The relationships between urinary glycosaminoglycan levels and phenotypes of mucopolysaccharidoses

Lin, Hsiang‐Yu; Lee, Chung‐Lin; Lo, Yun-Ting; Wang, Tuan-Jen; Huang, Sung-Fa; Chen, Tzu-Lin; Wang, Yushan; Niu, Dau‐Ming; Chen, Chuang

doi:10.1002/mgg3.471

Cited by 24 publications

(26 citation statements)

References 39 publications

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“…The relationships between uGAG-derived disaccharide levels, including DS and HS and the severity of the phenotype, were investigated, and the values of DS and HS closely matched the phenotypes of MPS. The MPS II patients with mental retardation had significantly higher levels of HS than those without mental retardation, and the DS values in the MPS II patients with hernia, hepatosplenomegaly, claw hands, coarse face, valvular heart disease, and joint stiffness were higher than in those without the symptoms reported by Lin et al [42]. In the current study, "positive" uGAG tests indicated that the Dimethylmethylene Blue/creatinine (DMB/Cre.)…”

Section: The Quantitative Analysis Of Urinary Gag-derived Disaccharidsupporting

confidence: 56%

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Lin

Chern

et al. 2019

IJMS

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Hunter syndrome (mucopolysaccharidosis II; MPS II) is caused by a defect of the iduronate-2-sulfatase (IDS) gene. Few studies have reported integrated mutation data of Taiwanese MPS II phenotypes. In this study, we summarized genotype and phenotype correlations of confirmed MPS II patients and asymptomatic MPS II infants in Taiwan. Regular polymerase chain reaction and DNA sequencing were used to identify genetic abnormalities of 191 cases, including 51 unrelated patients with confirmed MPS II and 140 asymptomatic infants. IDS activity was analyzed in individual novel IDS variants using in vitro expression studies. Nineteen novel mutations were identified, in which the percentages of IDS activity of the novel missense mutations c.and c.1403G>A were significantly decreased (p < 0.001), c.254C>T and c.1025A>G were moderately decreased (p < 0.01), and c.851C>T was slightly decreased (p < 0.05) comparing with normal enzyme activity. The activities of the other six missense mutations were reduced but were insignificant. The results of genomic studies and their phenotypes were highly correlated. A greater understanding of the positive correlations may help to prevent the irreversible manifestations of Hunter syndrome, particularly in infants suspected of having asymptomatic MPS II. In addition, urinary glycosaminoglycan assay is important to diagnose Hunter syndrome since gene mutations are not definitive (could be non-pathogenic).Sequencing data were obtained by scanning through the data to identify anomalies using Applied Biosystems Sequence Scanner Software v2.0 Sequence Trace Viewer and Editor (Applied Biosystems Co., CA, USA) and manual progressive alignment. A total of 51 mutations of the IDS gene from the 191 cases, including the confirmed patients (n = 51) and infants suspected of having MPS II (n = 140) that were identified. The suspected MPS II infants were classified into two groups: Those with either 1) "positive" uGAG biochemistry examinations, reduction in leukocyte IDS enzyme activity, and identified IDS variations (n = 7); or 2) "negative" uGAG biochemistry examinations, reduction in leukocyte IDS enzyme activity and identified IDS variations (n = 133). The 51 mutations of the IDS gene included 32 missense (62.7%), 3 nonsense (5.9%), 2 silent (3.9%), 6 splicing (11.8%), 4 small deletions (7.8%), 3 gross deletions (5.9%), and 1 complex inversion (2%) ( Table 1). Of these mutations, 35 were reported and verified as being pathogenic for MPS II with varying degrees of severity or non-pathogenic , and the other 16 were novel mutations (Figure 1), which needed to be verified according to individual IDS activity by using in vitro expression studies.

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Section: The Quantitative Analysis Of Urinary Gag-derived Disaccharidsupporting

confidence: 56%

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Lin

Chern

et al. 2019

IJMS

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“…The "skeletal" group is caused by KS and includes MPS IVA, with manifestations of joint laxity, odontoid hypoplasia, genu valgum, extreme short stature, and skeletal dysplasia. The amounts of the affected GAG-derived disaccharides have been associated with the clinical presentations, onset, and severity of MPS disorders [25][26][27][28]. Settembre et al [29] reported that GAG accumulation in lysosomes disrupts autophagy, which is important for chondrocyte metabolism during endochondral ossification, leading to chondrocyte viability and thus the development of skeletal abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Relationships among Height, Weight, Body Mass Index, and Age in Taiwanese Children with Different Types of Mucopolysaccharidoses

et al. 2019

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Background: Children with mucopolysaccharidosis (MPS) generally appear unaffected at birth but may develop multiple clinical manifestations including profound growth impairment as they grow older. Each type of MPS has a variable age at onset and variable rate of progression, however, information regarding growth in Asian children is limited. Methods: This retrospective analysis included 129 Taiwanese patients with MPS (age range, 0.7 to 19.5 years, median age, 7.9 years) from eight medical centers in Taiwan from January 1996 through December 2018. Results: The mean z scores for the first recorded values of height, weight, and body mass index in the patients’ medical records were −4.25, −1.04, and 0.41 for MPS I (n = 9), −2.31, 0.19, and 0.84 for MPS II (n = 49), −0.42, 0.08, and −0.12 for MPS III (n = 27), −6.02, −2.04, and 0.12 for MPS IVA (n = 30), and −4.46, −1.52, and 0.19 for MPS VI (n = 14), respectively. MPS IVA had the lowest mean z scores for both height and weight among all types of MPS, followed by MPS VI, MPS I, MPS II, and MPS III, which showed the mildest growth retardation. Both z scores for height and weight were negatively correlated with increasing age for all types of MPS (p < 0.01). Of 32 patients younger than 5 years of age, 16 (50%), and 23 (72%) had positive z scores of height and weight, respectively. A substantial number of younger patients with MPS I, II, III, and IVA had a positive height z score. The median age at diagnosis was 3.9 years (n = 115). Conclusions: The patients with MPS IVA had the most significant growth retardation among all types of MPS, followed by MPS VI, MPS I, MPS II, and MPS III. The height and weight of the MPS patients younger than 2–5 years of age were higher than those of healthy individuals, however, their growth significantly decelerated in subsequent years. Understanding the growth curve and potential involved in each type of MPS may allow for early diagnosis and timely management of the disease, which may improve the quality of life.

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“…Total urine GAGs concentrations have been used in the Phase II/III trials as markers of the biochemical efficacy of ERT [17][18][19]21,22,30,31,33] and their level can be correlated with the different severity of phenotypes [118,119]. Their decrease is dramatic in the first 6-12 months of treatment and is sustained over the years tending to normalize in almost all patients [29,[34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52].…”

Section: Gags and Other Possible Biomarkersmentioning

confidence: 99%

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Parini

Deodato

2020

IJMS

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The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.

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The relationships between urinary glycosaminoglycan levels and phenotypes of mucopolysaccharidoses

Cited by 24 publications

References 39 publications

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II)

Relationships among Height, Weight, Body Mass Index, and Age in Taiwanese Children with Different Types of Mucopolysaccharidoses

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

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