Hematopoietic Cell Transplantation in Patients with Mucopolysaccharidosis Type II

Song, Ari Association for Research of MPS and Rare Diseases 2021 Journal of mucopolysaccharidosis and rare disease Vol.5 No.1

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase, leading to the accumulation of glycosaminoglycans (GAGs), which affects multiple organs and systems. Current treatments for MPS II include enzyme replacement therapy (ERT) and hematopoietic cell transplantation (HCT) to reduce the accumulation of GAGs. HCT has the potential advantage that donor-derived enzyme-competent cells can provide a continuous secreting source of the enzyme. However, HCT as a treatment for MPS II remains controversial because its effectiveness is unclear, particularly in terms of neurological symptoms. To date, several clinical experiences with HCT in MPS II have been reported. In this paper, we review post-HCT outcomes in the previously published literature and discuss the effects of HCT on each of the clinical signs and symptoms of MPS II.

Birth of a healthy baby after preimplantation genetic diagnosis in a carrier of mucopolysaccharidosis type II: The first case in Korea

Ko, Duck Sung,Lee, Sun-Hee,Park, Chan Woo,Lim, Chun Kyu The Korean Society for Reproductive Medicine 2019 Clinical and Experimental Reproductive Medicine Vol.46 No.4

Mucopolysaccharidosis type II (MPS II) is a rare X-linked recessive lysosomal storage disease caused by mutation of the iduronate-2-sulfatase gene. The mutation results in iduronate-2-sulfatase deficiency, which causes the progressive accumulation of heparan sulfate and dermatan sulfate in cellular lysosomes. The phenotype, age of onset, and symptoms of MPS II vary; accordingly, the disease can be classified into either the early-onset type or the late-onset type, depending on the age of onset and the severity of the symptoms. In patients with severe MPS II, symptoms typically first appear between 2 and 5 years of age. Patients with severe MPS II usually die in the second decade of life although some patients with less severe disease have survived into their fifth or sixth decade. Here, we report the establishment of a preimplantation genetic diagnosis (PGD) strategy using multiplex nested polymerase chain reaction, direct sequencing, and linkage analysis. Unaffected embryos were selected via the diagnosis of a single blastomere, and a healthy boy was delivered by a female carrier of MPS II. This is the first successful application of PGD in a patient with MPS II in Korea.

Changes in Glycogen and Glycosaminoglycan Levels in Hepatocytes of Iduronate-2-Sulfatase Knockout Mice before and after Recombinant Iduronate-2-Sulfatase Supplementation

이지현,진동규,최연호,김수진,백경훈 연세대학교의과대학 2011 Yonsei medical journal Vol.52 No.2

Purpose: Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder caused by a deficiency of iduronate-2 sulfatase (IdS), which is involved in the degradation of glycosaminoglycan (GAG). In this study, the frequency of fasting hypoglycemia in patients with MPS II was investigated and changes in accumulation of glycogen and GAG in the hepatocytes of IdS-knockout (KO) mice were evaluated before and after recombinant IdS enzyme replacement therapy (ERT). Materials and Methods: Plasma glucose levels were evaluated after an 8-hour fast in 50 patients with MPS II. The IdS-KO mice were divided into three groups (group 2; saline, group 3; 0.15 mg/kg of IdS, and group 4; 0.5 mg/kg of IdS); wild-type mice were included as controls (group 1). ERT was initiated intravenously at four weeks of age, and continued every week until 20 weeks of age. Results: The mean glucose level after an 8-hour fast was 94.1 ± 23.7 mg/dL in the patients with MPS II. Two (4%) out of 50 patients had fasting hypoglycemia. For the mice, GAG in the lysosomes nearly disappeared and glycogen particles in the cytoplasm were restored to the normal range in group 4. Conclusion: Glucose metabolism in patients with MPS II appeared to function well despite hepatocytic GAG accumulation and hypothetical glycogen depletion. A higher dose of IdS infusion in MPS II mice led to disappearance of lysosomal GAG and restoration of glycogen to the cytoplasm of hepatocytes.

Novel variants of IDS gene, c.1224_1225insC, and recombinant variant of IDS gene, c.418+495_1006+1304del, in Two Families with Mucopolysaccharidosis type II

Cheon, Chong Kun Interdisciplinary Society of GeneticGenomic Medici 2019 Journal of interdisciplinary genomics Vol.1 No.1

In this report, the phenotypes of three patients from two families with mucopolysaccharidosis type II (MPS II) are compared: a novel variant and recombinant variant of IDS gene. The results of urine in patients showed a pronounced increase in glycosaminoglycan excretion with decreased iduronate-2-sulfatase enzyme activity in leukocyte, leading to a diagnosis of MPS II. A patient has a novel variant with 1 bp small insertion, c.1224_1225insC in exon 9, which caused frameshifts with a premature stop codon, and two patients have a recombination variant, c.418+495_1006+1304del, leading to the loss of exons 4, 5, 6, and 7 in genomic DNA, which is relatively common in Korean patients. They had different phenotypes even in the same mutation. The patients have now been enzyme replacement therapy with a significant decrease in glycosaminoglycan excretion. Further study on residual enzyme activity, as well as experience with more cases, may shed light on the relationship between phenotypes in MPS II and gene mutations.

Impact of Enzyme Replacement Therapy on Linear Growth in Korean Patients with Mucopolysaccharidosis Type II (Hunter Syndrome)

조성윤,허림,장미선,이지은,Younghee Kwun,Se-Hyun Maeng,김수진,손영배,박성원,권은경,Sun Ju Han,정주연,진동규 대한의학회 2014 Journal of Korean medical science Vol.29 No.2

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.

Clinical Spectrum and Short-term Effects of Enzyme Replacement Therapy for Mucopolysaccharidosis Type II

전종근,휴우리앙,Cheon, Chong Kun,Hwu, Wuh-Liang The Korean Society of Inherited Metabolic Disease 2018 대한유전성대사질환학회지 Vol.18 No.3

목적: 5명의 제2형 뮤코다당증 환자들의 임상적 스펙트럼과 효소대치요법의 단기간 치료 효과에 관해 알아 보고하고자 하였다. 방법: 5명의 환자들은 임상적 소견, 효소활성화 및 유전자검사에 의해 제2형 뮤코다당증으로 진단되었다. 이두설파제는 일주일 간격으로 0.5 mg/kg의 용량으로 정맥주사 주입을 하였으며, 효소대치요법 시작 전 후 12개월 이상 전신평가를 하였으며, 의무기록을 후향적으로 분석하였다. 결과: 3명의 환자들은 경증 유형, 2명의 환자들은 중증 유형의 제2형 뮤코다당증으로 진단되었다. 진단 시 중위연령은 9.6세(범위 3.4-26세)였다. 네 가계 중 다섯 명의 환자에서 4개의 서로 다른 유전자변이가 확인되었으며, 이중 두 개의 변이는 새로운 돌연변이였다(1개의 작은 삽입돌연변이: p.Thr409Hisfs*22, 1개의 과오돌연변이: p.Gly134Glu). 이중 동일한 유전자돌연변이를 지닌 두 명의 중중 유형의 형제 환자들은 서로 다른 임상적 특징들을 보였다. 12개월 간의 효소대치요법 후 소변 글리코사미노글리칸 배출은 유의하게 감소하였다(P=0.043). 간 및 비장의 용적은 모든 환자에서 유의하게 감소하였다(각각 P=0.043, P=0.043). 이외에도 좌심실질량지수(P=0.042), 어깨관절굽힘각도(P=0.043), 어깨관절벌림각도(P=0.039), 무릎관절굽힘각도(P=0.043), 팔꿉관절굽힘각도(P=0.042), 호흡장애지수(P=0.041)가 모두 호전된 소견을 보였다. 결론: 한국인 제2형 뮤코다당증 환자들은 임상적으로 다양한 특징을 보이며, 단기간의 이두설파제 치료는 주사주입관련 이상반응 없이 심장크기, 호흡장애지수를 포함한 여러 임상적 지표들의 호전에 효과적이었다. Purpose: We aimed to delineate clinical spectrum and short-term effects after enzyme replacement therapy (ERT) for 5 mucopolysaccharidosis type II (MPS II). Methods: Five patients were diagnosed with MPS II by clinical findings, enzyme activity, and genetic testing. Idursulfase was administered by intravenous infusion at a dose of 0.5 mg/kg every week. Observational chart analysis of patients, who underwent systematic investigations more than 12 months after initiation of ERT was done retrospectively. Results: Three patients were classified as having the attenuated type, and 2 patients were classified as having the severe type. The median age at the diagnosis was 9.6 years (range 3.4-26 years). Four different mutations in 5 Korean patients (4 families) with MPS II were identified, among which two were novel mutations (1 small insertion mutation: p.Thr409Hisfs*22, and 1 missense mutation: p.Gly134Glu). Two severe type sibling patients with the same mutation had different clinical manifestation. Urinary glycosaminoglycan excretion decreased within the twelve months of ERT (P=0.043). Liver and spleen volumes showed reductions that were maintained in all patients (P=0.043 and P=0.043, respectively). Improvements were also noted in left ventricular mass index (P=0.042), shoulder flexion (P=0.043), shoulder abduction (P=0.039), knee flexion (P=0.043), elbow flexion (P=0.042), and respiratory distress index (P=0.041). Conclusion: This study demonstrates that Korean patients with MPS II are clinically heterogeneous and indicates that idursulfase is relatively effective in several clinical parameters including heart size and respiratory distress index without infusion-related reactions in patients with MPS II.

COVID-19 in a 16-Year-Old Adolescent With Mucopolysaccharidosis Type II: Case Report and Review of Literature

Park So Yun,Kim Heung Sik,Chu Mi Ae,Chung Myeong-Hee,Kang Seokjin 대한소아감염학회 2022 Pediatric Infection and Vaccine Vol.29 No.2

Coronavirus disease 2019 (COVID-19) in patients with underlying diseases, is associated with high infection and mortality rates, which may result in acute respiratory distress syndrome and death. Mucopolysaccharidosis (MPS) type II is a progressive metabolic disorder that stems from cellular accumulation of the glycosaminoglycans, heparan, and dermatan sulfate. Upper and lower airway obstruction and restrictive pulmonary diseases are common complaints of patients with MPS, and respiratory infections of bacterial or viral origin could result in fatal outcomes. We report a case of COVID-19 in a 16-year-old adolescent with MPS type II, who had been treated with idursulfase since 5 years of age. Prior to infection, the patient’s clinical history included developmental delays, abdominal distension, snoring, and facial dysmorphism. His primary complaints at the time of admission included rhinorrhea, cough, and sputum without fever or increased oxygen demand. His heart rate, respiratory rate, and oxygen saturation were within the normal biological reference intervals, and chest radiography revealed no signs of pneumonia. Consequently, supportive therapy and quarantine were recommended. The patient experienced an uneventful course of COVID-19 despite underlying MPS type II, which may be the result of an unfavorable host cell environment and changes in expression patterns of proteins involved in interactions with viral proteins. Moreover, elevated serum heparan sulfate in patients with MPS may compete with cell surface heparan sulfate, which is essential for successful interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the host cell surface, thereby protecting against intracellular penetration by SARS-CoV-2. 코로나바이러스감염증-19 (COVID-19)의 임상 양상은 무증상부터 급성 호흡곤란 증후군에 이르기까지 다양하다. 점액 다당류증(mucopolysaccharidosis) 2형은 글라이코스아미노글라이칸(glycosaminoglycan)의 일종인 헤파란 황산염(heparan sulfate)과 더마탄 황산염(dermatan sulfate)의 분해를 촉매하는 효소 결핍에 의해 상기 물질이 리소좀(lysosome)에 축적되는 질환으로 전신 침범, 특히 호흡기침범을 특징으로 한다. 따라서 박테리아나 바이러스에 의한 호흡기 감염은 예후에 치명적일 수 있다. 현재 점액 다당류증 환자에서 제 2형 중증급성호흡기증후군 코로나 바이러스(SARS-CoV-2) 감염 후의 임상 양상에 대한 보고는 매우 드물고, 이에 점액 다당류증 2형으로 효소대체요법을 받고 있던 환자에서 상기 바이러스 감염 후의 임상 양상에 대해 보고하고 관련 문헌에 대해 고찰하고자 한다. 16세 남아로 가족간 전파로 코로나바이러스감염증이 발생하였다. 콧물, 기침, 가래 등 호흡기 증상이 관찰되었다. 발열이나 산소요구도 증가는 없었으며 심박수, 호흡수, 산소 포화도는 정상 범위였고 혈액검사결과에서 백혈구 감소증이 관찰되었다. 흉부 방사선 사진에서 폐렴 소견은 보이지 않았다. 보존적 치료와 격리만으로 증상이 호전되었다. 경미한 임상 양상의 원인으로 전구 물질의 축적으로 인해 바이러스에게 불리한 숙주의 세포 환경, 바이러스와의 상호작용에 관여하는 단백질을 암호화하는 유전자 발현의 특정방향으로의 변화가 제시되고 있다. 또한 점액 다당류증 환자에서 증가된 혈청 헤파란 황산염이 SARS-CoV-2 스파이크 단백질과 숙주 세포의 상호작용에 필수적인 세포 표면의 헤파란 황산염과 경쟁하여 SARS-CoV-2의 세포 내 침투로부터 보호한다는 가설도 있다. 향후 더 많은 사례를 통해 점액 다당류증 등의 리소좀 축적질환에서 코로나바이러스감염증의 발현 양상에 대한 연구가 필요하다.

A mother and daughter with the p.R443X mutation of mucopolysaccharidosis type II: Genotype and phenotype analysis

Sohn, Young Bae,Kim, Su Jin,Park, Sung Won,Park, Hyung‐,Doo,Ki, Chang‐,Seok,Kim, Chi Hwa,Huh, Seung Won,Yeau, Sunghee,Paik, Kyung‐,Hoon,Jin, Dong‐,Kyu Wiley Subscription Services, Inc., A Wiley Company 2010 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Vol.a152 No.12

<P><B>Abstract</B></P><P>Mucopolysaccharidosis type II (Hunter syndrome) is a lysosomal storage disease caused by a deficiency of iduronate‐2‐sulfatase. Most reported patients are males because of X‐linked recessive inheritance pattern. Only a few female patients with Hunter syndrome have been reported, and there is no prior report of offspring from a patient with Hunter syndrome. In this report, we describe a woman with mild manifestations of Hunter syndrome who gave birth to a daughter. Both the mother and daughter carried the p.R443X mutation in exon 9 of the <I>ID2S</I> gene. Iduronate‐2‐sulfatase activity in the mother was as low as that found in male Hunter syndrome patients, but it was in the low‐normal range in her daughter. Unlike her mother, the daughter did not show any physical signs of Hunter syndrome, and urinary excretion of glycosaminoglycan was within normal range. However, she had severe pulmonary vein stenosis with pulmonary hypertension and a large atrial septal defect and died at 11 months of age. © 2010 Wiley‐Liss, Inc.</P>

Graph Multi-Attention 알고리즘을 활용한 Asymmetric 장시간 교통 속도 예측

황지영,노병준,여화수 대한교통학회 2021 대한교통학회 학술대회지 Vol.85 No.-

정확한 교통 예측은 교통 운영 및 관리에서 중요한 부분을 차지하고 있다. 최근에는 교통의 비선형적, 시공간적 특성을 반영하기 위하여, 딥러닝 기반 교통 예측 모델이 발달해왔다. 그러나 기존 모델들은 1 시간 이내의 교통 상황을 예측하는 단기간 교통 예측에 중점을 두고 있다. 장기간 교통 예측은 교통 운영 및 관리뿐만 아니라 운전자 개인이 이동 시에도 사전에 교통 상황을 파악하고 효율적인 결정을 내릴 수 있게 한다. Graph Neural Network (GNN) 은 딥러닝 모델의 일종으로 실제 도로 상황의 연결성 및 관계성을 설명하기에 적합하다. 본 연구에서는 GNN 기반의 multi-attention 알고리즘과 실제 도로의 asymmetry 특성을 반영한 Asymmetric Long-Term Graph Multi-Attention Network(ALT-GMAN) 모델을 제안한다. 기존 모델인 GMAN 모델의 확장으로서, 본 모델은 단기간과 장기간 교통 속도예측이 모두 가능하다. 새로운 Spatial-Temporal Embedding을 적용하여 back propagation과 같은 교통 이론 및 교통 상황을 반영한다. ALT-GMAN를 적용하였을 때, 6개월 기간의 PeMS-Bay 고속도로 데이터로부터 3시간 6시간 예측에서 각각 3.79%, 4.05%의 MAPE 값이 도출되었다. 본 모델은 위의 결과와 같이 단기간, 장기간 교통 속도 예측에서 기존 모델 보다 정확한 결과를 보여준다.

A study of the relationship between clinical phenotypes and plasma iduronate-2-sulfatase enzyme activities in Hunter syndrome patients

Ok Jeong Lee,Su-Jin Kim,박형두,이수연,Chi-Hwa Kim,Ah-Ra Ko,Yeon-Joo Yook,Su-Jin Lee,박성원,Se-Hwa Kim,Sung-Yoon Cho,Eun-Kyung Kwon,Sun Ju Han,진동규,Young Bae Sohn 대한소아청소년과학회 2012 Clinical and Experimental Pediatrics (CEP) Vol.55 No.3

Purpose: Mucopolysaccharidosis type II (MPS II or Hunter syndrome)is a rare lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency. MPS II causes a wide phenotypic spectrum of symptoms ranging from mild to severe. IDS activity, which is measured in leukocyte pellets or fibroblasts, was reported to be related to clinical phenotype by Sukegawa-Hayasaka et al. Measurement of residual plasma IDS activity using a fluorometric assay is simpler than conventional measurements using skin fibroblasts or peripheral blood mononuclear cells. This is the first study to describe the relationship between plasma IDS activity and clinical phenotype of MPS II. Methods: We hypothesized that residual plasma IDS activity is related to clinical phenotype. We classified 43 Hunter syndrome patients as having attenuated or severe disease types based on clinical characteristics,especially intellectual and cognitive status. There were 27 patients with the severe type and 16 with the attenuated type. Plasma IDS activity was measured by a fluorometric enzyme assay using 4-methylumbelliferyl-α-iduronate 2-sulphate. Results: Plasma IDS activity in patients with the severe type was significantly lower than that in patients with the attenuated type (P=0.006). The optimal cut-off value of plasma IDS activity for distinguishing the severe type from the attenuated type was 0.63 nmol·4 hr-1·mL-1. This value had 88.2% sensitivity, 65.4% specificity, and an area under receiver-operator characteristics (ROC) curve of 0.768 (ROC curve analysis; P=0.003). Conclusion: These results show that the mild phenotype may be related to residual lysosomal enzyme activity.