive patterns were found on the segmented macular layers deviation maps. Spectralis OCT deviation maps should be interpreted carefully to avoid misdiagnosis, especially for eyes with higher degrees of myopic refractive error on the RNFL map, for which purpose, recognizing the characteristic false-positive patterns would be helpful in clinical practice.

Metoprolol, a selective β

Piroxicam is a non-steroidal anti-inflammatory drug used to alleviate symptoms of osteoarthritis and rheumatoid arthritis. CYP2C9 genetic polymorphism significantly influences the pharmacokinetics of piroxicam. The objective of this study was to develop and validate the piroxicam physiologically based pharmacokinetic (PBPK) model related to CYP2C9 genetic polymorphism. PK-Sim

Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA.In this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7-24 months of age when administered). They were all previously treated with nusinersen, 4-5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration.Liver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment.Our experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment.

Macular OCT angiography (OCTA) measurements have been reported to be useful for glaucoma diagnostics. However, research on highly myopic glaucoma is lacking, and the diagnostic value of macular OCTA measurements versus OCT parameters remains inconclusive. We aimed to evaluate the diagnostic ability of the macular microvasculature assessed with OCTA for highly myopic glaucoma and to compare it with that of macular thickness parameters, using deep learning (DL). A DL model was trained, validated and tested using 260 pairs of macular OCTA and OCT images from 260 eyes (203 eyes with highly myopic glaucoma, 57 eyes with healthy high myopia). The DL model achieved an AUC of 0.946 with the OCTA superficial capillary plexus (SCP) images, which was comparable to that with the OCT GCL+ (ganglion cell layer + inner plexiform layer; AUC, 0.982; P = 0.268) or OCT GCL++ (retinal nerve fiber layer + ganglion cell layer + inner plexiform layer) images (AUC, 0.997; P = 0.101), and significantly superior to that with the OCTA deep capillary plexus images (AUC, 0.779; P = 0.028). The DL model with macular OCTA SCP images demonstrated excellent and comparable diagnostic ability to that with macular OCT images in highly myopic glaucoma, which suggests macular OCTA microvasculature could serve as a potential biomarker for glaucoma diagnosis in high myopia.

Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C9*3 and *13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide. Twenty-four healthy Korean volunteers (11 subjects with CYP2C9*1/*1, 8 subjects with CYP2C9*1/*3, and 5 subjects with CYP2C9*1/*13) were recruited for this study. They were administered a single oral dose of glipizide 5 mg. The plasma concentration of glipizide was quantified for pharmacokinetic analysis and plasma glucose and insulin concentrations were measured as pharmacodynamic parameters. The results represented that CYP2C9*3 and *13 alleles significantly affected the pharmacokinetics of glipizide. In subjects with CYP2C9*1/*3 and CYP2C9*1/*13 genotypes, the mean AUC

Purpose: To investigate the clinical features of non-affected fellow eyes in patients with unilateral facial port-wine stain (PWS) and ipsilateral secondary glaucoma.Methods: We performed a retrospective analysis of the medical records of 35 patients with unilateral facial PWS glaucoma and those of controls (35 subjects without both facial PWS and glaucoma) between September 1996 and May 2020. We noted patients’ age at the glaucoma diagnosis (for unilateral facial PWS glaucoma patients) or at the initial examination (for controls), cup-to-disc ratio (CDR), and intraocular pressure (IOP). We compared the clinical features between the glaucoma-free eyes in patients with unilateral facial PWS glaucoma and the controls.Results: The mean age at the glaucoma diagnosis for unilateral facial PWS glaucoma patients was 0.56 ± 0.99 years (range, 0.08-4). The mean IOP of the glaucoma-free eyes was 16.68 ± 5.73 mmHg (range, 9-22.9), and the mean CDR was 0.37 ± 0.14 (range, 0.15-0.80) at glaucoma diagnosis. The mean IOP of the glaucoma-free eyes was 14.14 ± 6.29 mmHg (range, 8.1-26.7), and the mean CDR was 0.37 ± 0.12 (range, 0.26-0.82) at final examination. When comparing glaucoma-free eyes of the unilateral facial PWS glaucoma patients with the control group (mean age, 11.2 ± 7.4 years), the mean CDR was significantly greater (0.37 ± 0.12 vs. 0.30 ± 0.08; p = 0.014) but there was no significant difference in the mean IOP (14.14 ± 6.29 mmHg vs. 14.57 ± 2.49 mmHg; p = 0.712).Conclusions: The glaucoma-free eyes of unilateral facial PWS glaucoma patients showed greater CDR compared to the non-facial PWS and non-glaucoma controls. Additional longitudinal studies are needed to investigate the clinical course of those eyes, whether the risk of developing glaucoma is increased.

Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a heterogeneous group of inborn error of metabolic disease affecting the oxidation of fatty acids and amino acids, and choline metabolism. Genes involved in electrons transfer to the mitochondrial respiratory chain typically induce MADD. Recently, FLAD1, which encodes flavin adenine dinucleotide synthase, has also been reported as a cause of MADD. Here, we present a case of a 28-month girl with progressive weakness in facial and bulbar muscle. She has been suffering from feeding difficulty and recurrent respiratory distress. Lipid storage myopathy was evident from muscle biopsy. Furthermore, whole exome sequencing identified homozygous variant of c.745C > T (p.Arg249*) in FLAD1, confirming the diagnosis of FLAD1-related MADD. The patient showed improvements in her symptoms and exhibited catch-up growth following the supplementation of riboflavin. Lipid storage myopathy with FLAD1-related MADD is potentially treatable. Therefore, we should have high clinical suspicion, even though the diagnosis is challenging.

Tolperisone, a muscle relaxant used for post-stroke spasticity, has been reported to have a very wide interindividual pharmacokinetic variability. It is metabolized mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. CYP2D6 is a highly polymorphic enzyme, and CYP2D6*wt/*wt, CYP2D6*wt/*10 and CYP2D6*10/*10 genotypes constitute more than 90% of the CYP2D6 genotypes in the Korean population. Thus, effects of the CYP2D6*10 on tolperisone pharmacokinetics were investigated in this study to elucidate the reasons for the wide interindividual variability. Oral tolperisone 150 mg was given to sixty-four healthy Koreans, and plasma concentrations of tolperisone were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The CYP2D6*10/*10 and CYP2D6*wt/*10 groups had significantly higher C

Background Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system. Results During the program (2018–2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration. Conclusions The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare form of hereditary rickets, which is characterized by defective bone mineralization and renal phosphate wasting due to a loss-of-function variant in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene. Although pathogenic variant of ENPP1 has been known to manifest other phenotypes including arterial calcification, hearing loss, ossification of posterior longitudinal ligament, or pseudoxanthoma elasticum, there have been few reports including systematic examination in individuals diagnosed with ARHR2 to date. Herein, we report a case of ARHR2 with a bi-allelic pathogenic variant of ENPP1, in which the patient presented with gait abnormalities with severe genu varum at 26 months of age. Targeted gene panel sequencing was performed to investigate the genetic cause of rickets, and a homozygous nonsense variant in ENPP1, c.783C>G (p.Tyr261*), was identified. The patient was treated with oral phosphate and active vitamin D supplements and underwent corrective osteotomy for varus deformity. His phenotype was limited to rickets. A periodic systematic evaluation is needed to identify any comorbidities in ARHR2 patients since ENPP1 variants may present phenotypes other than rickets and symptoms may evolve or change over time.

BackgroundConsidering the roles of 25-hydroxyvitamin D (25OHD) in glucose homeostasis and immune modulation, vitamin D deficiency may be related to the development of type 1 diabetes (T1DM) and diabetic ketoacidosis (DKA). We evaluated the total, free, bioavailable 25OHD levels and vitamin D binding protein (VDBP) levels and genotypes between T1DM patients and controls.MethodsThis retrospective, cross-sectional study included 84 children with T1DM (38 boys and 46 girls, 8.0 ± 3.6 years) and 1:1 age- and sex-matched healthy controls. A multiplex liquid chromatography-tandem mass spectrometry-based assay was used to simultaneously measure vitamin D metabolites.ResultsPatients with T1DM had lower levels of total 25OHD (16.3 ± 5.1 vs. 19.9 ± 6.5 ng/mL, P< 0.001) and VDBP (146.0 ± 27.8 vs. 224.9 ± 36.1 µg/mL, P = 0.001), but higher free 25OHD (8.0 ± 2.5 vs. 6.5 ± 2.3 pg/mL, P< 0.001) than controls. Patients who presented with DKA had lower levels of 25OHD in the total (15.0 ± 4.6 vs. 17.6 ± 5.2 ng/mL, P = 0.020), free (7.5 ± 2.6 vs. 8.4 ± 2.4 pg/mL, P = 0.059), and bioavailable (2.3 ± 0.9 vs. 2.8 ± 0.8 ng/mL, P = 0.014) forms than those without DKA at the T1DM diagnosis. The lower the total, free, and bioavailable 25OHD levels at diagnosis, the lower the pH and HCO3-. The proportions of the VDBP genotypes did not differ between the patients and controls.ConclusionPatients with T1DM had higher levels of free 25OHD than healthy children, despite lower levels of total 25OHD. However, patients with DKA exhibited lower levels of bioavailable 25OHD than those without DKA at the T1DM diagnosis. The lower the concentrations of free and bioavailable 25OHD, the more severe the acidosis at the initial T1DM presentation.

OBJECTIVE We evaluated the frequency, risk factors and the follow-up outcomes of thyroid nodules, and genetic alterations in thyroid cancer, in youth with childhood-onset Hashimoto thyroiditis (HT) residing in an iodine-sufficient country. DESIGN A retrospective cohort study. PATIENTS AND MEASUREMENTS A total of 213 patients (194 females, mean age 10.6 years at the time of HT diagnosis) were ultrasonographically evaluated. Thyroid nodules were categorized using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TI-RADS). RESULTS Thyroid nodules were detected in 40 (18.8%) patients over a median follow-up period of 3.4 years, usually after the onset of puberty. A family history of thyroid disease (hazard ratio 2.1, p = .031) was predictive of thyroid nodule detection. Papillary thyroid carcinoma (PTC) was diagnosed in 9 (4.2% of all and 22.5% of nodule-positive patients). The malignant nodules had a higher K-TIRADS or ACR-TI-RADS risk level compared with benign nodules (p

Background The predictive value of immune monitoring with circulating CD8+ T lymphocytes for treatment response to programmed cell death protein 1 (PD-1) inhibitors has not been explored in non-small-cell lung cancer (NSCLC), prompting us to investigate whether dynamic changes in PD-1+CD8+ T lymphocytes have predictive value for durable clinical benefit (DCB) and survival after PD-1 blockade. Methods Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8+ T lymphocytes was conducted using multi-colour flow cytometry. Predictive values of dynamic changes in circulating PD-1+CD8+ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with a PD-1 inhibitor (NCT03486119). Results Circulating PD-1+CD8+ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1+ cells among CD8+ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in the analysis of tumour antigen NY-ESO-1-specific CD8+ T lymphocytes and the validation cohort. Mechanistically, PD-1 molecule expression on CD8+ T lymphocytes suppresses the effector functions of tumour antigen-specific CD8+ T lymphocytes. Conclusions Dynamic changes in circulating PD-1+CD8+ T lymphocytes predict clinical, and survival benefit from PD-1 blockade treatment in NSCLC, providing a useful tool to identify patient subgroups who will optimally benefit from PD-1 inhibitors.

Purpose This study investigated the clinical characteristics and risk factors of epilepsy in patients with neurofibromatosis type 1 (NF1) at a tertiary center. Methods The medical records of 103 children diagnosed with NF1 from February 2009 to July 2019 were retrospectively reviewed. Demographic features, NF1-related features, seizure characteristics, treatment outcomes, and electroencephalography and brain magnetic resonance imaging (MRI) findings were compared between patients with and without epilepsy. Results Among the 103 patients (median age, 11.5 years; age range, 1.0 to 34.8), 14 (13.6%) had epilepsy. The median age of seizure onset was 5.8 years (range, 1.1 to 18.9). Focal and generalized seizures were observed in nine (64.3%) and six (42.9%) patients, respectively. Five patients (35.7%) had a history of status epilepticus and one of them died of it. Two patients (14.3%) had drug-resistant epilepsy. On brain MRI obtained at the time of seizure onset, seven (50%) patients had unidentified bright objects and three (21.4%) had other structural abnormalities. Learning disability (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.17 to 17.5) and a family history of epilepsy (OR, 39.7; 95% CI, 3.78 to 416.53), but not structural abnormalities, were significant risk factors for epilepsy. Conclusion Epilepsy was more common in NF1 patients than in the general population. NF1 patients with epilepsy had various seizure types, but exhibited relatively good outcomes. The types of brain abnormalities were not significantly different between patients with and without epilepsy. Our results suggest that mechanisms other than structural brain abnormalities should be considered epileptogenic in NF1 patients.

Background Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructures, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system. Results During the program (2018–2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: I) those with a specific clinical diagnosis that required direct testing (32 patients); II) those with a clinical diagnosis with genetic and phenotypic heterogeneity (353 patients); and III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration. Conclusions The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare form of hereditary rickets, which is characterized by defective bone mineralization and renal phosphate wasting due to a loss-of-function variant in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (

Purpose Despite the prevalent use of insulin pump therapy worldwide, few studies have been conducted among young patients with type 1 diabetes (T1D) in Korea. We investigated the durability and effectiveness of insulin pump therapy among Korean pediatric and young adult patients with T1D. Methods This study included 54 patients with T1D diagnosed at pediatric ages (range, 1.1–14.1 years) who initiated insulin pump therapy during 2016–2019 at Seoul National University Children's Hospital and Seoul National University Bundang Hospital. Clinical and biochemical data, including anthropometric measurements, insulin dose, and glycated hemoglobin (HbA1c) levels were obtained from T1D diagnosis to last follow-up. Results Forty-four patients (81.5%) continued insulin pump therapy with a median pump use duration of 2.9 years (range, 0.2–3.5 years); 10 discontinued the therapy within 12 months (