Birth weight in patients with mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS).
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ABSTRACT:
SUBMITTER: Bodamer O
PROVIDER: S-EPMC5426030 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
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Birth weight in patients with mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS).
Bodamer Olaf O Scarpa Maurizio M Hung Christina C Pulles Tom T Giugliani Roberto R
Molecular genetics and metabolism reports 20170503
There is a need to identify early disease markers to facilitate diagnosis of mucopolysaccharidosis type II (MPS II; Hunter syndrome). Mean birth weight and its association with disease severity was investigated in 609 patients enrolled in the Hunter Outcome Survey (HOS). This analysis indicated that birth weight is not an early marker of MPS II and is not associated with disease severity. It remains important to investigate the utility of other factors for early/pre-symptomatic diagnosis. ...[more]
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Project description:Several cases of phenotypic variability among family members with mucopolysaccharidosis type II (MPS II) have been reported, but the data are limited. Data from patients enrolled in the Hunter Outcome Survey (HOS) were used to investigate intrafamilial variability in male siblings with MPS II. As of July 2015, data were available for 78 patients aged ?5 years at last visit who had at least one affected sibling (39 sibling pairs). These patients were followed prospectively (i.e., they were alive at enrollment in HOS). The median age at the onset of signs and symptoms was the same for the elder and younger brothers (2.0 years); however, the younger brothers were typically diagnosed at a younger age than the elder brothers (median age, 2.5 and 5.1 years, respectively). Of the 39 pairs, eight pairs were classified as being discordant (the status of four or more signs and symptoms differed between the siblings); 21 pairs had one, two, or three signs and symptoms that differed between the siblings, and 10 pairs had none. Regression status of the majority of the developmental milestones studied was generally concordant among siblings. Functional classification, a measure of central nervous system involvement, was the same in 24/28 pairs, although four pairs were considered discordant as functional classification differed between the siblings. Overall, this analysis revealed similarity in the clinical manifestations of MPS II among siblings. This information should help to improve our understanding of the clinical presentation of the disease, including phenotype prediction in affected family members.
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Project description:BACKGROUND:Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S). Treatment is available in the form of enzyme replacement therapy (ERT) with recombinant I2S. Clinical outcomes following ?3 years of ERT with idursulfase were investigated in a broad population of patients with MPS II enrolled in the Hunter Outcome Survey (HOS). METHODS:As of January 2016, 639 patients (excluding female patients, individuals who had received a bone marrow transplant and those enrolled in the phase 1/2 [TKT018] or phase 2/3 [TKT024] clinical trial) followed prospectively in the registry had received idursulfase for ?6 months. These individuals all had data available for ?1 clinical parameter at baseline and ?1 additional time point following treatment initiation. Changes in clinical parameters were assessed in the subcohorts of patients with a measurement at baseline and at year 1, 2 or 3 of treatment. Safety data from patients who started treatment at or after enrollment in HOS (n = 233) were also assessed. RESULTS:Median (10th, 90th percentiles) age at first treatment was 6.2 (2.1, 18.2) years and median treatment duration was 56.3 (18.2, 97.6) months. Urinary glycosaminoglycan (uGAG) levels decreased from baseline to year 3 in patients with data available at this time point (median change from baseline: -201.0 [-591.4, -21.9] ?g/mg creatinine [n = 121]). Improvements in the following parameters were observed at year 3 in the subcohorts: 6-min walking test (6MWT) distance, 10.6 (-33.6, 50.8)% (n = 26); left ventricular mass index (LVMI), -9.3 (-31.5, 19.7)% (n = 52); absolute forced vital capacity (FVC), 29.7 (-13.4, 66.7)% (n = 23); absolute forced expiratory volume in 1 s (FEV1), 22.8 (-15.2, 62.1)% (n = 22); palpable liver size, -54.5 (-85.7, 50.0)% (n = 53); palpable spleen size, -33.3 (-80.0, 33.3)% (n = 17). No new or unexpected safety concerns were identified in this analysis. CONCLUSIONS:These findings suggest that idursulfase has a positive effect on uGAG levels, 6MWT results, LVMI, FVC, FEV1 and hepatosplenomegaly after 1, 2 and 3 years treatment.
| S-EPMC5627440 | biostudies-literature
Project description:BACKGROUND:Mucopolysaccharidosis type II (MPS II) is the most frequently occurring MPS in Taiwan, with an incidence of 2.05 per 100,000 live male births, but little is known about clinical characteristics and surgical history in Taiwanese patients. METHODS:Medical history, demographics, signs and symptoms, and surgical history were analysed in all patients from Taiwanese centres in the Hunter Outcome Survey (HOS; NCT 03292887), a global, multicentre registry that collects real-world data on patients with MPS II. RESULTS:As of January 2016, 61 male Taiwanese patients were enrolled; 49% (24/49) had received at least one infusion of idursulfase. Median (10th, 90th percentiles) ages at signs and symptom onset and at diagnosis were 2.5 (0.2, 5.5) years (n?=?55) and 3.5 (1.2, 11.9) years (n?=?56), respectively. Hernia, facial features consistent with MPS II and claw hands were the earliest presenting signs and symptoms (median ages of 3.2 [0.4, 12.0] years, 4.3 [1.1, 12.0] years and 4.7 [2.5, 12.2] years [n?=?45, 53 and 50], respectively). More than 75% of patients had undergone a surgical procedure, most commonly hernia repair (57% of patients). Median age at first surgery for hernia repair was 4.2 (0.5, 9.8) years (n?=?35). Almost one-third (31.1%) of patients had at least one surgical procedure before diagnosis, and of the 20 procedures before diagnosis, 16 were hernia repair. CONCLUSIONS:This information from patients in HOS highlights the importance of both medical and surgical history in diagnosing MPS II in Taiwanese patients.
| S-EPMC5987665 | biostudies-literature
Project description:Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, inherited disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. As a result of this deficiency, glycosaminoglycans accumulate in lysosomes in many tissues, leading to progressive multisystemic disease. The cardiopulmonary and neurological problems associated with MPS II have received considerable attention. Orthopedic manifestations are common but not as well characterized. This study aimed to characterize the prevalence and severity of orthopedic manifestations of MPS II and to determine the relationship of these signs and symptoms with cardiovascular, pulmonary and central nervous system involvement.Orthopedic manifestations of MPS II were studied using cross-sectional data from the Hunter Outcome Survey (HOS). The HOS is a global, physician-led, multicenter observational database that collects information on the natural history of MPS II and the long-term safety and effectiveness of enzyme replacement therapy.As of January 2009, the HOS contained baseline data on joint range of motion in 124 males with MPS II. In total, 79% of patients had skeletal manifestations (median onset, 3.5 years) and 25% had abnormal gait (median onset, 5.4 years). Joint range of motion was restricted for all joints assessed (elbow, shoulder, hip, knee and ankle). Extension was the most severely affected movement: the exception to this was the shoulder. Surgery for orthopedic problems was rare. The presence of orthopedic manifestations was associated with the presence of central nervous system and pulmonary involvement, but not so clearly with cardiovascular involvement.Orthopedic interventions should be considered on an individual-patient basis. Although some orthopedic manifestations associated with MPS II may be managed routinely, a good knowledge of other concurrent organ system involvement is essential. A multidisciplinary approach is required.
| S-EPMC3143973 | biostudies-literature
Project description:BackgroundMucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates.ResultsIn total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > -75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start.ConclusionsThese findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.
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Project description:IntroductionMucopolysaccharidosis Type II (MPS II; Hunter syndrome) is an X- linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). IDS deficiency leads to primary accumulation of dermatan sulfate (DS) and heparan sulfate (HS). MPS II is both multi-systemic and progressive. Phenotypes are classified as either attenuated or severe (based on absence or presence of central nervous system impairment, respectively).Areas coveredCurrent treatments available are intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), anti-inflammatory treatment, and palliative care with symptomatic surgeries. Clinical trials are being conducted for intrathecal ERT and gene therapy is under pre-clinical investigation. Treatment approaches differ based on age, clinical severity, prognosis, availability and feasibility of therapy, and health insurance.This review provides a historical account of MPS II treatment as well as treatment development with insights into benefits and/or limitations of each specific treatment.Expert opinionConventional ERT and HSCT coupled with surgical intervention and palliative therapy are currently the treatment options available to MPS II patients. Intrathecal ERT and gene therapy are currently under investigation as future therapies. These investigative treatments are critical to address the limitations in treatment of the central nervous system (CNS).
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Project description:Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare lysosomal storage disease with progressive multisystem manifestations caused by deficient activity of the enzyme iduronate-2-sulfatase. Disease-specific treatment is available in the form of enzyme replacement therapy with intravenous idursulfase (Elaprase®, Shire). Since 2005, the Hunter Outcome Survey (HOS) has collected real-world, long-term data on the safety and effectiveness of this therapy, as well as the natural history of MPS II. Individuals with a confirmed diagnosis of MPS II who are untreated or who are receiving/have received treatment with idursulfase or bone marrow transplant can be enrolled in HOS. A broad range of disease- and treatment-related information is captured in the registry and, over the past decade, data from more than 1000 patients from 124 clinics in 29 countries have been collected. Evidence generated from HOS has helped to improve our understanding of disease progression in both treated and untreated patients and has extended findings from the formal clinical trials of idursulfase. As a long-term, global, observational registry, various challenges relating to data collection, entry, and analysis have been encountered. These have resulted in changes to the HOS database platform, and novel approaches to maximize the value of the information collected will also be needed in the future. The continued evolution of the registry should help to ensure that HOS provides further insights into the burden of the disease and patient care and management in the coming years.
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Project description:Hunter syndrome (mucopolysaccharidosis type II (MPS II)) is a rare metabolic disease that can severely compromise health, well-being and life expectancy. Little evidence has been published on the impact of MPS II on health-related quality of life (HRQL). The objective of this study was to describe this impact using the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire and a range of standard validated questionnaires previously used in paediatric populations.Clinical and demographic characteristics collected in a clinical trial and responses to four HRQL questionnaires completed both by patients and parents prior to enzyme replacement treatment were used. The association between questionnaire scores and clinical function parameters were tested using Spearman rank-order correlations. Results were compared to scores in other paediatric populations with chronic conditions obtained through a targeted literature search of published studies.Overall, 96 male patients with MPS II and their parents were enrolled in the trial. All parents completed the questionnaires and 53 patients above 12 years old also completed the self-reported versions. Parents' and patients' responses were analysed separately and results were very similar. Dysfunction according to the HS-FOCUS and the CHAQ was most pronounced in the physical function domains. Very low scores were reported in the Self Esteem and Family Cohesion domains in the CHQ and HUI3 disutility values indicated a moderate impact. Scores reported by patients and their parents were consistently lower than scores in the other paediatric populations identified (except the parent-reported Behaviour score); and considerably lower than normative values.This study describes the impact on HRQL in patients with MPS II and provides a broader context by comparing it with that of other chronic paediatric diseases. Physical function and the ability to perform day-to-day activities were the most affected areas and a considerable impact on the psychological aspects of patients' HRQL was also found, with a higher level of impairment across most dimensions (particularly Pain and Self Esteem) than that of other paediatric populations. Such humanistic data provide increasingly important support for establishing priorities for health care spending, and as a component of health economic analysis.
| S-EPMC3722040 | biostudies-literature
Project description:BackgroundHunter syndrome (mucopolysaccharidosis type II) is a recessive X-linked disorder due to mutations in the iduronate 2-sulfatase (IDS) gene. The IDS gene encodes a lysosomal enzyme, iduronate 2-sulfatase. The disease occurs almost exclusively in males. However, in the literature, 12 cases of the disease in females are known due to structural anomalies, a non-random chromosome X inactivation or chromosome X monosomy. The purpose of this article is to demonstrate a rare case of Hunter syndrome in a girl caused by a mutation in the IDS gene inherited from the mother and the presence of chromosome X of paternal origin, partially deleted in the long arm region - 46,X,del(X)(q22.1).Case presentationGirl M., 4 years old, entered the hospital with growth retardation, pain in the lower limbs, and joint stiffness, noted from the age of 18 months. After the karyotype analysis, which revealed a partial deletion of the long arm of chromosome X - 46, X, del (X) (q 22.1), Turner syndrome was diagnosed. However, due to the hurler-like facial phenotype, Hurler syndrome or type I mucopolysaccharidosis (MPS) was suspected. The study of lysosomal enzymes showed normal alpha-L-iduronidase activity and a sharp decrease in the activity of iduronate sulfatase in the blood: 0.001 μM/l/h, at a rate of 2.5-50 μM/l/h. Molecular genetic analysis revealed a hemizygous deletion in the IDS gene, which was not registered in the international Human Gene Mutation Database (HGMD) professional. This deletion was not detected in the girl's father, but was detected in her mother in the heterozygous state.ConclusionsThus, the girl confirmed comorbidity - Turner syndrome with a partial deletion of the long arm of chromosome X of paternal origin, affecting the Xq28 region (localization of the IDS gene), and Hunter syndrome due to a deletion of the IDS gene inherited from the mother. The structural defect of chromosome X in the girl confirmed the hemizygous state due to the mutation in the IDS gene, which has led to the formation of the clinical phenotype of Hunter syndrome.
| S-EPMC6498611 | biostudies-literature
Project description: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.137A>C, c.311A>T, c.454A>C, c.797C>G, c.817C>T, c.998C>T, c.1106C>G, c.1400C>T, c.1402C>T, 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).
| S-EPMC6982257 | biostudies-literature