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Objective: To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI., Methods: In 2005, the multi-national, MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A sub-analysis was performed in patients who started ERT at ≥16 years of age and had received galsulfase for ≥6 months. Urinary glycosaminoglycans (uGAG), 6-min walk test (6MWT), 3-min stair climb test (3MSCT), pulmonary function measures, cardiac function, ophthalmology measures, liver and spleen sizes, and safety were evaluated., Results: Of 223 patients enrolled in the CSP, 51 were included in the sub-analysis. Patients were between 16 and 63 years of age at first infusion. From pre-treatment baseline, uGAG level decreased by a mean (±standard deviation [SD]) of 66 (±45)% (N = 29) after a median follow-up of 7.2 years. 6MWT distance decreased slightly by a mean of 17 (±107) meters (N = 23) after 6.6 years. Stairs/min in the 3MSCT increased by a mean of 26 (±33) (N = 14) after 2.8 years. Pulmonary function measures, forced expiratory volume in 1 second and forced vital capacity, increased by a mean of 0.06 (±0.21) L after 7.3 years and 0.05 (±0.28) L after 7.2 years, respectively (N = 19 for both measures). Overall, galsulfase was well tolerated, with most adverse events reported being MPS-related clinical manifestations and not related to galsulfase., Conclusions: Results of this sub-analysis of the CSP suggest that initiation of galsulfase in adulthood is well tolerated and can possibly stabilize MPS VI in the long term., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distinct mutations in the B4GALNT1 gene, encoding GM2/GD2/GA2 synthase. Patients suffering from ST3GAL5 deficiency present a devastating syndrome characterized by early onset and dramatic neurological and cognitive impairment, sometimes associated with dyspigmentation and an increased blood lactate concentration. On the other hand, B4GALNT1 mutations give rise to a form of complicated hereditary spastic paraplegia (HSP), previously referred to as HSP26. It is characterized by the late onset of lower limb weakness and mild to moderate intellectual impairment, which is usually not progressive. In addition to the most typical signs, some patients present ocular and endocrine signs, pes cavus, and psychiatric illness. Since the nineties, mice lacking genes for single glycosyltransferases involved in ganglioside biosynthesis, including ST3GAL5 and B4GALNT1, were created and studied. The resulting phenotypes were frequently mild or very mild, so double knock-out animals were created to effectively study the function of gangliosides. The main clinical and biochemical features of patients suffering from GM3 synthase or GM2/GD2/GA2 synthase deficiency, compared with the phenotypes described in mice that are null for single or multiple glycosyltransferase genes, provide suggestions to improve the recognition of novel mutations and potentially related disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR-004). Changes in efficacy endpoints were evaluated over 120weeks, from MOR-004 baseline to MOR-005 week 96. We report the impact of ERT on activities of daily living (ADL) across three domains (mobility, self-care, and caregiver-assistance), as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ) after 72 and 120weeks or approximately 1 and 2years., Results: Mean baseline MPS-HAQ domain scores showed impairments in mobility, self-care, and independence. The MOR-005 intent-to-treat population (ITT; N=169, including 158 with 2years follow-up) showed sustained significant reductions (representing improvements) in mobility and self-care domain least square (LS) mean scores vs. baseline at 1 and 2years and a non-significant decrease in the caregiver-assistance domain at 2years. At week 120, LS mean (SE) changes from baseline were -0.5 (0.1) for mobility (P=0.002), -0.4 (0.1) for self-care (P=0.001), and -1.0 (0.5) for caregiver-assistance (P=0.06) (ITT population). Improvements in MPS-HAQ domain scores vs. baseline at 1 and 2years were greater in patients continuously treated with the weekly dosing regimen than in the total MOR-005 population and statistically significant across domains. A comparable untreated cohort of patients from the Morquio A Clinical Assessment Program (MorCAP) natural history study (ITT population, N=94, including 37 with 2years follow-up) showed no improvement over 2years, with two of the three domains worsening (LS mean (SE) changes from baseline: 0.3 (0.3) for mobility, 0.4 (0.2) for self-care, -0.5 (0.8) for caregiver-assistance). Changes in LS mean scores vs. baseline were statistically significantly different between MOR-005 and MorCAP for the mobility domain (-0.7 (SE 0.4), P=0.0490) and the self-care domain (-0.7 (SE 0.3), P=0.0146) at 2years., Conclusions: Together, these findings suggest that long-term elosulfase alfa ERT is associated with partial recovery of functional abilities, improving Morquio A patients' abilities to perform ADL., Trial Registration: ClinicalTrials.govNCT01415427. Registered 8 August 2011, retrospectively registered., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N=173), analyses were also performed for a modified per-protocol (MPP) population (N=124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3)m and 39.9 (10.1)m for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study (N=56) and 15.1 (7.1)m and 31.7 (6.8)m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0)stairs/min for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3)stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was -59.4 (1.8)% and -62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P<0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Hunter syndrome (mucopolysaccharidosis type II) affects growth but the overall impact is poorly understood. This study investigated the natural history of growth and related parameters and their relationship with disease severity (as indicated by cognitive impairment). Natural history data from males followed prospectively in the Hunter Outcome Survey registry and not receiving growth hormone or enzyme replacement therapy, or before treatment start, were analysed (N=676; January 2014). Analysis of first-reported measurements showed short stature by 8years of age; median age-corrected standardized height score (z-score) in patients aged 8-12years was -3.1 (1st, 3rd quartile: -4.3, -1.7; n=68). Analysis of growth velocity using consecutive values found no pubertal growth spurt. Patients had large head circumference at all ages, and above average body weight and body mass index (BMI) during early childhood (median z-score in patients aged 2-4years, weight [n=271]: 1.7 [0.9, 2.4]; BMI [n=249]: 2.0 [1.1, 2.7]). Analysis of repeated measurements over time found greater BMI in those with cognitive impairment than those without, but no difference in height, weight or head circumference. Logistic regression modelling (data from all time points) found that increased BMI was associated with the presence of cognitive impairment (odds ratio [95% CI], 3.329 [2.313-4.791]), as were increased weight (2.365 [1.630-3.433]) and head circumference (1.749 [1.195-2.562]), but not reduced height. Unlike some other MPS disorders, there is no evidence at present for predicting disease severity in patients with Hunter syndrome based on changes in growth characteristics., (Copyright © 2016. Published by Elsevier Inc.)

Objective: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA)., Methods: Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well., Results: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa., Conclusions: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population., (Copyright © 2014. Published by Elsevier Inc.)

Objectives: Baseline data from the Morquio A Clinical Assessment Program (MorCAP) revealed that individuals with Morquio A syndrome show substantial impairment in multiple domains including endurance and respiratory function (Harmatz et al., Mol Genet Metab, 2013). Here, 1- and 2-year longitudinal endurance and respiratory function data are presented., Methods: Endurance was assessed using the 6-minute walk test (6MWT) and the 3-minute stair climb test (3MSCT). Respiratory function was evaluated by measuring forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Data were analyzed using repeated measures ANCOVA models. Annualized estimates of change were determined using model estimates and interpolation., Results: 353, 184, and 78 subjects were assessed at Year 0 (baseline), Year 1, and Year 2, respectively. The overall annualized estimate of change (SE) in 6MWT distance was -4.86±3.25m; a larger decline of -6.84±5.38m was observed in the subset of subjects meeting the inclusion/exclusion criteria of the Phase 3 clinical trial of elosulfase alfa (≥5years of age with baseline 6MWT distance ≥30 and ≤325m). In contrast, little change (-0.14±0.60stairs/min) was observed in 3MSCT. Annualized changes (SE) in FVC and MVV were 2.44±0.68% and 1.01±2.38%, respectively. FVC and MVV increased in patients aged ≤14years, but decreased in older patients., Conclusions: The natural history of Morquio A syndrome is characterized by progressive impairment of endurance as measured by the 6MWT. Longitudinal trends in FVC and MVV showing increase in younger patients, but decrease in older patients, are likely to be influenced by growth. Changes in 6MWT may represent a sensitive measure of disease progression in ambulatory Morquio A patients., (Copyright © 2014. Published by Elsevier Inc.)

Objectives: The objectives of this study are to quantify endurance and respiratory function and better characterize spectrum of symptoms and biochemical abnormalities in mucopolysaccharidosis IVA subjects., Methods: MorCAP was a multicenter, multinational, cross sectional study amended to be longitudinal in 2011. Each study visit required collection of medical history, clinical assessments, and keratan sulfate (KS) levels., Results: Data from the first visit of 325 subjects (53% female) were available. Mean age was 14.5 years. Mean ± SD height z-scores were -5.6 ± 3.1 as determined by the CDC growth charts. Mean ± SD from the 6-minute-walk-test was 212.6 ± 152.2m, revealing limitations in functional endurance testing, and 30.0 ± 24.0 stairs/min for the 3-minute-stair-climb test. Respiratory function showed limitations comparable to MPS VI patients; mean ± SD was 1.2 ± 0.9l based on forced vital capacity and 34.8 ± 25.5l/min based on maximum voluntary ventilation. Mean urinary keratan sulfate (uKS) was elevated for all ages, and negatively correlated with age. Higher uKS correlated with greater clinical impairment based on height z-scores, endurance and respiratory function tests. The MPS Health Assessment Questionnaire reveals impairments in mobility and activities of daily living in comparison to an age-matched control population., Conclusions: MPS IVA is a multisystem disorder with a continuum of clinical presentation. All affected individuals experience significant functional limitations and reduced quality of life. Older patients have more severe exercise and respiratory capacity limitations, and more frequent cardiac pathology illustrating the progressive nature of disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hunter syndrome (mucopolysaccharidosis type II) is a rare and life-limiting multisystemic disorder with an X-linked recessive pattern of inheritance. Short stature is a prominent feature of this condition. This analysis aimed to investigate the effects of enzyme replacement therapy with idursulfase on growth in patients enrolled in HOS - the Hunter Outcome Survey which is a multinational observational database. As of Jan 2012, height data before treatment were available for 567 of 740 males followed prospectively after HOS entry. Cross-sectional analysis showed that short stature became apparent after approximately 8 years of age; before this, height remained within the normal range. Age-corrected standardized height scores (z-scores) before and after treatment were assessed using piecewise regression model analysis in 133 patients (8-15 years of age at treatment start; data available on ≥ 1 occasion within +/-24 months of treatment start; growth hormone-treated patients excluded). Results showed that the slope after treatment (slope=-0.005) was significantly improved compared with before treatment (slope=-0.043) (difference=0.038, p=0.004). Analysis of covariates (age at treatment start, cognitive involvement, presence of puberty at the start of ERT, mutation type, functional classification), showed a significant influence on growth of mutation type (height deficit in terms of z-scores most pronounced in patients with deletions/large rearrangements/nonsense mutations, p<0.0001) and age (most pronounced in the 12-15-year group, p<0.0001). Cognitive involvement, pubertal status at the start of ERT and functional classification were not related to the growth deficit or response to treatment. In conclusion, the data showed an improvement in growth rate in patients with Hunter syndrome following idursulfase treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)