A click-flipped enzyme substrate boosts the performance of the diagnostic screening for Hunter syndrome.
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ABSTRACT:
SUBMITTER: Schwarz M
PROVIDER: S-EPMC8163285 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mucopolysaccharidosis II (Hunter syndrome) is a rare x-linked disorder caused by a deficiency in the lysosomal enzyme iduronate-2-sulphatase, leading to an accumulation of the glycosaminoglycans (GAGs) dermatansulphate and heparan sulphate. The consequence of GAGs accumulation is progressive, multiorgan disease. Enzyme-replacement therapy is hypothesised to result in disease stabilisation and improved prognosis. We present a severe case of Hunter syndrome diagnosed at age 2 years and 4 months, who started enzyme-replacement therapy at the age of 3 years and 3 months. We report his evolution after 1 year of treatment. The treatment response was good and there was significant improvement in the quality of life. Owing to the rarity of Hunter syndrome, the multisystem nature and the heterogeneity of disease progression, patient care implies interdisciplinary consultations with a wide range of specialists. The best management can be provided in reference centres for metabolic diseases.
| S-EPMC3603921 | biostudies-literature
Project description:BackgroundNowadays, more and more novel enzymes can be easily found in the whole enzyme pool with the rapid development of genetic operation. However, experimental work for substrate screening of a new enzyme is laborious, time consuming and costly. On the other hand, many computational methods have been widely used in lead screening of drug design. Seeing that the ligand-target protein system in drug design and the substrate-enzyme system in enzyme applications share the similar molecular recognition mechanism, we aim to fulfill the goal of substrate screening by in silico means in the present study.ResultsA computer-aided substrate screening (CASS) system which was based on the enzyme structure was designed and employed successfully to help screen substrates of Candida antarctica lipase B (CALB). In this system, restricted molecular docking which was derived from the mechanism of the enzyme was applied to predict the energetically favorable poses of substrate-enzyme complexes. Thereafter, substrate conformation, distance between the oxygen atom of the alcohol part of the ester (in some compounds, this oxygen atom was replaced by nitrogen atom of the amine part of acid amine or sulfur atom of the thioester) and the hydrogen atom of imidazole of His224, distance between the carbon atom of the carbonyl group of the compound and the oxygen atom of hydroxyl group of Ser105 were used sequentially as the criteria to screen the binding poses. 223 out of 233 compounds were identified correctly for the enzyme by this screening system. Such high accuracy guaranteed the feasibility and reliability of the CASS system.ConclusionThe idea of computer-aided substrate screening is a creative combination of computational skills and enzymology. Although the case studied in this paper is tentative, high accuracy of the CASS system sheds light on the field of computer-aided substrate screening.
| S-EPMC2745390 | biostudies-literature
Project description:A 3.5 year old Hispanic female presented with signs and symptoms concerning for MPS II (Hunter Syndrome). The diagnosis of MPS II was confirmed by enzyme and molecular testing. Genetic evaluation revealed undetectable plasma iduronate-2-sulfatase enzyme activity and an inversion between intron 7 of the IDS gene and a region near exon 3 of IDS-2. This inversion is the molecular cause for ~8% of cases of MPS II and often results in a severe phenotype. X-inactivation studies revealed an inactivation ratio of 100:0. Given the patient's undetectable enzyme level, in combination with a severe IDS gene mutation, classic features at time of presentation, and the significantly skewed X inactivation, there was concern that she was at high risk of developing high and sustained antibody titers to idursulfase which would limit her benefit from enzyme replacement therapy (ERT). Anti-drug neutralizing antibodies to idursulfase have been associated with reduced systemic exposure to idursulfase and poorer clinical outcomes. Therefore, the decision was made to concurrently treat the patient with immune tolerance induction therapy during the first month of treatment with idursulfase in order to decrease the risk of developing high sustained antibody titers. The immune tolerance induction protocol consisted of rituximab weekly for 4 weeks, methotrexate three times a week for 3 weeks and monthly IVIG through B-cell and immunoglobulin recovery. Immune tolerance induction was initiated concurrently with the start of ERT. The patient had no significant adverse effects related to undergoing immune tolerance induction therapy and two and half years later is doing well with significantly reduced urine glycosaminoglycans and very low anti-drug antibody titers. This immune tolerance induction protocol could be considered for other patients with MPS II as well as patients with other lysosomal storage disorders who are starting on enzyme replacement therapy and are at high risk of developing neutralizing anti-drug antibodies.
| S-EPMC7253587 | biostudies-literature
Project description:UnlabelledIntravenous enzyme replacement therapy (ERT) with idursulfase for Hunter syndrome has not been demonstrated to and is not predicted to cross the blood-brain barrier. Nearly all published experience with ERT with idursulfase has therefore been in patients without cognitive impairment (attenuated phenotype). Little formal guidance is available on the issues surrounding ERT in cognitively impaired patients with the severe phenotype. An expert panel was therefore convened to provide guidance on these issues. The clinical experience of the panel with 66 patients suggests that somatic improvements (e.g., reduction in liver volume, increased mobility, and reduction in frequency of respiratory infections) may occur in most severe patients. Cognitive benefits have not been seen. It was agreed that, in general, severe patients are candidates for at least a 6-12-month trial of ERT, excluding patients who are severely neurologically impaired, those in a vegetative state, or those who have a condition that may lead to near-term death. It is imperative that the treating physician discuss the goals of treatment, methods of assessment of response, and criteria for discontinuation of treatment with the family before ERT is initiated.ConclusionThe decision to initiate ERT in severe Hunter syndrome should be made by the physician and parents and must be based on realistic expectations of benefits and risks, with the understanding that ERT may be withdrawn in the absence of demonstrable benefits.
| S-EPMC3249184 | biostudies-literature
Project description:To assess the variation in diagnostic performance among radiologists at screening computed tomographic (CT) colonography.In this HIPAA-compliant, institutional review board-approved study, 6866 asymptomatic adults underwent first-time CT colonographic screening at a single center between January 2005 and November 2011. Results of examinations were interpreted by one of eight board-certified abdominal radiologists (mean number of CT colonographic studies per reader, 858; range, 131-2202). Findings at CT colonography and subsequent colonoscopy were recorded, and key measures of diagnostic performance, including adenoma and advanced neoplasia detection rate, were compared among the radiologists.The overall prevalence of histopathologically confirmed advanced neoplasia was 3.6% and did not differ significantly among radiologists (range, 2.4%-4.4%; P = .067; P = .395 when one outlier was excluded). Overall, 19.5% of polyps detected at CT colonography proved to be advanced neoplasia and did not differ significantly among radiologists (range, 14.4%-23.2%; P = .223). The overall per-polyp endoscopic confirmation rate was 93.5%, ranging from 80.0% to 97.6% among radiologists (P = .585). The overall percentage of nondiagnostic CT colonographic examinations was 0.7% and was consistent among radiologists (range, 0.3%-1.1%; P = .509).Consistent performance for adenoma and advanced neoplasia detection, as well as other clinically relevant end points, were observed among radiologists at CT colonographic screening.
| S-EPMC3689445 | biostudies-other
Project description: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.
| S-EPMC3924006 | biostudies-literature
Project description:Patients with Hunter syndrome (mucopolysaccharidosis II) present with skeletal dysplasia including short stature as well as CNS and visceral organ involvement. A previous study on Hunter syndrome indicated an impact on brain and heart involvement after hematopoietic stem cell therapy (HSCT) at an early stage but little impact after enzyme replacement therapy (ERT) (Tanaka et al 2012). Meanwhile, impact on growth in patients with Hunter syndrome treated with ERT and HSCT has not been compared until now. We recently developed baseline growth charts for untreated patients with Hunter syndrome to evaluate the natural history of growth of these patients compared to unaffected controls (Patel et al, 2014). To assess impact of ERT and HSCT on growth, clinical data were obtained from 44 Japanese male patients with MPS II; 26 patients had been treated with ERT, 12 patients had been treated with HSCT, and 6 had been treated with both ERT and HSCT. Height and weight were compared to untreated patients and unaffected controls from the previous study. We demonstrated 1) that MPS II patients, who had been treated with either ERT or HSCT, had increased height and weight when compared to untreated patients, and 2) that HSCT and ERT were equally effective in restoring growth of MPS II patients. In conclusion, HSCT should be considered as one of the primary therapeutic options for early stage treatment of MPS II, as HSCT has also been reported to have a positive effect on brain and heart valve development (Tanaka et al 2012).
| S-EPMC4104387 | biostudies-literature
Project description:Serine peptidases of the prolyl oligopeptidase (POP) family are of substantial therapeutic importance because of their involvement in diseases such as diabetes, cancer, neurological diseases, and autoimmune disorders. Proper annotation and knowledge of substrate specificity mechanisms in this family are highly valuable. Although endopeptidase, dipeptidyl peptidase, tripeptidyl peptidase, and acylaminoacyl peptidase activities have been reported previously, here we report the first instance of carboxypeptidase activity in a POP family member. We determined the crystal structures of this carboxypeptidase, an S9C subfamily member from Deinococcus radiodurans, in its active and inactive states at 2.3-Å resolution, providing an unprecedented view of assembly and disassembly of the active site mediated by an arginine residue. We observed that this residue is poised to bind substrate in the active structure and disrupts the catalytic triad in the inactive structure. The assembly of the active site is accompanied by the ordering of gating loops, which reduces the effective size of the oligomeric pore. This prevents the entry of larger peptides and constitutes a novel mechanism for substrate screening. Furthermore, we observed structural adaptations that enable its carboxypeptidase activity, with a unique loop and two arginine residues in the active site cavity orienting the peptide substrate for catalysis. Using these structural features, we identified homologs of this enzyme in the POP family and confirmed the presence of carboxypeptidase activity in one of them. In conclusion, we have identified a new type within POP enzymes that exhibits not only unique activity but also a novel substrate-screening mechanism.
| S-EPMC6322877 | biostudies-literature
Project description:Children with mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, an X-linked disorder, suffer from a multisystem dysfunction caused by the accumulation of glycosaminoglycans. However, there has been no systemic report on the growth of patients with MPS II. The purpose of this study is to describe the growth patterns of patients with MPS II and to compare with the patterns of age-matched controls. Data (height, weight, age, etc.) was collected in a longitudinal study of Japanese male patients with MPS II (n = 111). The mean birth length was 50.31 ± 1.42 cm, while the mean birth weight was 3.35 ± 0.39 kg. The mean final height and weight at 18 years and older were 125.63 ± 9.09 cm and 37.18 ± 8.72 kg; corresponding to a difference of -46.40 cm and -25.89 kg lower, when compared with healthy Japanese male controls. The mean birth BMI was 10.84 ± 3.29 kg/m2, while the mean BMI at 18 years was 29.41 ± 6.15 kg/m2. The growth pattern in patients with MPS II was characterized by overgrowth for the first several years, although growth velocity fell below that of the normal healthy controls after one year of age. No statistical difference in height was observed between patients with the attenuated and severe phenotypes in each age class. In conclusion, this report describes the natural history of growth in patients with MPS II, which can help in monitoring the progression of the disease as well as assessing therapeutic efficacy.
| S-EPMC4060980 | biostudies-literature
Project description:Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a member of a group of inherited metabolic disorders together termed mucopolysaccharidosis (MPSs). It is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. The prevalence of this syndrome is 1:100,000 births. Insufficient enzyme activity results in accumulation of glycosaminoglycans (GAGS) in the lysosomes of various tissues and organs and leading to progressive multisystem pathologies. Here, we report a case of 13-year-old boy who presented with typical facial, skeletal and dental features without corneal clouding. It is possible that thorough and systematic clinical and radiological examination alone can help in diagnosis of this complex disorder.
| S-EPMC4437174 | biostudies-literature