Young Bae Sohn

Ajou University, Sŏul, Seoul, South Korea

Are you Young Bae Sohn?

Claim your profile

Publications (62)105.99 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal dominant inheritance; but, many autosomal recessive genes have been reported. We applied whole exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypo-functional nature of the two variants was demonstrated in a zebrafish assay.This article is protected by copyright. All rights reserved
    Human Mutation 11/2014; · 5.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with Prader–Willi syndrome (PWS) present with short stature and obesity. The growth pattern of children with PWS is different from that of the healthy population. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of children with PWS. We aimed to develop disease-specific growth charts for height and weight for nongrowth hormone-treated Korean infants with PWS aged between 0 and 36 months and to use these growth charts for the evaluation and management of infants with PWS. We conducted a retrospective review of the medical records of 122 infants with genetically confirmed PWS. Data on the patients’ height and weight measurements before they underwent growth hormone treatment were recorded. Disease-specific growth charts were generated and the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th centiles were calculated using the LMS (refers to λ, μ, and σ, respectively) smoothing procedure for height and weight. The disease-specific growth charts for Korean infants with PWS can be used when examining infants with PWS and when evaluating their growth at later stages for comparison purposes. They are also useful for monitoring growth patterns, nutritional assessments, and recording responses to growth hormone treatment. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2014; · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Idursulfase beta (Hunterase®) has been used for enzyme replacement therapy (ERT) of patients with mucopolysaccharidosis II (MPS II, Hunter syndrome) aged 6 years or older since 2012 in Korea. The objective of this study was to evaluate the safety and efficacy of ERT with idursulfase beta in Hunter syndrome children younger than 6 years. This study was a 52-week, single center, single arm, open-label clinical trial (NCT01645189). Idursulfase beta (0.5 mg/kg/week) was administered intravenously for 52 weeks. The primary endpoint was safety assessed by adverse events (AEs). Secondary endpoints included vital signs, physical examination, ECG, laboratory tests, anti-idursulfase antibodies, and efficacy represented by changes in urinary glycosaminoglycan (GAG) at week 53 from baseline. In addition, growth indices and developmental milestones (Denver II test) were evaluated as exploratory variables. All six patients experienced at least one AE. A total of 109 AEs were reported. One patient experienced a serious AE (hospitalization due to gastroenteritis) that was considered not to be treatment related. One patient (16.7%), experienced infusion-related adverse drug reactions (ADRs), developing urticaria six times and a cough five times. There were no serious ADRs and no clinically significant changes in vital signs, physical exam, laboratory parameters, or ECG. Of the six patients, four (66.7%) showed anti-idursulfase antibodies and neutralizing antibodies on at least one occasion during the study. At week 53, urinary GAG was significantly reduced by -35.1 ± 30.6 mg GAG/g creatine from baseline (P = 0.038). This study indicates that the safety and efficacy of idursulfase beta are similar to those reported in Hunter syndrome patients aged 6 years or older.
    Molecular Genetics and Metabolism 08/2014; · 2.83 Impact Factor
  • Sung Yoon Cho, Young Bae Sohn, Dong-Kyu Jin
    [Show abstract] [Hide abstract]
    ABSTRACT: Mucopolysaccharidosis (MPS) is a constellation of disorders characterized by the accumulation of mucopolysaccharides in tissues and organs. This accumulation results in the deterioration and degeneration of multiple organs. This paper describes the general distribution of types of MPS in patients, their clinical characteristics and genotypes, the development of animal studies and preclinical studies, enzyme replacement therapy in South Korea, and the development of idursulfase beta and clinical trials on idursulfase beta in South Korea. In addition, this paper discusses academic collaboration among specialists in MPS care in the Asia-Pacific region, which includes Japan, Taiwan, Malaysia, and South Korea, through an organization called the Asia-Pacific MPS Network (APMN). The Asia-Pacific MPS Registry, an electronic remote data entry system, has been developed by key doctors in the APMN. Rare diseases require international cooperation and collaboration to elucidate their mechanisms and carry out clinical trials; therefore, an organization such as the APMN is required. Furthermore, international collaboration among Asian countries and countries around the world will be of utmost importance in the future.
    Intractable & rare diseases research. 08/2014; 3(3):79-86.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analysed (Gly673Asp and Ile678Thr; based on PDE4D4). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity, which was identified by increased cAMP levels. However, cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia. We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction of other PDE4 isoforms that can be expected to be targeted to different signaling complexes and exert distinct effects on compartmentalised cAMP signalling.
    Cellular signalling. 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mucopolysaccharidosis II (MPS II, Hunter syndrome; OMIM 309900) is an X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs). For enzyme replacement therapy (ERT) of Hunter syndrome, two recombinant enzymes, idursulfase (Elaprase®, Shire Human Genetic Therapies, Lexington, MA) and idursulfase beta (Hunterase®, Green Cross Corporation, Yongin, Korea), are currently available in Korea. To compare the biochemical and physicochemical differences between idursulfase and idursulfase beta, we examined the formylglycine (FGly) content, specific enzyme activity, mannose-6-phosphate (M6P) content, sialic acid content, and in vitro cell uptake activity of normal human fibroblasts of these two enzymes.The FGly content, which determines the enzyme activity, of idursulfase beta was significantly higher than that of idursulfase (79.4 ± 0.9 vs. 68.1 ± 2.2 %, P < 0.001). In accordance with the FGly content, the specific enzyme activity of idursulfase beta was significantly higher than that of idursulfase (42.6 ± 1.1 vs. 27.8 ± 0.9 nmol/min/μg protein, P < 0.001). The levels of M6P and sialic acid were not significantly different (2.4 ± 0.1 vs 2.4 ± 0.3 mol/mol protein for M6P and 12.3 ± 0.7 vs. 12.4 ± 0.4 mol/mol protein for sialic acid). However, the cellular uptake activity of the normal human fibroblasts in vitro showed a significant difference (Kuptake, 5.09 ± 0.96 vs. 6.50 ± 1.28 nM protein, P = 0.017).In conclusion, idursulfase beta exhibited significantly higher specific enzyme activity than idursulfase, resulting from higher FGly content. These biochemical differences may be partly attributed to clinical efficacy. However, long-term clinical evaluations of Hunter syndrome patients treated with these two enzymes will be needed to demonstrate the clinical implications of significant difference of the enzyme activity and the FGly content.
    Glycoconjugate Journal 04/2014; · 1.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac systolic function is significantly decreased in a proportion of patients with Hunter syndrome. This study was performed to evaluate the change in myocardial function associated with enzyme replacement therapy (ERT) in a mouse model of cardiomyopathy associated with Hunter syndrome. Thirty 9-week-old iduronate-2-sulfatase (IDS) knockout mice received either intravenous injection of human recombinant IDS (ERT group, N=15) or saline (control group, N=15) for 5weeks. Echocardiography was performed at baseline and after treatment. Echocardiographic parameters of left ventricular (LV) systolic function and 2-dimensional radial and circumferential strain were assessed. At follow-up, there was a significant increase in LV fractional shortening and radial and circumferential strain in the ERT group only. Notable myocardial fibrosis was observed in the control group only. In the murine model of Hunter syndrome, ERT exerts beneficial effects on cardiac function, which can be evaluated by serial echocardiographic evaluation including 2-dimensional strain analysis.
    Molecular Genetics and Metabolism 04/2014; · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Kabuki syndrome (KS) (OMIM#147920) is a multiple congenital anomaly/mental retardation syndrome. Recently, pathogenic variants in KMT2D and KDM6A were identified as the causes of KS in 55.8-80.0% of patients. To elucidate further the molecular characteristics of Korean patients with KS, we screened a cohort of patients with clinically defined KS for mutations in KMT2D and KDM6A. Whole-exome sequencing and direct sequencing for validation were performed in 12 patients with a clinical suspicion of KS. KMT2D and KDM6A mutations were identified in 11 (91.7%) patients. No recurrent mutation was observed, and 10 out of the 11 mutations found were novel. KMT2D mutations were detected in 10 patients, including four small deletions or insertions and four nonsense and two missense mutations. One girl had a novel splice-site mutation in KDM6A. Each patient had a unique individual mutation. This is the first report of mutational analysis via exome sequencing in Korean patients with KS. Because the mutation-detection rate was high in this study, rigorous mutation analysis of KMT2D and KDM6A may be an important tool for the early diagnosis and genetic counseling of Korean patients with KS.Journal of Human Genetics advance online publication, 17 April 2014; doi:10.1038/jhg.2014.25.
    Journal of Human Genetics 04/2014; · 2.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hunter syndrome (or mucopolysaccharidosis type II [MPS II]) arises because of a deficiency in the lysosomal enzyme iduronate-2-sulfatase. Short stature is a prominent and consistent feature in MPS II. Enzyme replacement therapy (ERT) with idursulfase (Elaprase®) or idursulfase beta (Hunterase®) have been developed for these patients. The effect of ERT on the growth of Korean patients with Hunter syndrome was evaluated at a single center. This study comprised 32 patients, who had received ERT for at least 2 yr; they were divided into three groups according to their ages at the start of ERT: group 1 (<6 yr, n=14), group 2 (6-10 yr, n=11), and group 3 (10-20 yr, n=7). The patients showed marked growth retardation as they got older. ERT may have less effect on the growth of patients with the severe form of Hunter syndrome. The height z-scores in groups 2 and 3 revealed a significant change (the estimated slopes before and after the treatment were -0.047 and -0.007, respectively: difference in the slope, 0.04; P<0.001). Growth in response to ERT could be an important treatment outcome or an endpoint for future studies.
    Journal of Korean medical science 02/2014; 29(2):254-60. · 0.84 Impact Factor
  • So Hyun Park, Ji Eun Lee, Young Bae Sohn, Jung Min Ko
    [Show abstract] [Hide abstract]
    ABSTRACT: Sotos syndrome (SS) is a congenital overgrowth syndrome. NSD1 mutations are identifiable in most SS patients. There have been a few reports of familial inheritance of SS worldwide, but no familial cases have been reported in Korea. A 6-month-old girl had tall stature and macrocephaly with mild ventricular enlargement, and showed mild delay in motor and language development. Her mother also had tall stature and a long narrow face. The baby and her mother were suspected of having familial SS. Chromosome 5q35 microdeletion was first ruled out by fluorescence in situ hybridization analysis, and direct sequencing of NSD1 revealed a novel heterozygous mutation in exon 22 (c.6356delA; p.Asp2119Valfs*31). This report describes, for the first time, a Korean family with two generations of SS resulting from a novel intragenic NSD1 mutation.
    Annals of clinical and laboratory science 01/2014; 44(2):228-31. · 0.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A 21-year-old man with diabetic ketoacidosis (DKA) displayed short and clubbed fingers and marked eyebrow, which are typical of Hajdu-Cheney Syndrome (HCS). Laboratory findings confirmed type 1 diabetes mellitus (DM). After conservative care with hydration and insulin supply, metabolic impairment was improved. Examinations of bone and metabolism revealed osteoporosis and craniofacial abnormalities. The mutation (c.6443T>G) of the NOTCH2 gene was found. The patient was diagnosed with HCS and DM. There may be a relationship between HCS and DM, with development of pancreatic symptoms related to the NOTCH2 gene mutation.
    Journal of Korean medical science 11/2013; 28(11):1682-1686. · 0.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: This study analyzed and evaluated the demographic, clinical, and cytogenetic data [G-banded karyotyping and array-based comparative genomic hybridization (array CGH)] of patients with unexplained developmental delay or intellectual disability at a single Korean institution. Materials and Methods: We collected clinical and cytogenetic data based on retrospective charts at Ajou University Medical Center, Suwon, Korea from April 2008 to March 2012. Results: A total of 190 patients were identified. Mean age was 5.1±1.87 years. Array CGH yielded abnormal results in 26 of 190 patients (13.7%). Copy number losses were about two-fold more frequent than gains. A total of 61.5% of all patients had copy number losses. The most common deletion disorders included 22q11.2 deletion syndrome, 15q11.2q12 deletion and 18q deletion syndrome. Copy number gains were identified in 34.6% of patients, and common diseases among these included Potocki-Lupski syndrome, 15q11-13 duplication syndrome and duplication 22q. Abnormal karyotype with normal array CGH results was exhibited in 2.6% of patients; theses included balanced translocation (n=2), inversion (n=2) and low-level mosaicism (n=1). Facial abnormalities (p<0.001) and failure to thrive were (p<0.001) also more frequent in the group of patients with abnormal CGH findings. Conclusion: Array CGH is a useful diagnostic tool in clinical settings in patients with developmental delay or intellectual disability combined with facial abnormalities or failure to thrive.
    Yonsei medical journal 11/2013; 54(6):1463-70. · 0.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pseudohypoparathyroidism (PHP) is defined as resistance toward parathyroid hormones. PHP and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations within or upstream of the GNAS locus. This study investigated the clinical characteristics and performed a molecular analysis of PHP and PPHP.A total of 12 patients with (P)PHP from 11 unrelated families (4 with PHP-Ia, 6 with PHP-Ib, and 2 with PPHP) were characterized using both clinical and molecular methods. Clinical features included the presenting symptoms, Albright hereditary osteodystrophy features, and resistance to hormones. Comprehensive analysis of the GNAS and STX16 loci was undertaken to investigate the molecular defects underlying (P)PHP.All PHP-Ib patients displayed hypocalcemic symptoms. All PHP-Ia patients showed resistance toward TSH, in addition to PTH. In most patients with PHP, when the diagnosis of PHP was first established, hypocalcemia and hyperphosphatemia were associated with a significant increase in serum PTH levels. One patient with PHP-Ia was diagnosed with growth hormone deficiency and showed a good response to human recombinant growth hormone therapy. 6 patients with PHP-Ia and PPHP showed 5 different mutations in the GNAS gene. 5 patients with PHP-Ib displayed a loss of differentially methylated region (DMR) imprints of the maternal GNAS. One PHP-Ib patient showed a de novo microdeletion in STX16 and a loss of methylation of exon A/B on the maternal allele. No patients revealed paternal disomy among 4 patients with PHP-Ib.Identification of the molecular causes of PHP and PPHP explains their distinctive clinical features and enables confirmation of the diagnosis and exact genetic counseling.
    Experimental and Clinical Endocrinology & Diabetes 10/2013; 121(9):539-545. · 1.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The natural progression of the severe form of mucopolysaccharidosis II in children is a rapid decline of neurodevelopmental function with hydrocephalus. Recombinant human iduronate-2-sulfatase enzyme replacement therapy (ERT) under a standard regimen seems to have limited effect. Therefore, we determined whether early, high-dose ERT attenuated ventriculomegaly and histologic abnormalities in the brains of IdS-knockout mice. IdS-knockout mice received saline or recombinant human IdS (0.5/1.0/2.0 mg kg(-1)) intravenously once weekly, starting at 4 weeks of age and continuing until 20 weeks. ERT with 2.0 mg kg(-1), but not 0.5 or 1.0 mg kg(-1), significantly attenuated enlarged ventricles, as confirmed by in vivo 7-teslar brain magnetic reasonance image (MRI) at 20 weeks. However, neuronal cytoplasmic vacuolization and morphological alteration in the purkinje cells on brain histology and glycosaminoglycan (GAG) levels in brain homogenates were reduced in mice receiving ERT at lower dose than 2.0 mg kg(-1). Additionally, GAG levels significantly correlated with the percent volume ratio of ventricle to whole brain. These results suggested that high-dose systemic ERT started early in life could be a promising therapeutic modality for improving neurologic dysfunction including ventriculomegaly in children with severe Hunter syndrome.Journal of Human Genetics advance online publication, 5 September 2013; doi:10.1038/jhg.2013.92.
    Journal of Human Genetics 09/2013; · 2.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kabuki syndrome (KS) is a rare genetic disease with a distinctive dysmorphic face, intellectual disability, and multiple congenital abnormalities. KS is inherited in an autosomal dominant manner. As the primary cause of KS, MLL2 mutations have been identified in 56-76% of affected individuals who have been tested, suggesting that there may be additional genes associated with KS. Recently, a few KS individuals have been found to have de novo partial or complete deletions of an X chromosome gene, KDM6A, which encodes a histone demethylase that interacts with MLL2. Nevertheless, mutations in MLL2 are the major cause of KS. Although there are a few reports of KS patients in Korea, none of these had been confirmed by genetic analysis. Here, we report a case of a Korean patient with clinical features of KS. Using direct sequencing, we identified a frameshift heterozygous mutation for MLL2: (c.5256_5257delGA;p.Lys1753Alafs*34). Clinically, the patient presented with typical facial features, and diagnosis of KS was based on the diagnostic criteria. While KS is a rare disease, other malformations that overlap with those found in individuals with KS are common. Hence, the diagnosis of KS by mutational analysis can be a valuable method for patients with KS-like syndromes. Furthermore, in the near future, other genes could be identified in patients with KS without a detectable MLL2 mutation.
    Korean Journal of Pediatrics 08/2013; 56(8):355-8.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by bone fragility, frequent fractures, and low bone mass. Dominantly inherited COL1A1 or COL1A2 mutations appear to be causative in the majority of OI types, but rare recessively inherited genes have also been reported. Recently, SERPINF1 has been reported as another causative gene in OI type VI. To date, only eight SERPINF1 mutations have been reported and all are homozygous. Our patient showed no abnormalities at birth, frequent fractures, osteopenia, and poor response on pamidronate therapy. At the time of her most recent evaluation, she was 8 yr old, and could not walk independently due to frequent lower-extremity fractures, resulting in severe deformity. No clinical signs were seen of hearing impairment, blue sclera, or dentinogenesis imperfecta. In this study, we describe the clinical and radiological findings of one Korean patient with novel compound heterozygous mutations (c.77dupC and c.421dupC) of SERPINF1.
    Journal of Korean medical science 07/2013; 28(7):1107-10. · 0.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations of the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of pseudogenes, and the great variety of mutations. Also, few probable genotype-phenotype correlations have been found in NF1. In this study 78 Korean patients from 60 families were screened for NF1 mutations. Mutation analysis of the entire coding region and flanking splice sites was carried out and included the use of a combination of reverse transcription polymerase chain reaction, multiplex ligation probe amplification, or fluorescence in situ hybridization. Mutation spectrum and genotype-phenotype relationship were assessed. Fifty-two distinct NF1 mutations were identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense), 11 missplicing mutations, seven small insertion or deletions, and four gross deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were recurrently identified. The mutations were evenly distributed across exon 1 through intron 47 of NF1, and no mutational hot spots were found. A genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. As technologies advance in molecular genetics, the mutation detection rate will increase. Considering that 30.8% of detected mutations were novel, exhaustive mutation analysis of NF1 may be an important tool in early diagnosis and genetic counseling.
    Pediatric Neurology 06/2013; 48(6):447-53. · 1.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CATCH 22 Syndrome is caused by chromosome 22q11.2 microdeletion, characterized by developmental abnormalities of the third and fourth pharyngeal pouches. It has a prevalence estimated at 1:3,000-1:9,000. Most deletions occurs sporadic, but autosomal dominant inheritance observed in 6-10% of cases. CATCH22 often diagnosed due to hypocalcemia during neonatal period or decreased immunity or facial defect, so it is very rare being diagnosed CATCH22 in adulthood. We report a 57 year old female who referred to mental change due to hypocalcemia and is diagnosed CATCH22. She was presented with hypoparathyroidism, single kidney due to renal agenesis, and mild facial defect. Our patient responded well to calcium and vitamin D treatment and she is on follow-up in outpatient clinic.
    Journal of bone metabolism. 05/2013; 20(1):57-60.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome (OMIM 309900), is a rare, X-linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS; EC 3.1.6.13), which is involved in the lysosomal degradation of glycosaminoglycans (GAG). Although intermittent intrathecal (IT) injection of the enzyme has been introduced as a method to overcome the blood-brain barrier, continuous IT infusion of the enzyme would be more physiologic. This study was performed to investigate responses in the brain of MPS II mice to varying doses of continuous IT infusion of recombinant human IDS (rh-IDS) in MPS II mice by osmotic pump in three different doses (2.4, 4.8, and 12 µg/day) of rh-IDS for 3 weeks. The results showed that the group treated with 12 µg/day doses of rh-IDS demonstrated decreased GAG concentrations compared to the untreated KO mice group (P = 0.003). After 3 weeks of continuous IT ERT, the brain tissues of the high-dose IT-treated KO mice showed a reduction of vacuolation in the cerebral cortex, thalamus and cerebellar cortex, which was not observed in the low- and medium-dose KO mice groups. Moreover, the anti-NeuN signal representing intact neuron was restored in the cortexes of the high-dose group. In conclusion, continuous IT infusion of the deficient enzyme was effective in improving CNS defects in the MPS II mice, and could be a valuable therapeutic method for treating neurological deterioration in patients with MPS II. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2013; · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare X-linked lysosomal storage disorder caused by the deficiency of iduronate-2-sulfatase (IDS). In affected patients, glycosaminoglycan (GAG) accumulates in the lysosomes of many organs and tissues contributing to the pathology associated with MPS II. The objective of this phase I/II clinical study was to evaluate the efficacy and safety of recombinant human iduronate-2-sulfatase (idursulfase beta, Hunterase(R)) in the treatment of MPS II. METHODS: Thirty-one MPS II patients between 6 and 35 years of age were enrolled in a randomized, single-blinded, active comparator-controlled phase I/II trial for 24 weeks. Patients were randomized to active comparator infusions (N=11), 0.5 mg/kg idursulfase beta infusions (N=10), or 1.0 mg/kg idursulfase beta infusions (N=10). The primary efficacy variable was the level of urinary glycosaminoglycan (GAG) excretion. The secondary variables were changes in the distance walked in 6 minutes (6-minute walk test, 6MWT), echocardiographic findings, pulmonary function tests, and joint mobility. RESULTS: Patients in all three groups exhibited reduction in urine GAG and this reduced GAG level was maintained for 24 weeks. Urine GAG was also significantly reduced in the 0.5 mg/kg and 1.0 mg/kg idursulfase beta groups when compared to the active comparator group (P = 0.043, 0.002, respectively). Changes in 6MWT were significantly greater in the 0.5 mg/kg and 1.0 mg/kg idursulfase groups than in the active comparator group (p= 0.003, 0.015, respectively). Both idursulfase beta infusions were generally safe and well tolerated, and elicited no serious adverse drug reactions. The most frequent adverse events were urticaria and skin rash, which were easily controlled with administration of antihistamines. CONCLUSIONS: This study indicates that idursulfase beta generates clinically significant reduction of urinary GAG, improvements in endurance as measured by 6MWT, and it has an acceptable safety profile for the treatment of MPS II.Trial registration: ClinicalTrials.gov: NCT01301898.
    Orphanet Journal of Rare Diseases 03/2013; 8(1):42. · 4.32 Impact Factor