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Background: Associated with enzyme deficiencies causing glycosaminoglycans (GAGs) accumulation, mucopolysaccharidosis type VI (MPS VI) is lysosomal storage disorder. In the treatment of MPS VI, galsulfase (Naglazyme) is commonly used as an enzyme replacement therapy (ERT). There remains a need for comprehensive real-world data on its safety and associated adverse events (AEs). Objective: An analysis of the FDA Adverse Event Reporting System (FAERS) database will be conducted to identify potential risks and adverse reactions associated with galsulfase in real-life settings. Methods: The FAERS database was used to extract data from Q2 2005 to Q4 2023. A total of 20,281,876 reports were analyzed after duplicate elimination, with 3,195 AE reports related to galsulfase identified. The association between galsulfase and AEs was investigated by utilizing four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). The analysis focused on the timing of onset, signs of AEs, and clinical significance. Results: Twenty seven organ systems were involved, and significant system organ classes (SOCs) included respiratory, thoracic and mediastinal disorders, and infections and infestations. At the PT level, 72 PTs corresponding to 15 SOCs were identified, with some AEs not previously mentioned in the product label. AEs associated with galsulfase had a median onset time of 1,471 days, with over half of the cases occurred within the first 5 years of treatment initiation. Conclusion: This investigation delivers an exhaustive and indicative assessment of galsulfase's safety profile, grounded in authentic, real-world evidence. The findings emphasis the importance of continuous safety surveillance and the emergence of new AEs. The identification of previously unreported urologic adverse events, such as glomerulonephritis membranous and nephritic syndrome, warrants further investigation. The study emphasizes the need for enhanced pharmacovigilance to ensure patient safety and the effectiveness of galsulfase treatment. [ABSTRACT FROM AUTHOR]

IntroductionMucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI.Methods26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Mucopolysaccharidosis type VI (Maroteaux–Lamy syndrome) is an orphan genetic disease caused by deficiency of the lysosomal enzyme arylsulfatase B (ASB). The need to develop a highly productive cell line for the production of recombinant ASB, is behind the concept and relevance of this study. The most promising approach seems to be the development of CHO producer cell lines coexpressing the target ASB enzyme and an auxiliary formylglycine-generating enzyme (FGE). At the same time, it is important from a practical perspective to have the possibility of cultivating producer cell lines as suspensions free of serum or other components of animal origin. The aim of the study was to develop highly productive cell lines for the production of recombinant ASB by coexpression of the auxiliary FGE. Materials and methods: a suspension CHO cell line was used in the study. CHO cells were transfected by electroporation using the MaxCyte STX system. Monoclonal cell lines were obtained with the help of the Cell Metric system. Enzyme-linked immunosorbent assay was used for determination of ASB concentration in the culture fluid. Culture fluid samples were analysed using polyacrylamide gel electrophoresis and Western blotting. The mRNA level was measured by real-time polymerase chain reaction. Results: producer cell lines coexpressing the target ASB enzyme and auxiliary FGE were obtained. An increase in the yield of the active target ASB enzyme from 2 to 100 mg/L was achieved by selecting the optimal ratio of plasmids during transfection. The highest yield of the target ASB enzyme was achieved at the 90:10 ratio (%) of plasmids encoding the ASB and FGE genes, respectively. Conclusions: the authors developed highly productive cell lines for the production of recombinant ASB, which coexpress the target and auxiliary enzymes. The coexpression of ASB and FGE improves the growth and production characteristics of the cell line, probably due to the modification of the ASB active site. The obtained results will help resolve the problem of low enzyme yield, which is typical of this class of medicines.

To describe and compare the systemic and ocular findings in two siblings with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), one treated with recombinant galsulfase, and one who was untreated. One female patient aged 33 years (case 1) who had received galsulfase enzyme replacement therapy for 11 years, and her younger male sibling by 3 years (case 2), who had declined systemic treatment, underwent clinical ophthalmic examination and retinal ocular coherence tomography. The female sibling underwent electrophysiology testing of visual function. Case 1 had best corrected visual acuity right 6/4.8 and left 6/6. Case 2 had best corrected visual acuity of 6/6 in each eye. Case 1 had bilateral mild corneal haze and a clinically unremarkable posterior segment examination. Case 2 had bilateral very mild corneal haze and retinal striae on examination. Ocular coherence tomography showed choroidal folds at the maculae in both patients, more pronounced in Case 2, who also had retinal folds and epiretinal membrane. Electroretinography showed very mild involvement of the rods only in Case 1. These two siblings with mucopolysaccharidosis type VI, one treated and one untreated, displayed variable levels of systemic, corneal, and chorioretinal involvement in their disease Further studies of choroidal changes in MPS VI may prove useful as a biomarker of ocular response to treatment outside the blood-retina barrier. Both patients have provided written consent to publish case details. [ABSTRACT FROM AUTHOR]

Background. Mucopolysaccharidosis type VI (MPS VI, Maroteaux–Lamy syndrome) is rare autosomal-recessive multisystem disease, one of the group of lysosomal storage diseases. The MPS VI pathogenesis is determined by arylsulfatase B enzyme deficiency caused by mutations in the ARSB gene. There are only few published clinical examples of this disease that covers the results of early enzyme replacement therapy (ERT) onset.Clinical case description. The child was suspected to have lysosomal storage disease at the age of 1.5 months, it was based on microscopic analysis of blood smears: Alder abnormality was revealed (granulations and red-violet inclusions in neutrophils, monocytes, lymphocytes cytoplasm). The diagnosis was confirmed at the age of 3 months: increased glycosaminoglycans (GAGs) concentration in the urine, arylsulfatase B activity decrease in dried blood spots, and pathogenic variant c.943C>T (p. R315X) in the ARSB gene in homozygous state were revealed. ERT with galsulfase was started at the age of 7 months. There was decrease in excretion of GAGs in urine to normal level after 9 and 15 months of therapy. Normal growth and body proportions for the patient’s age were determined 3 years after continuous ERT. However, there was progression of multiple dysostosis and joint stiffness, as well as eyes lesion.Conclusion. Early ERT onset cannot completely stop MPS VI progression but it allows to reduce the severity of several symptoms and improves patient’s quality of life.

Abstract Background The objective of this study was to describe clinical manifestations and events of patients with mucopolysaccharidosis (MPS) VI in Turkey who are treated with galsulfase enzyme replacement therapy (ERT). Clinical data of 14 children with MPS VI who were followed up at the Department of Pediatrics of the Gazi University Faculty of Medicine in Ankara, Turkey were retrospectively collected from the patients’ medical records. Patients were selected based on availability of a pre-ERT baseline and follow-up clinical data for a similar period of time (1.9–3.2 years). Event data (occurrence of acute clinical events, onset of chronic events, surgeries) collected during hospital visits and telemedicine were available for up to 10 years after initiation of ERT (2.5–10 years). Results Age at initiation of ERT ranged from 2.8 to 15.8 years (mean age 7.5 years). All patients presented with reduced endurance and skeletal abnormalities (dysostosis multiplex) on radiography. Other common clinical manifestations were cardiac valve disease (N = 13), short stature (N = 11), cranial abnormalities on MRI (N = 10), spinal abnormalities on MRI (N = 7), and mild cognitive impairment (N = 6). School attendance was generally poor, and several patients had urinary incontinence. After 1.9 to 3.2 years of ERT, most patients showed improvements in endurance in the 6-min walk test and 3-min stair climb tests; the frequency of urinary incontinence decreased. ERT did not seem to prevent progression of cardiac valve disease, eye disorders, hearing loss, or bone disease. Long-term event-based data showed a high incidence of respiratory tract infections, adenotonsillectomy/adenoidectomy, reduced sleep quality, sleep apnea, and depression before initiation of ERT. The number of events tended to remain stable or decrease in all patients over 2.5–10 years follow-up. However, the nature of the events shifted over time, with a reduction in the frequency of respiratory tract infections and sleep problems and an increase in ophthalmologic events, ear tube insertions, and depression. Conclusions This case series shows the high disease burden of the MPS VI population in Turkey and provides a unique insight into their clinical journey based on real-life clinical and event-based data collected before and after initiation of ERT.

Abstract We report a patient with mucopolysaccharidosis type VI, on long‐term enzyme replacement home therapy. Results support the efficacy and safety benefits, with additional advantage of home therapy to minimize the risk of community‐transmitted infections.

Background: Associated with enzyme deficiencies causing glycosaminoglycans (GAGs) accumulation, mucopolysaccharidosis type VI (MPS VI) is lysosomal storage disorder. In the treatment of MPS VI, galsulfase (Naglazyme) is commonly used as an enzyme replacement therapy (ERT). There remains a need for comprehensive real-world data on its safety and associated adverse events (AEs)., Objective: An analysis of the FDA Adverse Event Reporting System (FAERS) database will be conducted to identify potential risks and adverse reactions associated with galsulfase in real-life settings., Methods: The FAERS database was used to extract data from Q2 2005 to Q4 2023. A total of 20,281,876 reports were analyzed after duplicate elimination, with 3,195 AE reports related to galsulfase identified. The association between galsulfase and AEs was investigated by utilizing four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). The analysis focused on the timing of onset, signs of AEs, and clinical significance., Results: Twenty seven organ systems were involved, and significant system organ classes (SOCs) included respiratory, thoracic and mediastinal disorders, and infections and infestations. At the PT level, 72 PTs corresponding to 15 SOCs were identified, with some AEs not previously mentioned in the product label. AEs associated with galsulfase had a median onset time of 1,471 days, with over half of the cases occurred within the first 5 years of treatment initiation., Conclusion: This investigation delivers an exhaustive and indicative assessment of galsulfase's safety profile, grounded in authentic, real-world evidence. The findings emphasis the importance of continuous safety surveillance and the emergence of new AEs. The identification of previously unreported urologic adverse events, such as glomerulonephritis membranous and nephritic syndrome, warrants further investigation. The study emphasizes the need for enhanced pharmacovigilance to ensure patient safety and the effectiveness of galsulfase treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Huang, Meng, Liu, Qian, Zou and Yang.)

Background: The objective of this study was to describe clinical manifestations and events of patients with mucopolysaccharidosis (MPS) VI in Turkey who are treated with galsulfase enzyme replacement therapy (ERT). Clinical data of 14 children with MPS VI who were followed up at the Department of Pediatrics of the Gazi University Faculty of Medicine in Ankara, Turkey were retrospectively collected from the patients' medical records. Patients were selected based on availability of a pre-ERT baseline and follow-up clinical data for a similar period of time (1.9-3.2 years). Event data (occurrence of acute clinical events, onset of chronic events, surgeries) collected during hospital visits and telemedicine were available for up to 10 years after initiation of ERT (2.5-10 years).Results: Age at initiation of ERT ranged from 2.8 to 15.8 years (mean age 7.5 years). All patients presented with reduced endurance and skeletal abnormalities (dysostosis multiplex) on radiography. Other common clinical manifestations were cardiac valve disease (N = 13), short stature (N = 11), cranial abnormalities on MRI (N = 10), spinal abnormalities on MRI (N = 7), and mild cognitive impairment (N = 6). School attendance was generally poor, and several patients had urinary incontinence. After 1.9 to 3.2 years of ERT, most patients showed improvements in endurance in the 6-min walk test and 3-min stair climb tests; the frequency of urinary incontinence decreased. ERT did not seem to prevent progression of cardiac valve disease, eye disorders, hearing loss, or bone disease. Long-term event-based data showed a high incidence of respiratory tract infections, adenotonsillectomy/adenoidectomy, reduced sleep quality, sleep apnea, and depression before initiation of ERT. The number of events tended to remain stable or decrease in all patients over 2.5-10 years follow-up. However, the nature of the events shifted over time, with a reduction in the frequency of respiratory tract infections and sleep problems and an increase in ophthalmologic events, ear tube insertions, and depression.Conclusions: This case series shows the high disease burden of the MPS VI population in Turkey and provides a unique insight into their clinical journey based on real-life clinical and event-based data collected before and after initiation of ERT. [ABSTRACT FROM AUTHOR]

Abstract Introduction Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI. Methods 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. Results A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). Conclusion This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated. The study was a multicenter, prospective evaluation using data from infants with MPS VI generated during a phase 4 study (ASB-008; Clinicaltrials.gov NCT00299000) and clinical data collected ≥5 years after completion of the study. Parents of three subjects from ASB-008 (subjects 1, 2, and 4) provided written informed consent to participate in the follow-up study. One subject was excluded as consent was not provided. Subjects 1, 2, and 4 were aged 0.7, 0.3, and 1.1 years, respectively, at initiation of galsulfase and 10.5, 7.9, and 10.5 years, respectively, at follow-up. All subjects had classical MPS VI based on pre-treatment urinary glycosaminoglycans and the early onset of clinical manifestations. At follow-up, subject 4 had normal stature for age; subjects 1 and 2 had short stature, but height remained around the 90th percentile of growth curves for untreated classical MPS VI. Six-minute walk distance was normal for age/height in subjects 1 (550 m) and 4 (506 m), and reduced for subject 2 (340 m). Subject 2 preserved normal respiratory function, while percent predicted forced vital capacity and forced expiratory volume in 1 s decreased over time in the other subjects. Skeletal dysplasia was already apparent in all subjects at baseline and continued to progress. Cardiac valve disease showed mild progression in subject 1, mild improvement in subject 4, and remained trivial in subject 2. All subjects had considerably reduced pinch and grip strength at follow-up, but functional dexterity was relatively normal for age and there was limited impact on activities of daily living. Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) results showed that subjects 2 and 4 had numerous fine and gross motor competencies. Corneal clouding progressed in all subjects, while progression of hearing impairment was variable. Liver size normalized from baseline in subjects 1 and 4, and remained normal in subject 2. Very early and continuous ERT appears to slow down the clinical course of MPS VI, as shown by preservation of endurance, functional dexterity, and several fine and gross motor competencies after 7.7–9.8 years of treatment, and less growth impairment or progression of cardiac disease than could be expected based on the patients' classical phenotype. ERT does not seem to prevent progression of skeletal or eye disease in the long term. [ABSTRACT FROM AUTHOR]

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT. [ABSTRACT FROM AUTHOR]

Background. There are limited data on the efficacy of long-term enzyme replacement therapy (ERT) in children with mucopolysaccharidosis (MPS).Objective. Our aim was to study the efficacy and safety of long-term ERT in children with MPS type I, II, and VI.Methods. We analyzed the results of ERT with laronidase, idursulfase, and galsulfase in children with MPS type I, II, and VI admitted to the federal research center from January 2007 to November 2016. The response rate was assessed by the level of normalized urinary excretion of glycosaminoglycans (GAGs) (the ratio of GAGs concentration to urine creatinine) recalculated in percent (%) exceedance of the upper limit of normal for the corresponding age. Data on the administered therapy and its results, including adverse events, is extracted from the medical records of in-patients.Results. The results of treatment (intravenous infusions, intervals between administrations from 4 to 10 days) were studied in 33 children (5 of them were girls) with MPS type I (n = 4; laronidase at a dose of 0.58 mg/kg), II (n = 26; idursulfase at a dose of 0.5 mg/kg), and VI (n = 3; galsulfase at a dose of 1 mg/kg). A decrease in the normalized urinary excretion of GAGs from 376% (172; 791) to 54% (0; 146) exceedance of the upper limit of normal for the age (p < 0.001) was noted in the course of ERT lasting (median) 27 (14; 41) months. A decrease in the normalized GAGs excretion below the upper limit of normal for the age was established in 12/33 (36%) patients. ERT-associated adverse events were identified in 12 patients; one case required a two-fold therapy interruption. The development of nephrotic syndrome in the course of ERT in patients with severe MPS II was first described.Conclusion. Long-term ERT in children with MPS type I, II, and VI is characterized by acceptable efficacy and safety. Key words: children, mucopolysaccharidosis, enzyme replacement therapy, laronidase, idursulfase, galsulfase, glycosaminoglycans.

We report a patient with mucopolysaccharidosis type VI, on long‐term enzyme replacement home therapy. Results support the efficacy and safety benefits, with additional advantage of home therapy to minimize the risk of community‐transmitted infections. [ABSTRACT FROM AUTHOR]

Early initiation of enzyme replacement therapy (ERT) has demonstrated clinical benefit in patients with mucopolysaccharidosis type VI (MPS VI), a progressive, multisystem autosomal recessive lysosomal disorder caused by N-acetylgalactosamine-4-sulphatase (ASB) deficiency and the consequent accumulation of glycosaminoglycan. A previous case report highlighted that 3 years of ERT with recombinant human ASB (galsulfase) was well tolerated and effective in two Japanese siblings with MPS VI who initiated ERT at 5.6 years and 6 weeks of age, respectively. This report describes 10-year follow-up data from these two siblings who continued ERT with weekly infusions of galsulfase 1 mg/kg. Ten years of ERT was well tolerated, and the older sibling reached puberty. He had typical MPS VI phenotypic features, but exhibited significant improvement in shoulder range of motion and had largely unchanged hearing and cardiac function. His skeletal deformity remained unchanged. In contrast, in the younger sibling, typical symptoms of MPS VI, including progressive dysmorphic facial features, hepatosplenomegaly, and hearing impairment were largely absent. Her joint mobility was preserved, although skeletal deformity, including claw-hand deformity, was observed. Both siblings had progressive corneal clouding. The observations in these two patients suggest that early ERT initiated in newborns can be well tolerated and effective in preventing or slowing MPS VI disease progression, but is limited in terms of its effects on bone symptoms. For this, new approaches or bone-targeting treatments would be necessary.

To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The impact of galsulfase enzyme replacement therapy in patients with mucopolysaccharidosis (MPS) VI with phenotypes at either end of the disease spectrum was evaluated. The MPS VI Clinical Surveillance Program (CSP) was established to collect long‐term observational data from routine clinical and laboratory assessments. A subanalysis of the CSP was performed in patients with pretreatment urinary glycosaminoglycan (uGAG) levels <100 μg/mg and ≥200 μg/mg creatinine (low‐ and high‐uGAG) who had received galsulfase for ≥6 months. uGAG, 6‐minute walk test (6MWT), 3‐minute stair climb test (3MSCT), pulmonary function measures, height/growth, cardiac function, and safety were evaluated. Patients with a high‐uGAG level at pre‐treatment baseline (N = 68) showed greater impairments in endurance and pulmonary function than those with low‐baseline uGAG levels (N = 39). From pre‐treatment baseline, the distance walked on the 6MWT in the low‐ and high‐uGAG groups increased by a mean (±SD) of 49 (±151) meters and 42 (±165) meters (median follow‐up 5.5 and 7.7 years), respectively. The number of stairs/min climbed in the 3MSCT in the low‐ and high‐uGAG groups increased by a mean of 18 (±33) and 30 (±45) (median follow‐up 2.8 and 3.5 years), respectively. Overall, pulmonary function remained unchanged for both groups. No impact was seen on cardiac function. Galsulfase was generally well tolerated in both groups, with most adverse events being MPS‐related complications unrelated to galsulfase. Results of this CSP sub‐analysis suggest that galsulfase stabilizes MPS VI in the long‐term and has an acceptable safety profile, regardless of baseline disease severity. [ABSTRACT FROM AUTHOR]

Clinical and biochemical improvements are reported on Mucopolysaccharidosis type VI (MPS VI) patients on Enzyme Replacement Therapy (ERT) with rhASB (galsulfase, Naglazyme®), and preclinical and clinical studies have shown clinical benefits of early initiation. We report four unrelated MPS VI children who began ERT as infants (ages 5 days–10 months). The three older patients showed the first clinical signs of MPS VI at baseline, also presenting different degrees of dysostosis multiplex, and two had mild heart disease. The two oldest also had mild facial coarseness, one had hearing conduction deficit and sleep disorder and the other corneal clouding at baseline. After six years on ERT, all four patients have normal urinary GAG values. Although they all showed normal motor and mental development, brain and cervical spine MRI images available from two of the older patients showed abnormalities, while the youngest child continues having normal images. The four patients presented slower progression of bone and joint disease when compared to their affected older siblings. It should be noticed that only two patients in this sample are currently below the 3rd percentile for height: the youngest who has a constitutional factor associated and the eldest who already presented frank dysostosis at 10 months of age. These findings confirm previous studies that report that skeletal features of the disease cannot be completely prevented despite early ERT. Heart disease already present in two of the four infants at baseline got worse over time and appeared in another patient, but the youngest child on ERT introduction still has a normal echocardiogram at six years of age; he also is the only one without corneal clouding after six years follow-up. Our results also suggest that early ERT prevented storage in spleen and liver and may also have improved or prevented progression of facial dysmorphic features, corroborating similar findings seen in previous studies. No safety concerns were identified and none of the patients experienced a serious adverse event. The baseline severity of the disorder of these four infants seems related to age and it is tempting to say that severity on the first year of life is progressive and ERT effectiveness is indirectly related to it. Despite being known that MPS VI progresses differently among patients, the fact that these infants had a slower progression than their older siblings speaks in favor of a very early start of ERT. In conclusion, this report confirms the early manifestations of the disease and provides additional evidence on safety and of the beneficial effects of ERT in patients less than 1 year of age.

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N -acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (> 200 μg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18 years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z -score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z -score for those beginning treatment at 0–3, > 3–6, > 6–9, > 9–12, and > 12–15 years of age ( p < 0.05). Increases in Z -score were not detected for patients who began treatment between 15 and 18 years of age, nor for patients with low (≤ 200 μg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6 years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth. [ABSTRACT FROM AUTHOR]

This article reflects the current representation of one of the most common diseases among hereditary lysosomal storage diseases - mucopolysaccharide disorders, in particular VI type of this disease - Maroteaux-Lamy syndrome. It summarizes the listed literature as well as our own observations on issues of etiology, pathogenesis, terms of manifestation and clinical symptoms of the disease, methods of diagnosis, modern treatment and prevention methods of mucopolysaccharidosis type VI. The work presents a case study of classic form of Maroteaux-Lamy syndrome. It is argued that the basis of prevention Maroteaux-Lamy syndrome is an effective medical and genetic counseling. [ABSTRACT FROM AUTHOR]

Background Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N -acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N -acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI. Methods Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4 weeks, animals received weekly 2-h ( N = 6) or 4-h ( N = 6) IV infusions of rhASB for 26 weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats ( N = 6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48 h after the last infusion and tissue concentration of ASB, GAG and β-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2 weeks of euthanasia. Results At week 13, the mean AUC 0 − t in animals treated with 4-h infusions was similar to 2-h infusions while the C max of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC 0 − t of the 4-h infusion was 1.3-fold higher than the 2-h infusion ( p < 0.05) while C max of the 4-h infusion was 70% of the 2-h infusion ( p < 0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and β-glucuronidase but all were significantly different than control animals (for each, p < 0.001). Radiographic skeletal abnormality scores for animals were also similar for both treatment groups and significantly higher than control animals ( p < 0.001). There was no significant difference in corneal clouding scores among treated and untreated animals. Conclusions There was no significant difference in clinical outcomes when rhASB was administered to MPS VI affected cats as 2- and 4-h infusions over 26 weeks. Additional studies may determine if shorter infusion times are appropriate for MPS VI patients without significant infusion-associated reactions. [ABSTRACT FROM AUTHOR]

Abstract: The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment. [Copyright &y& Elsevier]

Background: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B). Methods: We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome. in vitro Results: Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase . in vitro Conclusions: The clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic and multisystem lysosomal storage disease with a wide disease spectrum. Clinical and biochemical improvements have been reported for MPS VI patients on enzyme replacement therapy (ERT) with rhASB (recombinant human arylsulfatase B; galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.), making early diagnosis and intervention imperative for optimal patient outcomes. Few studies have included children younger than five years of age. This report describes 34 MPS VI patients that started treatment with galsulfase before five years of age. Methods: Data from patients who initiated treatment at <5years of age were collected from patients' medical records. Baseline and follow-up assessments of common symptoms that led to diagnosis and that were used to evaluate disease progression and treatment efficacy were evaluated. Results: A significant negative correlation was seen with treatment with ERT and urinary GAG levels. Of those with baseline and follow-up growth data, 47% remained on their pre-treatment growth curve or moved to a higher percentile after treatment. Of the 9 patients with baseline and follow-up sleep studies, 5 remained unaffected and 1 patient initially with mild sleep apnea showed improvement. Data regarding cardiac, ophthalmic, central nervous system, hearing, surgical interventions and development are also reported. No patient discontinued treatment due to an adverse event and all that were treatment-emergent resolved. Conclusions: The prescribed dosage of 1mg/kg IV weekly with galsulfase ERT is shown to be safe and effective in slowing and/or improving certain aspects of the disease, although patients should be closely monitored for complications associated with the natural history of the disease, especially cardiac valve involvement and spinal cord compression. A long-term follow-up investigation of this group of children will provide further information on the benefits of early treatment as well as disease progression and treatment efficacy and safety in this young patient population. [Copyright &y& Elsevier]

Abstract: Mucopolysaccharidosis type VI (MPS VI) is a progressive, multisystem autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine-4-sulphatase (ASB) and the consequent accumulation of glycosaminoglycan (GAG). Preclinical and clinical studies had demonstrated clinical benefits of early initiation of systemic therapies in patients with MPS. In this case report, two siblings with MPS VI started enzyme replacement therapy (ERT) with weekly infusions of recombinant human ASB (Galsulfase) at 1mg/kg. Sibling 1 started ERT 5.6years of age and Sibling 2 was 6weeks old. The disease status in these two siblings prior to and for no less than 36months of ERT was followed up and compared. The treatment was well tolerated by both siblings. During 36months of ERT, symptoms typical of MPS VI including short stature, progressive dysmorphic facial features, hepatosplenomegaly, hearing impairment, corneal clouding, and dysostosis multiplex were largely absent in the younger sibling. Her cardiac functions and joint mobility were well preserved. On the other hand, her affected brother had typical MPS VI phenotypic features described above before commencing ERT at the equivalent age, of 3years. There was significant improvement in the shoulder range of motion and hearing loss after 36months of treatment and cardiac function was largely preserved. His skeletal deformity and short stature remained unchanged. The results showed that early ERT initiated at newborn is safe and effective in preventing or slowing down disease progression of MPS VI including bone deformities. These observations indicate that early diagnosis and treatment of MPS VI before development of an irreversible disease is critical for optimal clinical outcome. [Copyright &y& Elsevier]

Abstract: Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy Syndrome) is one of approximately 50 known lysosomal storage disorders. MPS VI is characterized by an absence or deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B) resulting in accumulation of dermatan sulfate. Prior to the availability of enzyme replacement therapy (ERT), the clinical management of MPS VI was limited to supportive care and allogeneic hematopoietic stem cell transplantation (HSCT); however, due to the rarity of this disease, little is known about the long-term outcomes of HSCT for MPS VI. The following retrospective study was performed using aggregate data gathered by the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1982 and 2007 to determine survival probability for patients with MPS VI following allogeneic HSCT. This analysis identified 45 MPS VI patients with a median age of 5years (range, 1–22years) at the time they received an allogeneic HSCT. Cumulative incidence (95% CI) of acute graft-vs.-host disease at 100days was 36% (21–53%). Probability of survival was 78% (65–89%) at 100days and 66% (52–79%) at 1 and 3years. While these data are based upon small numbers of recipients, they represent the largest series to date and may help clinicians assess the relative risks and benefits of currently available therapies. [ABSTRACT FROM AUTHOR]

The article presents abstracts on pediatric topics which includes continuity of care in infancy, vaccination of 14-year-old adolescents and administration of psychotropic drugs in children with autism spectrum disorders.

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease that is characterized by systemic clinical manifestations and significant functional impairment. Diagnosis and management are often challenging because of the considerable variability in symptom presentation and rate of progression. The optimal standard of care should be based on evidence from randomized, controlled trials, meta-analyses, systematic reviews, and expert opinion. In support of this goal, comprehensive management guidelines have been drafted by an international group of experts in the management of patients with mucopolysaccharidosis VI. The guidelines provide a detailed outline of disease manifestations by body system, recommendations for regular assessments, and an overview of current treatment options. [ABSTRACT FROM AUTHOR]

Abstract: Background: Maroteaux–Lamy syndrome, or mucopolysaccharidosis (MPS) type VI, is the autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine 4-sulfatase (ARSB) and the consequent accumulation of glycosaminoglycan (GAG). Patients fully engrafted after hematopoietic stem cell transplantation (HSCT) demonstrate several indicators of metabolic correction such as reduction in liver size, absence of hepatic ultrastructural pathology, and patients do not develop cervical cord compression. Engrafted patients demonstrate reduction in urine GAG achieving near-normal levels. Hypothesis: We presumed that HSCT engraftment from a normal individual would provide sufficient systemic enzyme to accomplish maximal metabolic correction, and that no additional benefit would accrue from additional therapy such as with intravenous recombinant human ARSB protein, galsulfase. Materials and methods: A 22-year-old male had received an allogeneic bone marrow transplant from an HLA-identical sibling donor, and remained fully engrafted after 20years. In response to his request regarding the potential benefit of enzyme replacement therapy, we administered a single, standard dose of galsulfase while monitoring urine GAG daily, before and after the treatment. Results: Urine GAG declined from slightly high pre-treatment levels (7.63mg GAG/mmol creatinine; range 7.0–8.5, N =3) progressively declining below the age-specific normal range (<6.5) over 10days to the lowest level of 4.4, with a mean post-treatment level of 5.60 (N =10). Conclusions: Somewhat surprisingly, the biomarker urine GAG was significantly reduced after a single treatment of intravenous galsulfase thus suggesting that supplemental enzyme replacement therapy might improve the clinical outcome for donor-engrafted patients with MPS VI. [ABSTRACT FROM AUTHOR]

MPS VI (mucopolysaccharidosis VI, known as Maroteaux–Lamy syndrome) is a multi-systemic inherited disease, resulting from a deficiency of N-acetylgalactosamine-4-sulfatase, causing accumulation of the glycosaminoglycan (GAG) dermatan sulfate in all tissues. It is one of almost 50 lysosomal storage disorders. Ocular pathology is common in patients with MPS VI, with complications including ocular hypertension, progressive corneal clouding, optic nerve swelling (or papilledema) often associated with communicating hydrocephalus (Ashworth et al., Eye 20(5), 553–563, 2006; Goldberg et al., AJO 69(6), 969–975), and raised intracranial pressure (ICP) progressing to atrophy with loss of vision (Goodrich et al., Loss of vision in MPS VI is a consequence of increased intracranial pressure, 2002). This is the first case report of reversed papilledema and improved visual acuity in an 11-year-old MPS VI patient receiving galsulfase (Naglazyme®), an enzyme-replacement therapy (ERT) of recombinant human arylsulfatase B (rhASB) (Harmatz et al., J Pediatr 148(4), 533–539, 2006). [ABSTRACT FROM AUTHOR]

Background: Although LC-MS/MS is preferred as a reliable method, therapeutic enzyme drugs in the blood matrix may lead to false results., Objective: The purpose of this article is to experimentally investigate the effect of five different enzymes used in the treatment of metabolic diseases on blood immunosuppressant measurement., Methods: Five different enzyme drugs (galsulfase, alglucosidase alfa, imiglucerase, elosulfase alfa, laronidase) were added to control materials containing tacrolimus, everolimus, sirolimus, and cyclosporine A drugs. Measurements were performed using an LC-MS/MS instrument (Shimadzu 8040, Japan). The amount of deviations from the target values was calculated., Results: Blood Immunosuppressant levels significantly changed after the administration of enzyme drugs. Four different enzyme drugs led to false-positive results in the tacrolimus levels at a rate of 10.58% (95% CI, 9.83-11.32) to 37.28% (95% CI, 33.55-41.27). The highest deviations were observed with the administration of galsulfase and alglucosidase alpha in the sirolimus levels at rates of 336.54% (95% CI, 306.25-366.82) and 395.88% (95% CI, 360.25-431.50), respectively. Imiglucerase was the least effective enzyme for the sirolimus level (0.80% (95% CI, 0.71-0.89). Different deviations between the ratios of - 9.37% (95% CI, -10.40 - -8.33) and 8.33% (95% CI, 7.41-9.24) were determined at the cyclosporin A level., Conclusion: Galsulfase, alglucosidase alpha, imigluserase, elosulfase alpha and laronidase can significantly interfere with immunosuppressant measurements with LC-MS/MS. False immunosuppressant results associated with enzyme injection may result in immunosuppression failure, organ rejection. For the measurement of immunosuppressant levels, sampling should be done before the enzyme infusion. Clinicians should question the time of enzyme infusion and sampling when confounding results in immunosuppressant measurement., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)