Publications by authors named "Han-Wook Yoo"

258 Publications

Endocrine Complications in Children and Adolescents With Non-Central Nervous System Solid Tumors.

Front Endocrinol (Lausanne) 2021 17;12:610730. Epub 2021 Mar 17.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea.

Background: Due to remarkable progress in cancer treatment, endocrine complications are now the major medical issues facing childhood cancer survivors. Although non-central nervous system solid tumors (NCSTs) account for approximately 40% of all pediatric cancers, there have been few studies on endocrine complications associated with NCSTs. This study investigated endocrinopathies following the treatment of pediatric NCSTs.

Design And Setting: Retrospective study in a single academic center.

Methods: This study analyzed 253 survivors of childhood NCSTs who were diagnosed between January of 2000 and December of 2018. The medical charts were reviewed regarding the frequency of endocrinopathies and treatment modalities. The hazard ratios were assessed by multivariable Cox regression analysis. The final height-SDS were analyzed by multivariable linear regression analysis.

Results: There were 76 patients (30%) that developed at least one endocrine complication. Forty-four patients (17.4%) experienced endocrine complications within five years of their cancer diagnosis. The most common endocrine complication was growth failure (n = 35), followed by obesity (n = 18), and primary gonadal failure (n = 16). High cumulative doses of alkylating agents increased the risk of developing at least one endocrine complication. Hematopoietic stem cell transplantation was an important risk factor for primary gonadal failure.

Conclusions: This study described the comprehensive endocrine outcomes, including growth failure, obesity, primary gonadal failure, primary hypothyroidism, dyslipidemia, and osteoporosis, following the treatment of childhood NCSTs. As endocrinopathies occurred within five years of primary tumor diagnosis, surveillance for endocrine dysfunction is required for early intervention and management.
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http://dx.doi.org/10.3389/fendo.2021.610730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011158PMC
March 2021

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

BMC Pediatr 2021 Mar 4;21(1):108. Epub 2021 Mar 4.

Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.

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, β-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.
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http://dx.doi.org/10.1186/s12887-021-02575-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931559PMC
March 2021

Direct Measurement of ATP7B Peptides is Highly Effective in the Diagnosis of Wilson Disease.

Gastroenterology 2021 Feb 25. Epub 2021 Feb 25.

Seattle Children's Research Institute; University of Washington School of Medicine, Seattle, WA U.S.A. Electronic address:

Background And Aims: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson's Disease (WD) often creating ambiguities in patient identification leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot (DBS) samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared to biochemical and genetic results from individual patients.

Methods: 264 samples from biorepositories at three international and two domestic academic centers and 150 normal controls were obtained after IRB approval. Genetically or clinically confirmed WD patients with a Leipzig score over 3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry.

Results: Two ATP7B peptides were used to measure ATP7B protein concentration. ROC curve analysis generates an AUC of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value (PPV) of 98.0%, and a negative predictive (NPV) value of 91.5%. In patients with normal ceruloplasmin concentrations (> 20 mg/dL), 14/16 (87.5%) were ATP7B deficient. In patients without clear genetic results, 94% were ATP7B deficient.

Conclusions: Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from Cp and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in non-invasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.
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http://dx.doi.org/10.1053/j.gastro.2021.02.052DOI Listing
February 2021

Inborn Errors of Mitochondrial Fatty Acid Oxidation: Overview from a Clinical Perspective.

Authors:
Han-Wook Yoo

J Lipid Atheroscler 2021 Jan 1;10(1):1-7. Epub 2020 Dec 1.

Department of Pediatrics and Medical Genetics & Genomics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Mitochondrial fatty acid β-oxidation (mFAO), which is the major pathway for the degradation of fatty acids and is critical for maintaining energy homeostasis in the human body, consists of carnitine transport, the carnitine shuttle, and fatty acid β-oxidation. Inherited metabolic defects of mFAO result in more than 15 distinct mFAO disorders (mFAODs) with varying clinical manifestations. The common elements of the clinical presentation of mFAODs are hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis, indicating the importance of FAO during fasting or stressful situations. The management of all mFAODs includes avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine or appropriate nutritional support, if necessary. Through the introduction of newborn screening using tandem mass spectrometry, early identification of mFAODs became feasible, leading to an early initiation of treatment with improved outcomes. However, many unmet needs remain with regard to the long-term management of patients with mFAODs.
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http://dx.doi.org/10.12997/jla.2021.10.1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838517PMC
January 2021

Growth, puberty, and bone health in children and adolescents with inflammatory bowel disease.

BMC Pediatr 2021 Jan 14;21(1):35. Epub 2021 Jan 14.

Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, 05505, Seoul, Republic of Korea.

Background: Endocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents.

Methods: This study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D [25(OH)D] levels, and BMD were reviewed retrospectively.

Results: Short stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below - 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased.

Conclusions: Vitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health.
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http://dx.doi.org/10.1186/s12887-021-02496-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807425PMC
January 2021

The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects.

Orphanet J Rare Dis 2020 11 11;15(1):318. Epub 2020 Nov 11.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea.

Background: Gaucher disease (GD) is caused by a deficiency of β-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients.

Results: The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2-57) years. No patients developed neurological symptoms during follow-up periods of 2.2-20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3075 years.

Conclusion: The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.
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http://dx.doi.org/10.1186/s13023-020-01597-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656680PMC
November 2020

Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.

J Med Genet 2020 Oct 13. Epub 2020 Oct 13.

Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea

Background: ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway.

Methods: The phenotypes of 22 patients with either an heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with haploinsufficiency as well as using the mouse model of haploinsufficiency by CRISPR/Cas9 gene editing.

Results: The phenotypic characteristics of deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, haploinsufficient mice exhibited reduced body size and learning/memory deficit. haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation.

Discussion: haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.
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http://dx.doi.org/10.1136/jmedgenet-2020-107111DOI Listing
October 2020

A late-onset male Fabry disease patient with somatic mosaicism of a classical GLA mutation: a case report.

Ann Palliat Med 2020 Sep 27. Epub 2020 Sep 27.

Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA). Male patients of FD develop early sign and symptoms in childhood or adolescence. However, "de novo somatic mosaicism" is rare and might be developed a relatively mild phenotype despite carrying a classic type. A 34-year-old male patient visited with foamy urine. Renal biopsy findings were consistent with FD. Leukocyte α-galactosidase activity was markedly reduced at 5.3 nmol/hr/mg (normal range, 25-126). Sequence analysis of the patient's GLA gene identified mosaicism for the mutation GLA[NM_000169.2] c.820=/G>C. This mutation results in a substitution of the amino acid in position 274 from glycine to arginine. However, no family members showed FD-related symptoms, and the daughter of the patient was also tested for paternity and was identified as a real biological daughter, but DNA sequence analysis for FD showed no mutations. Based on these results, we diagnosed the patients as de novo mutation with somatic mosaicism. Next generation sequencing turned out that 58% of the readings had the mutated allele in buccal cells, 84% in blood, and 85% in urine, when 100% should be expected in a hemizygous affected male confirming the presence of somatic mosaicisms. The patient has been on treatment for enzyme replacement therapy (agalsidase-β, 1.0 mg/kg biweekly) for past 9 years and has maintained normal renal function (serum creatinine 1.0 mg/dL) with mild albuminuria (123 mg/g Cr). Therefore, this case suggests somatic mosaicism is one of important phenotype modifiers.
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http://dx.doi.org/10.21037/apm-19-635DOI Listing
September 2020

Clinical and molecular spectra of BRAF-associated RASopathy.

J Hum Genet 2021 Apr 10;66(4):389-399. Epub 2020 Oct 10.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea.

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.
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http://dx.doi.org/10.1038/s10038-020-00852-3DOI Listing
April 2021

Molecular Characteristics of Sequence Variants in GATA4 in Patients with 46,XY Disorders of Sex Development without Cardiac Defects.

Sex Dev 2019 26;13(5-6):240-245. Epub 2020 Sep 26.

A GATA4 haploinsufficiency has been well described in patients with congenital heart defects (CHDs), whilst only a few studies have reported mutations related to a 46,XY disorder of sex development (DSD) phenotype. This study investigated the clinical phenotypes and molecular characteristics of two 46,XY DSD patients harboring GATA4 variants. Mutation analysis was performed using a targeted gene panel or whole-exome sequencing. The transactivation activity of each variant protein was examined by in vitro luciferase reporter assay using the AMH and SRY promoters. Subject 1 presented with a micropenis and hypospadias. Subject 2 showed complete female external genitalia with a 46,XY karyotype. Both patients were responsive to hCG stimulation tests and did not manifest CHD. A novel heterozygous variant, c.643A>G (p.R215G), in GATA4 was identified in Subject 1, whereas Subject 2 harbored a previously reported variant, c.1220C>A (p.P407Q), in GATA4 and a previously known pathogenic mutation, i.e., c.226C>T (p.Q76*) in the AR gene. The reporter assays using the SRY and AMH promoters revealed decreased transcriptional activity of both p.P407Q and p.R215G. However, the GATA4 p.P407Q variant was classified as likely benign. In conclusion, it is essential to integrate clinical features and endocrine findings when interpreting sequence variants.
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http://dx.doi.org/10.1159/000511258DOI Listing
September 2020

Correction to: SHP2 mutations induce precocious gliogenesis of Noonan syndrome-derived iPSCs during neural development in vitro.

Stem Cell Res Ther 2020 Jul 16;11(1):282. Epub 2020 Jul 16.

Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13287-020-01775-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364466PMC
July 2020

Efficacy and safety of parenteral vitamin D therapy in infants and children with vitamin D deficiency caused by intestinal malabsorption.

Ann Pediatr Endocrinol Metab 2020 Jun 30;25(2):112-117. Epub 2020 Jun 30.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Oral supplementation of vitamin D can be inefficient in patients with vitamin D deficiency caused by intestinal malabsorption. This study investigated the efficacy and safety of parenteral vitamin D supplementation in infants and children with vitamin D deficiency caused by intestinal malabsorption.

Methods: This study included 11 patients with vitamin D deficiency who were unresponsive to oral vitamin D or were unable to try oral vitamin D therapy due to underlying conditions. All patients were treated with weekly intramuscular injection of cholecalciferol 50,000 IU. Radiological findings and biochemical parameters including serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D3 (25(OH)D3), and parathyroid hormone levels were reviewed retrospectively.

Results: Underlying diseases included small bowel atresia (n=3), necrotizing enterocolitis (n=3), congenital megacolon (n=2), chronic intestinal pseudoobstruction (n=1), congenital mesenteric band (n=1), and Crohn disease (n=1). Three patients exhibited rickets on X-ray findings. The mean duration of treatment was 4.8±2.9 weeks. The alkaline phosphatase levels were decreased from 710±650 IU/L to 442±284 IU/L (P=0.143). The 25(OH)D3 level was increased from 6.0±3.4 ng/mL to 50.4±28.8 ng/mL (P=0.008) after 3 months. Two patients with rickets showed improved radiologic findings after parenteral treatment.

Conclusion: Parenteral vitamin D therapy was effective and safe in patients with vitamin D deficiency caused by intestinal malabsorption. Long-term follow-up is needed to establish the efficacy of parenteral vitamin D therapy in a large number of patients.
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http://dx.doi.org/10.6065/apem.1938142.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336258PMC
June 2020

Clinical, endocrinological, and molecular features of four Korean cases of cytochrome P450 oxidoreductase deficiency.

Ann Pediatr Endocrinol Metab 2020 Jun 30;25(2):97-103. Epub 2020 Jun 30.

Depar tment of Pediatrics, Asan Medical Center, Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder caused by mutations in the POR gene encoding an electron donor for all microsomal P450 enzymes. It is characterized by adrenal insufficiency, ambiguous genitalia, maternal virilization during pregnancy, and skeletal dysplasia. In this study, we investigated the clinical, hormonal, and molecular characteristics of patients with POR deficiency in Korea.

Methods: This study included four patients with POR deficiency confirmed by biochemical and molecular analysis of POR. Clinical and biochemical findings were reviewed retrospectively. Mutation analysis of POR was performed by Sanger sequencing after polymerase chain reaction amplification of all coding exons and the exon-intron boundaries.

Results: All patients presented with adrenal insufficiency and ambiguous genitalia regardless of their genetic sex. Two patients harbored homozygous p.R457H mutations in POR and presented with adrenal insufficiency and genital ambiguity without skeletal phenotypes. The other two patients with compound heterozygous mutations of c.[1329_1330insC];[1370G>A] (p.[I444Hfs*6];[R457H]) manifested skeletal abnormalities, such as craniosynostosis and radiohumeral synostosis, suggesting Antley-Bixler syndrome. They also had multiple congenital anomalies involving heart, kidney, and hearing ability. All patients were treated with physiologic doses of oral hydrocortisone.

Conclusion: We report the cases of 4 patients with POR deficiency identified by mutation analysis of POR. Although the study involved a small number of patients, the POR p.R457H mutation was the most common, suggesting founder effect in Korea. POR deficiency is rare and can be misdiagnosed as 21-hydroxylase or 17α-hydroxylase/17,20-lyase deficiency. Therefore, molecular analysis is critical for confirmatory diagnosis.
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http://dx.doi.org/10.6065/apem.1938152.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336261PMC
June 2020

Efficacy and Safety Evaluation of Human Growth Hormone Therapy in Patients with Idiopathic Short Stature in Korea - A Randomised Controlled Trial.

Eur Endocrinol 2020 Apr 15;16(1):54-59. Epub 2019 Oct 15.

Severance Hospital, Yonsei University Health System, Seoul, South Korea.

Background: This trial evaluated the efficacy and safety of growth hormone (GH) therapy (Norditropin®; Novo Nordisk, Bagsværd, Denmark) in paediatric patients with idiopathic short stature (ISS) in Korea.

Methods: This was an open-label, parallel-group, multicentre, interventional trial (ClinicalTrials.gov identifier: NCT01778023). Pre-pubertal patients (mean age 6.2 years; height, 107.1 cm) were randomised 2:1 to 12 months' GH treatment (0.469 mg/kg/week; group A, n=36) or 6 months untreated followed by 6 months' GH treatment (group B, n=18). Safety analysis was based on adverse events (AEs) in all GH-treated patients.

Results: After 6 months, height velocity (Ht-V), change in both height standard deviation score (Ht-SDS) and insulin-like growth factor 1 (mean difference [95% confidence interval {CI}]: 5.15 cm/year [4.09, 6.21]; 0.57 [0.43, 0.71]; 164.56 ng/mL [112.04, 217.08], respectively; all p<0.0001) were greater in group A than in group B. Mean difference in Ht-V for 0-6 months versus 6-12 months was 2.80 cm/year (95% CI 1.55, 4.04) for group A and -4.60 cm/year (95% CI -6.12, -3.09; both p<0.0001) for group B. No unexpected AEs were reported.

Conclusions: During the first 6 months, height was significantly increased in GH-treated patients versus untreated patients with ISS. Safety of GH was consistent with the known safety profile.
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http://dx.doi.org/10.17925/EE.2020.16.1.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308103PMC
April 2020

SHP2 mutations induce precocious gliogenesis of Noonan syndrome-derived iPSCs during neural development in vitro.

Stem Cell Res Ther 2020 06 3;11(1):209. Epub 2020 Jun 3.

Department of Biological Sciences, KAIST, Daejeon, 34141, Republic of Korea.

Background: Noonan syndrome (NS) is a developmental disorder caused by mutations of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2). Although NS patients have diverse neurological manifestations, the mechanisms underlying the involvement of SHP2 mutations in neurological dysfunction remain elusive.

Methods: Induced pluripotent stem cells generated from dermal fibroblasts of three NS-patients (NS-iPSCs) differentiated to the neural cells by using two different culture systems, 2D- and 3D-cultured systems in vitro.

Results: Here we represent that SHP2 mutations cause aberrant neural development. The NS-iPSCs exhibited impaired development of EBs in which BMP and TGF-β signalings were activated. Defective early neuroectodermal development of NS-iPSCs recovered by inhibition of both signalings and further differentiated into NPCs. Intriguingly, neural cells developed from NS-NPCs exhibited abundancy of the glial cells, neurites of neuronal cells, and low electrophysiological property. Those aberrant phenotypes were also detected in NS-cerebral organoids. SHP2 inhibition in the NS-NPCs and NS-cerebral organoids ameliorated those anomalies such as biased glial differentiation and low neural activity.

Conclusion: Our findings demonstrate that SHP2 mutations contribute to precocious gliogenesis in NS-iPSCs during neural development in vitro.
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http://dx.doi.org/10.1186/s13287-020-01709-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268229PMC
June 2020

Functional Characteristics of Novel FGFR1 Mutations in Patients with Isolated Gonadotropin-Releasing Hormone Deficiency.

Exp Clin Endocrinol Diabetes 2020 Jun 2. Epub 2020 Jun 2.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Background: Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) has a wide phenotypic spectrum including Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). mutations have been identified in 3-10% of patients with KS or nIHH. This study was performed to investigate clinical phenotypes and functional characteristics of mutations in patients with IGD.

Methods: This study included 8 patients (from 7 families) with mutations identified by targeted gene panel sequencing or whole exome sequencing (WES). The impact of the identified mutations on FGFR1 function was assessed using studies.

Results: Seven heterozygous mutations in were identified in 8 patients from 7 independent families. The patients exhibited a wide spectrum of pubertal development, including anosmia in a prepubertal boy (n=1), delayed puberty (n=2), nIHH (n=3), and KS (n=2). Four of the mutations were classified as likely pathogenic, and the other three were variants of uncertain significance. FGF8-FGFR1 signaling activities for the novel FGFR1 variants (p.Y339H, p.S681I, and p.N185Kfs*16) were reduced by functional assay, indicating loss-of-function mutations.

Conclusions: This study identified seven rare sequence variants in in patients with KS and nIHH. Probands with an mutations displayed a wide phenotypic spectrum ranging from KS to anosmia. A prepubertal male with anosmia should be followed up to assess pubertal development because they can manifest hypogonadotropic hypogonadism after puberty. These results expand the phenotypic spectrum of mutations and suggest a broader biologic role of FGFR1 in reproduction.
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http://dx.doi.org/10.1055/a-1151-4800DOI Listing
June 2020

Human Embryonic Stem Cell-Derived Wilson's Disease Model for Screening Drug Efficacy.

Cells 2020 04 2;9(4). Epub 2020 Apr 2.

Department of Stem Cell Research, NEXEL Co., Ltd., 8th floor, 55, Magokdong-ro, Gangseo-gu, Seoul 07802, Korea.

Human pluripotent stem cells (hPSCs) including human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) have been extensively studied as an alternative cellular model for recapitulating phenotypic and pathophysiologic characters of human diseases. Particularly, hiPSCs generated from the genetic disease somatic cells could provide a good cellular model to screen potential drugs for treating human genetic disorders. However, the patient-derived cellular model has a limitation when the patient samples bearing genetic mutations are difficult to obtain due to their rarity. Thus, in this study, we explored the potential use of hPSC-derived Wilson's disease model generated without a patient sample to provide an alternative approach for modeling human genetic disease by applying gene editing technology. Wilson's disease hPSCs were generated by introducing a R778L mutation in the gene (c.2333G>T) using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system into wildtype hESCs. Established Wilson's disease hESCs were further differentiated into hepatocyte-like cells (HLCs) and analyzed for disease phenotypes and responses against therapeutic agent treatment. R778L mutation in the gene was successfully introduced into wildtype hESCs, and the introduction of the mutation neither altered the self-renewal ability of hESCs nor the differentiation capability into HLCs. However, R778L mutation-introduced HLCs exhibited higher vulnerability against excessive copper supplementation than wildtype HLCs. Finally, the applicability of the R778L mutation introduced HLCs in drug screening was further demonstrated using therapeutic agents against the Wilson's diseases. Therefore, the established model in this study could effectively mimic the Wilson's disease without patient's somatic cells and could provide a reliable alternative model for studying and drug screening of Wilson's disease.
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http://dx.doi.org/10.3390/cells9040872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226780PMC
April 2020

The definition of neuronopathic Gaucher disease.

J Inherit Metab Dis 2020 09 3;43(5):1056-1059. Epub 2020 Apr 3.

Gaucher Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.
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http://dx.doi.org/10.1002/jimd.12235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540563PMC
September 2020

Use of a rare disease registry for establishing phenotypic classification of previously unassigned variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup.

J Med Genet 2020 08 11;57(8):542-551. Epub 2020 Mar 11.

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: Fabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified variants from the -specific fabry-database.org database.

Methods: A Fabry disease genotype-phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan-Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes.

Results: Final consensus on classifications of 'pathogenic' was achieved for 32 of 33 variants (26 'classic' phenotype, 171 males; 6 'later-onset' phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between 'classic' and 'later-onset' phenotypes.

Conclusion: The iterative system implemented by a Fabry disease genotype-phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants.
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http://dx.doi.org/10.1136/jmedgenet-2019-106467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418626PMC
August 2020

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

J Hum Genet 2020 Jun 6;65(6):551-555. Epub 2020 Mar 6.

Department of Pediatrics & Medical Genetics, Asan Medical, Center University of Ulsan College of Medicine, Seoul, South Korea.

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.
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http://dx.doi.org/10.1038/s10038-020-0735-9DOI Listing
June 2020

Predominance of the c.648G > T G6PC gene mutation and late complications in Korean patients with glycogen storage disease type Ia.

Orphanet J Rare Dis 2020 02 11;15(1):45. Epub 2020 Feb 11.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan, College of Medicine, Seoul, Korea.

Background: Glycogen storage disease (GSD) Ia, caused by mutations in the glucose-6-phosphatase (G6PC) gene, is characterized by hepatomegaly, hypoglycemia, lactic acidosis, dyslipidemia, and hyperuricemia. This study aimed to investigate clinical and molecular features and late complications in Korean patients with GSD Ia.

Results: Fifty-four Korean patients (33 males and 21 females) from 47 unrelated families, who were diagnosed with GSD Ia, based on genetic and biochemical data, between 1999 and 2017, were included in this study. The median age at diagnosis was 3.9 years (range: 5 months to 42 years), and the follow-up period was 8.0 ± 6.8 years. Most patients presented with hepatomegaly during infancy, but hypoglycemic symptoms were not predominant. Genetic analysis showed that all the patients had at least one c.648G > T allele. Homozygous c.648G > T mutations in the G6PC gene were identified in 34 families (72.3%), and compound heterozygotes with c.648G > T were found in the other families. The allele frequency of c.648G > T was 86.2% (81/94), and p.F51S, p.R83H, p.G122D, p.Y128*, p.G222R, and p.T255A were identified. Of 26 adult patients, 14 had multiple hepatic adenomas, and two were diagnosed with hepatocellular carcinoma. Thirteen patients showed renal complications, and seven patients presented gout, despite preventive allopurinol treatment. Twelve patients had osteoporosis, and two patients had pulmonary hypertension. The final heights were 157.9 cm (standard deviation score: - 3.1) in males and 157.8 cm (standard deviation score: - 0.6) in females.

Conclusion: In our Korean patients with GSD Ia, the most common mutation in the G6PC gene was c.648G > T, suggesting a founder effect. Because of only mild hypoglycemia, the patients tended to be diagnosed late. Thus, adult patients with GSD Ia eventually developed diverse and serious complications, which indicates a need for careful monitoring and proper management of this disease.
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http://dx.doi.org/10.1186/s13023-020-1321-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014716PMC
February 2020

Enhanced thrombospondin-1 causes dysfunction of vascular endothelial cells derived from Fabry disease-induced pluripotent stem cells.

EBioMedicine 2020 Feb 23;52:102633. Epub 2020 Jan 23.

Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea. Electronic address:

Background: Fabry disease (FD) is a recessive X-linked lysosomal storage disorder caused by α-galactosidase A (GLA) deficiency. Although the mechanism is unclear, GLA deficiency causes an accumulation of globotriaosylceramide (Gb3), leading to vasculopathy.

Methods: To explore the relationship between the accumulation of Gb3 and vasculopathy, induced pluripotent stem cells generated from four Fabry patients (FD-iPSCs) were differentiated into vascular endothelial cells (VECs). Genome editing using CRISPR-Cas9 system was carried out to correct the GLA mutation or to delete Thrombospondin-1 (TSP-1). Global transcriptomes were compared between wild-type (WT)- and FD-VECs by RNA-sequencing analysis.

Findings: Here, we report that overexpression of TSP-1 contributes to the dysfunction of VECs in FD. VECs originating from FD-iPSCs (FD-VECs) showed aberrant angiogenic functionality even upon treatment with recombinant α-galactosidase. Intriguingly, FD-VECs produced more p-SMAD2 and TSP-1 than WT-VECs. We also found elevated TSP-1 in the peritubular capillaries of renal tissues biopsied from FD patients. Inhibition of SMAD2 signaling or knock out of TSP-1 (TSP-1) rescues normal vascular functionality in FD-VECs, like in gene-corrected FD-VECs. In addition, the enhanced oxygen consumption rate is reduced in TSP-1 FD-VECs.

Interpretation: The overexpression of TSP-1 secondary to Gb3 accumulation is primarily responsible for the observed FD-VEC dysfunction. Our findings implicate dysfunctional VEC angiogenesis in the peritubular capillaries in some of the complications of Fabry disease.

Funding: This study was supported by grant 2018M3A9H1078330 from the National Research Foundation of the Republic of Korea.
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http://dx.doi.org/10.1016/j.ebiom.2020.102633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992938PMC
February 2020

Development of tablet personal computer-based cognitive training programs for children with developmental disabilities whose cognitive age is less than 4 years.

Medicine (Baltimore) 2020 Jan;99(2):e18674

Department of Rehabilitation Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

This study was to develop tablet personal computer-based cognitive training programs for children with developmental disabilities whose cognitive age is less than 4 years. Twelve cognitive training programs (named Injini) were designed comprising cognitive domains that included attention, visual and auditory perception, memory, executive function, language, and reasoning. In addition, programs related to learning experiences, such as self-regulation, role play, learning of number, and letter/shape concepts, comparison, classification, and pattern matching, were included. Six of 12 programs comprised approximately 10 levels for each program, with different difficulty levels. Other programs consisted of universal tasks that did not have a difficulty level. To ensure that the difficulty level was appropriate, we pre-tested the pilot version of Injini among 80 children with typical development aged 18 to 41 months. After modifying the pilot version, we developed the final version and tested it among 80 children with cognitive impairment whose cognitive age was 18 to 41 months. All children were assessed using the Bayley Scales of Infant and Toddler Development to determine their development and cognitive age. The difficulty level analyses in children with typical development revealed several inappropriate results wherein the success rate did not decrease with increase in level in some programs. After adjusting the difficulty level, the analyses in children with cognitive impairment demonstrated that the success rate gradually decreased with increasing level in all programs. Cognitive training programs for children with developmental disabilities were successfully developed.
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http://dx.doi.org/10.1097/MD.0000000000018674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959963PMC
January 2020

Pubertal outcomes and sex of rearing of patients with ovotesticular disorder of sex development and mixed gonadal dysgenesis.

Ann Pediatr Endocrinol Metab 2019 Dec 31;24(4):231-236. Epub 2019 Dec 31.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic variations in internal and external genitalia. The differential diagnosis of these conditions is based on karyotype and pathological findings of the gonads. This study investigated the clinical features at presentation, karyotype, sex of rearing, and pubertal outcomes of patients with ovotesticular DSD and MGD.

Methods: The study comprised 23 patients with DSD who presented with asymmetric gonads. The presenting features, karyotype, sex of rearing, and pubertal outcomes were reviewed retrospectively.

Results: All 23 patients presented with ambiguous genitalia at a median age of 1 month (range, 1 day-1.6 years). Müllerian duct remnants were identified in 15 of 23 patients (65.2%). Fourteen patients were diagnosed with ovotesticular DSD, whereas the other 9 were diagnosed with MGD. Eight of 14 patients (57.1%) with ovotesticular DSD were raised as males, while 7 of 9 patients with MGD (77.8%) were assigned as males. One male-assigned patient with ovotesticular DSD changed to female sex at age 20 years.

Conclusion: Patients with ovotesticular DSD and MGD manifest overlapping clinical presentations and hormonal profiles. It is difficult to determine the sex of rearing and predict long-term pubertal outcomes. Therefore, long-term follow-up is required to monitor spontaneous puberty, sex outcome, and urological and gynecological complications.
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http://dx.doi.org/10.6065/apem.2019.24.4.231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944855PMC
December 2019

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

J Hum Genet 2020 Jan 28;65(2):79-89. Epub 2019 Nov 28.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.

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.
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http://dx.doi.org/10.1038/s10038-019-0695-0DOI Listing
January 2020

Niemann-Pick Disease Type C Misdiagnosed as Cerebral Palsy: A Case Report.

Ann Rehabil Med 2019 Oct 31;43(5):621-624. Epub 2019 Oct 31.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Niemann-Pick disease type C (NP-C) is a rare autosomal recessive neurovisceral lysosomal lipid storage disorder. The clinical manifestations of the disorder are variable. This report describes the case of a 27-month-old girl with NP-C whose condition had been misdiagnosed as spastic cerebral palsy (CP). She had spasticity, particularly at both ankles, and gait disturbance. Magnetic resonance imaging of the brain revealed findings suspicious of sequelae from a previous insult, such as periventricular leukomalacia, leading to the diagnosis of CP. However, she had a history of hepatosplenomegaly when she was a fetus and her motor development had deteriorated, with symptoms of vertical supranuclear gaze palsy, cataplexy, and ataxia developing gradually. Therefore, NP-C was considered and confirmed with a genetic study, which showed mutation of the NPC1 gene. Thus, if a child with CP-like symptoms presents with a deteriorating course and NP-C-specific symptoms, NP-C should be cautiously considered.
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http://dx.doi.org/10.5535/arm.2019.43.5.621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835131PMC
October 2019

Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy.

J Med Genet 2020 02 24;57(2):124-131. Epub 2019 Oct 24.

Department of Pediatrics, Asan Medical Center Children's Hospital, College of Medicine University of Ulsan, Seoul, The Republic of Korea

Background: Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.

Methods: ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.

Results: Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.

Conclusions: Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.
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http://dx.doi.org/10.1136/jmedgenet-2019-106132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029246PMC
February 2020

Novel Gene Mutations in a Child with Progressive Familial Intrahepatic Cholestasis Type 1.

Pediatr Gastroenterol Hepatol Nutr 2019 Sep 11;22(5):479-486. Epub 2019 Sep 11.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic disorders, inherited in an autosomal recessive manner, causing cholestasis of hepatocellular origin, later progressing to biliary cirrhosis and liver failure. This is the first report of PFIC type 1 with novel compound heterozygous mutations in Korea. The patient was presented with intrahepatic cholestasis, a normal level of serum γ-glutamyl transferase, steatorrhea, and growth failure. Genetic testing of this patient revealed novel compound heterozygous mutations (p.Glu585Ter and p.Leu749Pro) in the gene. After a liver transplantation at age 19 months, the patient developed severe post-transplant steatohepatitis.
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http://dx.doi.org/10.5223/pghn.2019.22.5.479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751104PMC
September 2019

Effects of recombinant human growth hormone treatment on growth, body composition, and safety in infants or toddlers with Prader-Willi syndrome: a randomized, active-controlled trial.

Orphanet J Rare Dis 2019 09 11;14(1):216. Epub 2019 Sep 11.

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: Prader-Willi syndrome (PWS) is a rare complex genetic disorder and is characterized by short stature, muscular hypotonia, abnormal body composition, psychomotor retardation, and hyperphagia. Recombinant human growth hormone (rhGH) treatment improves the symptoms in children with PWS, and early treatment results in more favorable outcomes. However, systematic studies in infants and toddlers under 2 years of age are lacking. This multicenter, randomized, active-controlled, parallel-group, open-label, Phase III study aimed to evaluate the safety of rhGH (Eutropin, LG Chem, Ltd.) and its efficacy on growth, body composition, and motor and cognitive development in infants and toddlers with PWS compared with a comparator treatment (Genotropin, Pfizer, Inc.). Eligible Korean infants or toddlers with PWS were randomly assigned to receive Eutropin or comparator (both 0.24 mg/kg/week, 6 times/week) for 1 year. Height standard deviation score (SDS), body composition, and motor and cognitive development were measured.

Results: Thirty-four subjects (less than 24 months old) were randomized into either the Eutropin (N = 17) group or the comparator (N = 17) group. After 52 weeks of rhGH treatment, height SDS and lean body mass increased significantly from baseline in both groups: the mean height SDS change (SD) was 0.75 (0.59) in the Eutropin group and 0.95 (0.66) in the comparator group, and the mean lean body mass change (SD) was 2377.79 (536.25) g in the Eutropin group and 2607.10 (641.36) g in the comparator group. In addition, percent body fat decreased significantly: the mean (SD) change from baseline was - 8.12% (9.86%) in the Eutropin group and - 7.48% (10.26%) in the comparator group. Motor and cognitive developments were also improved in both groups after the 1-year treatment. The incidence of adverse events was similar between the groups.

Conclusions: rhGH treatment for 52 weeks in infants and toddlers with PWS improved growth, body composition, and motor and cognitive development, and efficacy and safety outcomes of Eutropin were comparable to those of Genotropin. Hence, Eutropin is expected to provide safe and clinically meaningful improvements in pediatric patients with PWS.

Trial Registration: The study was registered at ClinicalTrials.gov (identifier: NCT02204163) on July 30, 2014. URL: https://clinicaltrials.gov/ct2/show/NCT02204163?term=NCT02204163&rank=1.
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http://dx.doi.org/10.1186/s13023-019-1195-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739953PMC
September 2019

Identification of extremely rare mitochondrial disorders by whole exome sequencing.

J Hum Genet 2019 Nov 26;64(11):1117-1125. Epub 2019 Aug 26.

Department of Pediatrics, ASAN Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

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.
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http://dx.doi.org/10.1038/s10038-019-0660-yDOI Listing
November 2019