Clinical and molecular characteristics of Korean patients with Kabuki syndrome.

INTRODUCTION: Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. METHODS: This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. RESULTS: The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. CONCLUSION: This study enhances the understanding of the clinical and genetic characteristics of KS.

Aberrant expression of PAX6 gene associated with classical aniridia: identification and functional characterization of novel noncoding mutations.

The PAX6 is essential for ocular morphogenesis and is known to be highly sensitive to changes in gene expression, where neither over- nor under-expression ensures normal ocular development. Two unrelated probands with classical aniridia who were previously considered "PAX6-negative", were studied by whole-genome sequencing. Through the use of multiple in silico deep learning-based algorithms, we identified two novel putative causal mutations, c.-133_-132del in the 5' untranslated region (5'-UTR) and c.-52 + 5G>A in an intron upstream of the PAX6 gene. The luciferase activity was significantly increased and VAX2 binding was disrupted with the former 5'-UTR variant compared with wild-type sequence, which resulted in a striking overexpression of PAX6. The minigene assay showed that the c.-52 + 5G>A mutation caused defective splicing, which resulted in the formation of truncated transcripts.

Clinical and molecular spectra of BRAF-associated RASopathy.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

Etiologic distribution and clinical characteristics of pediatric diabetes in 276 children and adolescents with diabetes at a single academic center.

BACKGROUND: The prevalence of monogenic diabetes is estimated to be 1.1-6.3% of patients with diabetes mellitus (DM) in Europe. The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, who presented at a single tertiary center over the last 20 years. METHODS: This study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019 in Korea. Clinical features, biochemical findings, ß-cell autoantibodies, and molecular characteristics were reviewed retrospectively. RESULTS: Of the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients suspected to have monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness. CONCLUSIONS: Genetically confirmed monogenic diabetes accounted for 5.1% of patients evaluated at a single tertiary center over 20-year period. Based on the findings for our sample, the frequency of mutations in the major genes of MODY appears to be low among pediatric patients in Korea. It is critical to identify the genetic cause of DM to provide appropriate therapeutic options and genetic counseling.

A female with typical fragile-X phenotype caused by maternal isodisomy of the entire X chromosome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, especially in males. Females with FXS tend to be relatively mildly affected because of compensation by a second X chromosome with a normal FMR1 gene. In most cases, FXS is caused by an expansion of the CGG repeats (>200 triplets, full mutation, FM) in the 5'-untranslated region of the FMR1 gene. Premutation alleles (PM, 55-200 repeats), usually lack the clinical features of FXS, are highly unstable when transmitted to offspring and can give rise to FM, especially in female meiosis. We describe a 3-year-old girl with typical FXS, with only a fully expanded FMR1 allele (288 CGG repeats) due to uniparental isodisomy of X chromosome, inherited from mother carrying a premutation allele. The patient's FMR1 methylation region is completely methylated due to full mutation of CGG repeat. This unusual and rare case indicates the importance of a detailed genomic approach to explain nontraditional Mendelian inheritance pattern.

Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1 gene. NF1 is one of the most common human genetic diseases. However, the overall genotype-phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1 mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1+), we investigated the correlation of NF1+ and mutation types. NF1+ was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p = 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1+ was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p = 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.

Identification of extremely rare mitochondrial disorders by whole exome sequencing.

Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1. In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.

Biochemical and molecular characterisation of neurological Wilson disease.

BACKGROUND: To identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup. METHODS: Detailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients) from 368 unrelated Korean families were analysed. RESULTS: Compared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings and higher serum creatinine levels, and a lower proportion with favourable outcome (62% vs 80%, P<0.016). At diagnosis, the neurological subgroup had lower serum ceruloplasmin (3.1±2.1 mg/dL vs 4.2±3.2 mg/dL, P<0.001), total copper (26.4±13.8 µg/dL vs 35.8±42.4 µg/dL, P=0.005), free copper (17.2±12.5 µg/dL vs 23.5±38.2 µg/dL, P=0.038) and urinary copper (280.9±162.9 µg/day vs 611.1±1124.2 µg/day, P<0.001) levels. Serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and total bilirubin levels, as well as prothrombin time, were also lower in the neurological subgroup. Liver cirrhosis was more common but mostly compensated in the neurological subgroup. Frameshift, nonsense or splice-site ATP7B mutations and mutations in transduction or ATP hinge domains (2.4% vs 23.1%, P=0.006) were less common in the neurological subgroup. CONCLUSION: The neurological subgroup had distinct clinical, biochemical and genetic profiles. Further studies are required to identify the factors, with or without association with copper metabolism, underlying the neurological presentation for which treatment needs to be targeted to improve the clinical outcome of this subgroup.

Phenotypic and molecular spectrum of Korean patients with Lesch-Nyhan syndrome and attenuated clinical variants.

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder caused by mutations in the HPRT1 gene. The clinical features and mutation spectrum of 26 Korean LNS patients from 23 unrelated families were retrospectively reviewed. The HPRT1 gene was analyzed by direct sequencing of genomic DNA. The median age at diagnosis was 2.3 years (range, 4 months-22.6 years) and the initial presenting features included developmental delay, orange colored urine, and self-injurious behaviors. Most patients were wheelchair-bound and suffered from urinary complications and neurologic problems such as self-mutilation and developmental delay. Twenty different mutations in HPRT1 were identified among 23 independent pedigrees, including six novel mutations. The most common mutation type was truncating mutations including nonsense and frameshift mutations (45%). Large deletions in the HPRT1 gene were identified in exon 1, exons 5-6, exons 1-9, and at chr X:134,459,540-134,467,241 (7702 bp) including the 5'-untranslated region, exon 1, and a portion of intron 1. In conclusion, this study describes the phenotypic spectrum of LNS and has identified 20 mutations from 23 Korean families, including six novel mutations in Korean patients with LNS.

A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing.

BACKGROUND: Adrenal hypoplasia is a rare congenital disorder, which can be classified into a non-syndromic form, without extra-adrenal features, and a syndromic form, with such features. Despite biochemical and molecular genetic evaluation, etiologic diagnosis cannot be performed in many patients with adrenal hypoplasia. CASE PRESENTATION: The patient in this case was a boy born at 31 weeks of gestation with a weight of 882 g (< 3rd percentile) to non-consanguineous parents. Genital examination showed micropenis and bilateral cryptorchidism. On the third day of life, he manifested hypotension with high urine output, hyponatremia, hyperkalemia, hypernatriuria, high plasma adrenocorticotropic hormone level, and high plasma renin activity, suggesting acute adrenal insufficiency. The serum 17α-hydroxyprogesterone level was normal. Adrenal insufficiency improved following administration of hydrocortisone and 9α-fludrocortisone, but the patient died of recurrent infection at 4 months of age. He was suspected as IMAGE (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) syndrome. However, no mutation in CDKN1C was identified. Targeted exome sequencing using the TruSight One Sequencing Panel (Illumina) identified a heterozygous mutation of c.2944C > T (p.R982C) in exon 3 in SAMD9. CONCLUSION: This report describes the first Korean case of MIRAGE syndrome. The patient presented with severe primary adrenal insufficiency, intrauterine growth retardation, and recurrent infection. SAMD9 mutation should be considered in patients who present with adrenal hypoplasia and extra-adrenal phenotypes.

Low prevalence of argininosuccinate lyase deficiency among inherited urea cycle disorders in Korea.

Argininosuccinic aciduria (ASA), which is considered to be the second most common urea cycle disorder (UCD), is caused by an argininosuccinate lyase deficiency and is biochemically characterized by elevation of argininosuccinic acid and arginine deficiency. In addition to hyperammonemia, other characteristic features of ASA include hepatic fibrosis, hypertension, neurocognitive deficiencies, and trichorrhexis nodosa. Herein, we retrospectively reviewed the clinical findings, biochemical profiles, and genotypic characteristics of five Korean patients with ASA, who showed typical phenotypes and biochemical findings of the disease. Molecular analysis of these patients revealed six novel ASL mutations. Next, we investigated the prevalence of all types of UCDs in Korea. Of note, over a two decade periods, ASA was only detected in 6.3% of patients with a UCD, which made it the fourth most common UCD in Korea. In comparison with Caucasians, in whom ASA is the second most common UCD, ASA is comparatively rare in East Asian populations, including Japanese and Koreans. These findings suggest the possibility of geographic variation in UCDs among ethnic groups.

Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy.

BACKGROUND: Fabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology. METHODS: Two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry disease RESULTS: After short-term ERT (4-12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, ß-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46-96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients. CONCLUSION: These results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation.

Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening.

BACKGROUND: Fatty acid oxidation disorders (FAODs) include more than 15 distinct disorders with variable clinical manifestations. After the introduction of newborn screening using tandem mass spectrometry, early identification of FAODs became feasible. This study describes the clinical, biochemical and molecular characteristics of FAODs patients detected by newborn screening (NBS) compared with those of 9 patients with symptomatic presentations. METHODS: Clinical and genetic features of FAODs patients diagnosed by NBS and by symptomatic presentations were reviewed. RESULTS: Fourteen patients were diagnosed with FAODs by NBS at the age of 54.8 ± 4.8 days: 5 with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 5 with medium chain acyl-CoA dehydrogenase (MCAD) deficiency, 1 with primary carnitine deficiency, 1 with carnitine palmitoyltransferase 1A (CPT1A) deficiency, 1 with long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCAHD/MTP) deficiency, and 1 with short chain acyl-CoA dehydrogenase (SCAD) deficiency. Three patients with VLCAD or LCHAD/MTP deficiency developed recurrent rhabdomyolysis or cardiomyopathy, and one patient died of cardiomyopathy. The other 10 patients remained neurodevelopmentally normal and asymptomatic during the follow-up. In 8 patients with symptomatic presentation, FAODs manifested as LCHAD/MTP deficiencies by recurrent rhabdomyolysis or cadiomyopathy (6 patients), and VLCAD deficiency by cardiomyopathy (1 patient), and CPT1A deficiency by hepatic failure (1 patient). Two patients with LCHAD/MTP deficiencies died due to severe cardiomyopathy in the neonatal period, and developmental disability was noted in CPT1A deficiency (1 patient). CONCLUSIONS: NBS helped to identify the broad spectrum of FAODs and introduce early intervention to improve the clinical outcome of each patient. However, severe clinical manifestations developed in some patients, indicating that careful, life-long observation is warranted in all FAODs patients.

Novel PTCH1 Gene Mutation in Nevoid Basal Cell Carcinoma Syndrome.

The purpose of this study was to report clinical characteristics, surgical results, and new PTCH1 gene mutations in nevoid basal cell carcinoma syndrome (NBCCS). Five patients were referred to the Department of Oral and Maxillofacial Surgery from local dental clinics between 2006 and 2016 to treat multiple keratocystic odontogenic tumors (KOTs). The cystic lesions were enucleated and peripheral ostectomy was performed to obtain safety margin. Recurrence and/or de novo development of KOT were assessed. Gene analysis using peripheral blood was performed in all patients to identify the mutation of PTCH1 gene. Three patients showed familial history of first-degree relatives. Of the major criteria, all patients presented KOT but only 1 patient had basal cell carcinoma. Of the minor criteria, 4 of the 5 patients presented macrocephaly and hypertelorism. During follow-up periods, all patients showed recurrence and/or de novo development of KOT in the jaw bone. Mutation analysis of PTCH1 gene showed 3 frameshifts (c.817_818ins(T), c.1226_1227ins(A), and c.2748del(C)), 1 splicing (c.1504-2A>T), and 1 missense (c.385T>C) mutation. Mutations were found in exon 1, 6, 9, 17, and intron 10. Regular follow-up is necessary because recurrence rate of KOT was very high. To help early diagnosis, it is essential to routinely perform genetic testing to detect PTCH1 gene mutations among patients with NBCCS.

Mutation Spectrum of STAR and a Founder Effect of the p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia.

Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia, caused by defects in the steroidogenic acute regulatory protein (STAR). The STAR p.Q258* mutation is the most common mutation in China, Japan, and Korea, suggesting a founder effect. This study aimed to investigate the phenotypic and mutation spectrum of STAR defects and identify a founder effect of the p.Q258* mutation in Korean patients with CLAH. For 45 patients from 42 independent pedigrees, haplotype analysis was performed in 10 unrelated trio families, including patients with the p.Q258* mutation whose DNA samples were available, using 1,972 single nucleotide polymorphism (SNP) and six short tandem repeat (STR) markers. An Illumina Infinium® Human Omni2.5-8 v1.3 performed the SNP genotyping. Among 84 alleles from 42 unrelated families, mutation p.Q258* was found in 74 alleles (88.1%) from 41 families. A shared haplotype was identified in 17 of 20 alleles from 10 patients (size, 198 kb). The age of the founder mutation was estimated as 4,875 years (95% credible set: 3,575-7,925 years) assuming an intergenerational time interval of 25 years. The STAR p.Q258* mutation is the most common in Korean patients with CLAH, suggesting a founder effect. The age of the mutation corresponded with the date when the Korean people settled in the Korean peninsula. The high prevalence of p.Q258* in Japan and China also suggests a founder effect in Asian countries.

Biochemical and molecular characteristics of citrin deficiency in Korean children.

Mutations in SLC25A13 cause citrin deficiency, which has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and adult-onset type 2 citrullinemia (CTLN2). The purpose of this study was to determine the mutation spectrum and the clinical and biochemical characteristics of citrin deficiency in Korean patients. Thirty-four patients were diagnosed with citrin deficiency based on mutations in SLC25A13, as verified by direct sequencing and long PCR screening of a large transposon insertion. A total of 66 alleles from 33 unrelated families of 34 patients with citrin deficiency (27 NICCD, 2 FTTDCD and 5 CTLN2) were retrospectively identified. The common pathogenic alleles were IVS16ins3kb (33%), c.851_854del (30%) and c.1177+1G>A (12%), and three novel variants were identified. Levels of citrulline, threonine, methionine, tyrosine and arginine and the threonine-to-serine ratio were higher in children with neonatal intrahepatic cholestasis caused by NICCD compared with that in patients with idiopathic neonatal hepatitis (INH). We concluded that Korean patients with citrin deficiency showed the highest frequency of the IVS16ins3kb mutation and that plasma amino-acid profiles can be used to differentiate between NICCD and INH.

DEND Syndrome with Heterozygous KCNJ11 Mutation Successfully Treated with Sulfonylurea.

Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (KATP channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.

Genotype and Phenotype Analysis in Pediatric Patients with Cystinuria.

Cystinuria is an inherited disorder characterized by defective renal reabsorption of cystine and dibasic amino acids leading to nephrolithiasis. This study was conducted to analyze the genotypes and phenotypes of pediatric patients with cystinuria. Eight children from Seoul National University Hospital and Asan Medical Center presenting with cystinuria from January 2003 to June 2016 were retrospectively analyzed. Mutational studies were performed by direct sequencing. Two of the 8 were male and 6 were female. The median ages at onset and diagnosis were 1.5 (range, 0.3-13.6) and 2.6 (range, 0.7-16.7) years, respectively. The median followed up was 7.7 (range, 3.4-14.0) years. Mutational analyses were performed in 7 patients and revealed biallelic SLC3A1 mutations (AA genotype) in 4 patients, a single heterozygous SLC3A1 mutation (A- genotype) in 1 patient, biallelic SLC7A9 mutations (BB genotype) in 1 patient, and a single heterozygous SLC7A9 mutation (B- genotype) in 1 patient. Two of the mutations were novel. No genotype-phenotype correlations were observed, except for earlier onset age in patients with non-AA genotypes than in patients with the AA genotype. All patients suffered from recurrent attacks of symptomatic nephrolithiasis, which lead to urologic interventions. At the last follow-up, 3 patients had a mild-to-moderate degree of renal dysfunction. This is the first study of genotypic and phenotypic analyses of patients with cystinuria in Korea.

Long-term enzyme replacement therapy for Fabry disease: efficacy and unmet needs in cardiac and renal outcomes.

Fabry disease is a progressive lysosomal storage disease caused by alpha-galactosidase A deficiency. This condition is characterized by progressive accumulation of glycosphingolipids with functional impairment in various organs, including the kidney, heart and cerebrovascular system. Enzyme replacement therapy (ERT) is essential because it attenuates the disease progression. The present study investigated the long-term efficacy of ERT in 19 Korean Fabry patients (11 adult males, 4 symptomatic female carriers and 4 pediatric males) who had received ERT for 8.1±2.2 years (range, 5.3-10.5 years). In the 11 adult males, the mean reduction in the estimated glomerular filtration rate (eGFR) was -3.8±4.5 ml-1 min 1.73 m-2. The rate of eGFR decline was significantly lower in patients with lower proteinuria (<1 g per day) before ERT. The left ventricular mass index decreased or was stable throughout the ERT in male patients with or without left ventricular hypertrophy before ERT initiation. In female carriers and pediatric male patients, renal and cardiac functions remained stable with ERT. Arrhythmias were observed in 10 adult males and 1 female patient before ERT and persisted during ERT. One pediatric patient newly developed arrhythmia despite ERT. In conclusion, long-term ERT has beneficial effects on the renal and cardiac outcomes of Fabry patients but has limited effect in patients with irreversible organ damage. Identification of patients in the early disease stage and rapid ERT initiation might be the best strategy to improve the natural course of the disease.

Cardiac Manifestations and Associations with Gene Mutations in Patients Diagnosed with RASopathies.

RASopathies are a group of syndromes caused by germline mutations of the RAS/MAPK pathway. They include Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines, which share many characteristic features including cardiac abnormalities. Here, we retrospectively reviewed the clinical manifestations and evaluated the genotype-phenotype associations with special focus on cardiac lesions of the patients with RASopathies. Cardiac symptoms were the most common initial presentation (27 %), except for admission to neonatal intensive care. Although there was a significant gap between the first visit to the hospital and the diagnosis of the genetic syndrome (19.9 ± 39.1 months), the age at the clinical diagnosis of the genetic syndrome was significantly lower in patients with CHD than in patients without CHD (47.26 ± 67.42 vs. 86.17 ± 85.66 months, p = 0.005). A wide spectrum of cardiac lesions was detected in 76.1 % (118/155) of included patients. The most common lesion was pulmonary stenosis, followed by atrial septal defect and hypertrophic cardiomyopathy (HCMP). About half of the pulmonary stenosis and HCMP patients progressed during the median follow-up period of 109.9 (range 9.7-315.4) months. Early rapid aggravation of cardiac lesions was linked to poor prognosis. MEK1, KRAS, and SOS1 mutations tend to be highly associated with pulmonary stenosis. Cardiologists may play important roles in early detection and diagnosis of RASopathies as well as associated CHDs. Due to the variety of clinical presentations and their progression of severity, proper management with regular long-term follow-up of these patients is essential.