Article

Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase

September 2008
Molecular Genetics and Metabolism 94(4):469-75

DOI:10.1016/j.ymgme.2008.04.001

Source
PubMed

Authors:

Paul Richard Harmatz

Children's Hospital & Research Center Oakland

Roberto Giugliani

Federal University of Rio Grande do Sul

Ida Vanessa Schwartz

Federal University of Rio Grande do Sul

Nathalie Guffon

Hospices Civils de Lyon (Centre Hospitalier Universitaire de Lyon)

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Unlabelled: The objective of this study was to evaluate the long-term clinical benefits and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome), a lysosomal storage disease. Fifty-six patients derived from 3 clinical studies were followed in open-label extension studies for a total period of 97-260 Weeks. All patients received weekly infusions of rhASB at 1 mg/kg. Efficacy was evaluated by (1) distance walked in a 12-minute walk test (12MWT) or 6-minute walk test (6MWT), (2) stairs climbed in the 3-minute stair climb (3MSC), and (3) reduction in urinary glycosaminoglycans (GAG). Safety was evaluated by compliance, adverse event (AE) reporting and adherence to treatment. Results: A significant reduction in urinary GAG (71-79%) was sustained. For the 12MWT, subjects in Phase 2 showed improvement of 255+/-191 m (mean+/-SD) at Week 144; those in Phase 3 Extension demonstrated improvement from study baseline of 183+/-26 m (mean+/- SE) in the rhASB/rhASB group at Week 96 and from treatment baseline (Week 24) of 117+/-25 m in the placebo/rhASB group. The Phase 1/2 6MWT and the 3MSC from Phase 2 and 3 also showed sustained improvements through the final study measurements. Compliance was 98% overall. Only 560 of 4121 reported AEs (14%) were related to treatment with only 10 of 560 (2%) described as severe. Conclusion: rhASB treatment up to 5 years results in sustained improvements in endurance and has an acceptable safety profile.

Clinical and event-based outcomes of patients with mucopolysaccharidosis VI receiving enzyme replacement therapy in Turkey: a case series

Article

Full-text available

Dec 2021
ORPHANET J RARE DIS

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.

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program

Article

Full-text available

Jul 2019

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.

Leukocyte Imbalances in Mucopolysaccharidoses Patients

Article

Full-text available

Jun 2023

Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. In MPS VI, there is dermatan sulfate lysosomal accumulation due to pathogenic mutations in the ARSB gene, leading to arylsulfatase B deficiency. Alterations in the immune system of MPS mouse models have already been described, but data concerning MPSs patients is still scarce. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of natural killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT, and B cells in both groups of MPS disease patients. However, we discovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and, consequently, lower memory T cell frequency than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficiency in the lysosome may have a particular effect on the normal cellular composition of the immune system.

Gasser cell: A biomarker of response to enzyme replacement therapy in patients with mucopolysaccharidosis type VI

Article

Full-text available

May 2021

The mucopolysaccharidosis (MPS) type VI is a rare lysosomal storage disease presenting leukocyte inclusions (Alder-Reilly anomaly) and lymphocytes with metachromatic inclusion surrounded by clear spaces, Gasser cells. Currently, an enzyme replacement therapy (ERT) with galsulfase is used to treat MPS type VI. This study evaluated 14 patients with MPS type VI performed cell counts Gasser before and after six months from the beginning of ERT. It was observed an average of 12.7% cells per patient, and after six months was found complete cell Gasser disappearance, proving to be an effective biomarker of response to ERT.

Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985-2019)

Preprint

Full-text available

Jun 2020

Background Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs. Methods An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated. Results Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p<0.01). Pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively introduced in Taiwan from 2016, and 48% (16/33) of MPS patients diagnosed between 2016 and 2019 were diagnosed by one of these screening programs, with a median diagnostic age at 0.2 years. For patients born between 2016 and 2019, up to 94% (16/17) were diagnosed with MPS via the newborn screening programs. At the time of this study, 81 patients had passed away with a median age at death of 15.6 years. Age at diagnosis was positively correlated with life expectancy (p<0.01). Life expectancy also significantly increased between 1985 and 2019, however this increase was gradual (p<0.01). Conclusions The life expectancy of Taiwanese patients with MPS has improved in recent decades and patients are being diagnosed earlier. Because of the progressive nature of the disease, early diagnosis by newborn screening programs and timely implementation of early therapeutic interventions may lead to better clinical outcomes.

Therapeutic options for mucopolysaccharidoses: Current and emerging treatments

Article

Feb 2020

Therapeutic Options for Mucopolysaccharidoses: Current and Emerging Treatments

Article

Full-text available

Jun 2019

Mucopolysaccharidoses (MPS) are inborn errors of metabolism produced by a deficiency of one of the enzymes involved in the degradation of glycosaminoglycans (GAGs). Although taken separately, each type is rare. As a group, MPS are relatively frequent, with an overall estimated incidence of around 1 in 20,000–25,000 births. Development of therapeutic options for MPS, including hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), has modified the natural history of many MPS types. In spite of the improvement in some tissues and organs, significant challenges remain unsolved, including blood–brain barrier (BBB) penetration and treatment of lesions in avascular cartilage, heart valves, and corneas. Newer approaches, such as intrathecal ERT, ERT with fusion proteins to cross the BBB, gene therapy, substrate reduction therapy (SRT), chaperone therapy, and some combination of these strategies may provide better outcomes for MPS patients in the near future. As early diagnosis and early treatment are imperative to improve therapeutic efficacy, the inclusion of MPS in newborn screening programs should enhance the potential impact of treatment in reducing the morbidity associated with MPS diseases. In this review, we evaluate available treatments, including ERT and HSCT, and future treatments, such as gene therapy, SRT, and chaperone therapy, and describe the advantages and disadvantages. We also assess the current clinical endpoints and biomarkers used in clinical trials.

Consensus-based expert recommendations on the management of MPS IVa and VI in Saudi Arabia

Article

Full-text available

Jul 2024
ORPHANET J RARE DIS

Background Mucopolysaccharidosis type IVa (Morquio A syndrome) and mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) are rare inherited lysosomal storage diseases associated with significant functional impairment and a wide spectrum of debilitating clinical manifestations. These conditions are thought to have higher-than-average prevalence rates in Saudi Arabia due to high rates of consanguineous marriage in the country. There are several unmet needs associated with the management of these diseases in Saudi Arabia. Main body The aim of this manuscript is to contextualize unmet management needs and provide recommendations to optimize diagnosis, multidisciplinary care delivery, and local data generation in this disease area. An expert panel was assembled comprising seven consultant geneticists from across Saudi Arabia. The Delphi methodology was used to obtain a consensus on statements relating to several aspects of mucopolysaccharidosis types IVa and VI. A consensus was reached for all statements by means of an online, anonymized voting system. The consensus statements pertain to screening and diagnosis, management approaches, including recommendations pertaining to enzyme replacement therapy, and local data generation. Conclusion The consensus statements presented provide specific recommendations to improve diagnostic and treatment approaches, promote multidisciplinary care and data sharing, and optimize the overall management of these rare inherited diseases in Saudi Arabia.

Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)

Article

Full-text available

Dec 2023

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 μg/μg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 μg/μg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 μg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 μg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.

Leukocyte Imbalances in Mucopolysaccharidoses Patients

Preprint

Full-text available

May 2023

Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. MPS VI has dermatan sulfate lysosomal storage, owing to a deficiency of arylsulfatase B, due to pathogenic mutations in the ARSB gene. Alterations in the immune system of MPSs mouse models have been described but the data is still scarce concerning MPSs patients. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of Natural Killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT and B cells in both groups of MPS disease patients. However, we uncovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and consequently lower frequency of memory T cells than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficient in the lysosome may have a particular effect on the normal cellular composition of the immune system.

Application of pathogenicity scores as diagnostic and prognostic markers for MPS disorders: In-silico analysis in MPS I

Preprint

Full-text available

May 2022

Mucopolysaccharidoses (MPSs) is a major group of the Lysosomal storage disorders (LSDs) with defective degradation of glycosaminoglycans (GAGs) due to deficiency of certain lysosomal enzymes. Enzyme replacement therapy (ERT) or bone marrow transplantation are the key therapeutic options available for MPS disorders. Early diagnosis and appropriate intervention improve the therapeutic efficacy. To establish a genotype-phenotype correlation of MPS disorders, a combination of bioinformatic tools including FATHMM, I-Mutant, PolyPhen-2, PATHER, PHD-SNP, SNP&GO, SIFT, PROVEAN, CUPSAT, SNAP2 are utilized. These in silico tools and urinary GAG levels helped in monitoring the response to enzyme replacement therapy (ERT). Enzyme activity was inversely associated with SNAP2 (r= -0.36, p = 0.04), Polyphen-2 (r = − 0.44, p = 0.009) and Evolutionary preservation time (r= -0.396, p = 0.02). This suggests that subjects having mutations with higher SNAP2 and Polyphen-2 score tend to have lower enzyme activity. ERT lead to 7–31% decrease in urinary GAG levels in seven MPS I patients. The determined pathogenicity scores using the bioinformatic tools are serving as prognostic markers indicating a response to therapy. Urinary GAG excretion is the primary end point to monitor the therapeutic efficacy.

Modifying enzyme replacement therapy – A perspective

Article

Full-text available

Dec 2022
J CELL MOL MED

Philipp Schaible

Several diseases are caused by the lack of functional proteins, including lysosomal storage diseases or haemophilia A and B. Patients suffering from one of these diseases are treated via enzyme replacement therapies to restore the missing protein. Although this treatment strategy prevents some disease symptoms, enzyme replacement therapies are very expensive and require very frequent infusions, which can cause infusion adverse reactions and massively impair the quality of life of the patients. This review proposes a technology to sustainably produce proteins within the patient to potentially make frequent protein‐infusions redundant. This technology is based on blood circulating immune cells as producers of the needed therapeutic protein. To ensure a stable protein concentration over time the cells are equipped with a system, which induces cell proliferation when low therapeutic protein levels are detected and a system inhibiting cell proliferation when high therapeutic protein levels are detected.

Generation of a novel disease model mouse for mucopolysaccharidosis type VI via c. 252T>C human ARSB mutation knock-in

Article

Full-text available

Sep 2022

Kosuke Hosoba

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a mutation in the ARSB gene, which encodes arylsulfatase B (ARSB), and is characterized by glycosaminoglycan accumulation. Some pathogenic mutations have been identified in or near the substrate-binding pocket of ARSB, whereas many missense mutations present far from the substrate-binding pocket. Each MPS VI patient shows different severity of clinical symptoms. To understand the relationship between mutation patterns and the severity of MPS VI clinical symptoms, mutations located far from the substrate-binding pocket must be investigated using mutation knock-in mice. Here, I generated a knock-in mouse model of human ARSB Y85H mutation identified in Japanese MPS VI patients using a CRISPR-Cas9-mediated approach. The generated mouse model exhibited phenotypes similar to those of MPS VI patients, including facial features, mucopolysaccharide accumulation, and smaller body size, suggesting that this mouse will be a valuable model for understanding MPS VI pathology.

Utility of pathogenicity scores as diagnostic and prognostic markers for MPS disorders: In-silico analysis in MPS I

Preprint

Full-text available

May 2022

Mucopolysaccharidoses (MPSs) is a major group of the lysosomal storage disorders (LSDs) with defective degradation of glycosaminoglycans (GAGs). Enzyme replacement therapy or bone marrow transplantation are the key therapeutic options available. Early diagnosis and appropriate intervention improve the therapeutic efficacy. We have used FATHMM, I-Mutant, PolyPhen-2, PATHER, PHD-SNP, SNP&GO, SIFT, PROVEAN, CUPSAT, SNAP2 for in silico analysis. These in silico tools and urinary GAG levels helped in monitoring the response to enzyme replacement therapy (ERT). Enzyme activity was inversely associated with SNAP2 (r= -0.36, p=0.04), Polyphen-2 (r= - 0.44, p=0.009) and Evolutionary preservation time (r= -0.396, p=0.02). This suggests that subjects having mutations with higher SNAP2 and Polyphen-2 score tend to have lower enzyme activity. ERT lead to 7 – 31% decrease in urinary GAG levels in seven MPS I patients. The determined pathogenicity scores are serving as prognostic markers indicating a response to therapy. Urinary GAG excretion is the primary end point to monitor the therapeutic efficacy.

Increasing productivity of arylsulfatase B-producing cell line by coexpression of formylglycine-generating enzyme

Article

Full-text available

Apr 2022

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. Mater ials 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.

Early Diagnosis and Results of Enzyme Replacement Therapy in the Patient with Mucopolysaccharidosis Type VI: Clinical Case

Article

Full-text available

Dec 2021

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.

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease

Article

Full-text available

Dec 2021
INT J MOL SCI

Mucopolysaccharidosis type VI, or Maroteaux–Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10–15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.

Oral Treatment for Mucopolysaccharidosis VI : Outcomes of the First Phase IIa Study with Odiparcil

Article

Dec 2021

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally-available small molecule that results in the synthesis of odiparcil linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. iMProveS (improve MPS treatment) was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics (PK/PD), and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26-week, randomized, double-blind, placebo-controlled trial in patients receiving ERT and an open-label, non-comparative, single dose cohort not receiving ERT. Patients aged >16 years receiving ERT were randomized to odiparcil 250 mg or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAG), chondroitin sulfate (CS), and dermatan sulfate (DS) concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements on pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs. placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed. This article is protected by copyright. All rights reserved.

Hyo-Mental Angle and Distance: An Important Adjunct in Airway Assessment of Adult Mucopolysaccharidosis

Article

Full-text available

Oct 2021

Background: Mucopolysaccharidosis (MPS) is a rare congenital lysosomal storage disorder with complex airways. High anterior larynx is assessed by thyromental distance (TMD) nasendoscopy. A simpler method to assess this hyoid bone is described. The distance between the central-hyoid and symphysis of the mandible (hyo-mental distance; HMD) and inclination of this line to the horizontal axis (hyo-mental angle; HMA) in neutrally positioned patients is investigated. Methods: HMA, HMD in MPS, and non-MPS were compared, and their correlation with height and weight were assessed. Results: 50 adult MPS patients (M = 32, F = 18, age range = 19-66 years; mean BMI = 26.8 kg/m2) of MPS I, II, III, IV, and VI were compared with 50 non-MPS (M = 25, F = 25; age range = 22-84 years; mean BMI = 26.5 kg/m2). Mean HMA in MPS was 25.72° (-10 to +50) versus 2.42° (-35 to +28) in non-MPS. Mean HMD was 46.5 (25.7-66) millimeters in MPS versus 41.8 (27-60.3) in non-MPS. HMA versus height and weight showed a moderate correlation (r = -0.4, p < 0.05) in MPS and no significant correlation (r < 0.4, p > 0.05) in non-MPS. HMD versus height and weight showed no correlation (r < 0.4, p > 0.05) in both groups. Conclusions: HMA seems more acute in MPS despite nearly the same HMD as non-MPS, signifying a high larynx, which may be missed by TMD.

Airway Abnormalities in Adult Mucopolysaccharidosis and Development of Salford Mucopolysaccharidosis Airway Score

Article

Full-text available

Jul 2021

(1) Background: Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders caused by the absence of enzymes required for degradation of glycosaminoglycans (GAGs). GAGs deposition in tissues leads to progressive airway narrowing and/or tortuosity. Increased longevity of patients has posed newer problems, especially the airway. This study aims to characterise various airway abnormalities in adult MPS from a regional centre and proposes a method to quantify the severity of the airway disease. (2) Methods: Retrospective analysis by case notes review, clinical examination, endoscopy, cross-sectional imaging, 3-dimensional reconstruction, and physiological investigations were used to assess the airway abnormalities. Quantitative assessment of the airway severity was performed a validated questionnaire of 15 parameters to derive Salford Mucopolysaccharidosis Airway Score (SMAS). (3) Results: Thirty-one adult MPS patients (21M/ 9F; median 26.7 years; range 19–42 years) were reviewed. There were 9 MPS I, 12 MPS II, 2 MPS III, 5 MPS IV, 2 MPS VI, and 1 MPS VII. Airway abnormalities in each MPS type are described. Patients scoring more than 35 on SMAS had some form of airway intervention. The area under curve of 0.9 was noted at a score of 25, so SMAS more than 25 may predict a difficult airway and potential to have complications. Pearson’s correlation between SMAS and height, weight, BMI were poor (p < 0.05). (4) Conclusions: Airway abnormalities in adult MPS are varied and complex. Assessment of the airway should be holistic and include multiple parameters. An objective multidimensional score such as SMAS may help to predict and manage difficult airways warranting further investigation and validation.

Disease burden, management patterns and multidisciplinary clinical approaches for patients with MPS IVA and VI in selected Latin American Countries

Article

Full-text available

Sep 2021

Background There is a paucity of real-world epidemiological data on patients with mucopolysaccharidoses (MPS) in Latin America. This real-world study assessed the disease burden, management patterns and multidisciplinary clinical approaches for MPS-IVA and MPS-VI patients in Latin America (Colombia, Ecuador, Mexico, Peru). Methods Data were collected from physicians/specialists experienced in treating MPS patients between April–June 2020, via an online patient-diary survey. Results Overall, 29 physicians/specialists participated in this study. Data from 98 patients were analyzed (MPS-IVA, 71 patients and MPS-VI, 27 patients). Mean age for MPS-IVA patients was 17.5 years and for MPS-VI patients was 11.6 years, and the majority were females (52% and 78%, respectively). MPS-IVA and VI patients presented a high absenteeism from school (55% and 37%, respectively; <18 years age) and workplace (78% and 100%, respectively; >18 years age), indicating an impact of the disease on some aspects of the patients' quality of life. The onset of the first symptom occurred at the age of 3.1 years for MPS-IVA patients and at 1 year for MPS-VI, with delay in diagnosis (3.5–3.9 years from symptom onset) and enzyme replacement therapy (ERT) initiation (1.1–3.6 years from diagnosis). ERT interruptions were observed for MPS-IVA (48%) and MPS-VI patients (44%), with non-availability of medication recorded as the main reason for non-adherence (46% and 60% patients, respectively). ERT showed noticeable treatment benefits in MPS-IVA/VI patients, with stabilization/reduction in complications or the number of surgeries. A multidisciplinary clinical team approach was used for patient management. Conclusion The disease burden for MPS-IVA/VI was high in Latin America, with consistent management, treatment and socio-demographic trends throughout the region.

Enzyme replacement combinational therapy: Effective treatments for mucopolysaccharidoses

Article

Mar 2021

Alireza Khabazi

Enzyme replacement combinational therapy: Effective treatments for mucopolysaccharidoses

Article

Mar 2021

Introduction: Mucopolysaccharidoses (MPS), as a group of inherited lysosomal storage disorders (LSDs), are clinically heterogeneous and characterized by multi-systemic manifestations such as skeletal abnormalities and neurological dysfunctions. The currently used enzyme replacement therapy (ERT) might associate with several limitations including the low biodistribution of the enzymes into the main targets, immunological responses against the foreign enzyme, and the high cost of the treatment procedure. Therefore, a suitable combination approach can be considered for the successful treatment of each type of MPS. Areas covered: In this review, we aimed to provide comprehensive insights into the ERT-based combination therapies of MPS through reviewing the published literature on PubMed and Scopus databases. We also discuss the recent advancements in the treatment of MPS and bring up the hopes and hurdles in the futuristic treatment strategies. Expert opinion: Given the complex pathophysiology of MPS and its involvement of different tissues, the combination therapy of MPS with combined treatment modalities (e.g., stem cell therapy, gene therapy) is deemed to provide a personalized precision care program with the highest therapeutic responses and minimal side effects. By the same token, new combinational approaches need to be evaluated by using drugs that target alternative and secondary pathological pathways.

Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985–2019)

Article

Full-text available

Dec 2020
ORPHANET J RARE DIS

Background Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs. Methods An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated. Results Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades ( p < 0.01). Pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively introduced in Taiwan from 2016, and 48% (16/33) of MPS patients diagnosed between 2016 and 2019 were diagnosed by one of these screening programs, with a median diagnostic age at 0.2 years. For patients born between 2016 and 2019, up to 94% (16/17) were diagnosed with MPS via the newborn screening programs. At the time of this study, 81 patients had passed away with a median age at death of 15.6 years. Age at diagnosis was positively correlated with life expectancy ( p < 0.01). Life expectancy also significantly increased between 1985 and 2019, however this increase was gradual ( p < 0.01). Conclusions The life expectancy of Taiwanese patients with MPS has improved in recent decades and patients are being diagnosed earlier. Because of the progressive nature of the disease, early diagnosis by newborn screening programs and timely implementation of early therapeutic interventions may lead to better clinical outcomes.

Home treatment of type VI mucopolysaccharidosis (Maroteaux‐Lamy syndrome) an alternative at this time of COVID‐19 pandemic: A case in Peru

Article

Full-text available

Oct 2020

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. 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.

Novel therapies for mucopolysaccharidosis type III

Article

Full-text available

Sep 2020
J INHERIT METAB DIS

Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation and early death. Unlike other MPS, no disease-modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno-associated (AAV) or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first-in-man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease-modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints

Article

Aug 2020

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.

Clinical and Molecular Analysis of Hereditary Morquio Syndrome

Thesis

Full-text available

Aug 2014

Sarmad Mehmood

Lysosome is an organelle which serves as a recycle bin in a cell. It has the enzymatic machinery to catalyze the degradation of micro as well as macro molecules. The improper working of the lysosome would result in the progressive accumulation in the organelle. This aggregation would cause size augmentation of lysosome, resulting in less space for the other vital organelles. This masking of space and increase in size would result in inhibited enzyme activity. Mutations in any of the genes involved in the production of any of the lysosomal enzyme would result in the above said condition. In the present study three consanguineous families showing autosomal recessive (A, B, C) showing hereditary morquio syndrome was clinically and genetically evaluated. Homozygosity mapping was used to scrutinize the gene responsible for autosomal recessive morquio syndrome in three families. Affected individuals of family (A, B, C) showed the clinical presentation of Morquio Syndrome which include short stature, knee knocking, abnormal joints and pigeon shaped chest. Highly polymorphic microsatellite markers were used for genotyping. The family A showed linkage to GALNS gene on chromosome 16q24.3. Sequence analysis of the gene GALNS revealed a novel homozygous missense mutation in the cDNA (c.647T>C), which results in misfolding of protein. In homozygosity mapping with polymorphic microsatellite markers, family B and C were excluded from the known loci involved in mucopolysaccharidosis (MPS), which beckons towards the involvement of some novel or undiscovered molecular reason of pathology.

M.Phil thesis-Sarmad Mehmood

Thesis

Aug 2014

Sarmad Mehmood

Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985-2019)

Preprint

Full-text available

Jun 2020

Mucopolissacaridose tipo VI

Article

Full-text available

Mar 2001

Introdução. A mucopolissacaridose VI é causada pela deficiência da n-acetilgalactosamina-4-sulfatase, uma das onze enzimas lisossomais responsáveis pela degradação de glicosaminoglicanos, estes, ao se acumularem causam dano ao lisossomo, morte celular e disfunção orgânica. Objetivo. O objetivo deste trabalho é realizar uma revisão de literatura sobre a mucopolissacaridose VI, com ênfase no diagnóstico precoce e a evolução do manejo terapêutico. Método. Foi realizada uma pesquisa de publicações nacionais e internacionais, em meios de comunicação especializados na área médica e de saúde, utilizando os unitermos relacionados. Conclusão. A conclusão foi que, apesar da MPS VI ser uma doença rara, o diagnóstico clínico precoce é possível e indispensável para proporcionar qualidade de vida a esses pacientes através da terapêutica adequada, justificando a importância deste artigo para o conhecimento da comunidade científica.

Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings

Article

Full-text available

Feb 2020

Enzyme replacement therapy (ERT) is one of the available therapies for mucopolysaccharidosis (MPS). This study presents a follow-up of two siblings with MPS IVA (Morquio A disease) that received ERT. Both siblings received weekly intravenous infusions of elosulfase alfa for 4.5 years. One sibling (patient 1, P1; male) started therapy at 54 months of age, and the other sibling (patient 2, P2; female) started at 11 months of age. ERT was well-tolerated. In comparison to P1, P2’s growth curves deviated less from the norm. The orthopedic deformities of P1 were more severe than those of P2 and required several surgical corrections. P1’s sleep test at 48 months revealed obstructive sleep apnea, while by the age of 102 months, parameters were normal. P2 never had sleep apnea. Only P1 demonstrated ear, nose, and throat clinical illnesses. In comparison to P1, P2’s physical function was better maintained. In conclusion, ERT was safe in both patients during a 4.5-year follow-up. Although the typical characteristics of this disease were similar in both patients, P1 had a complex clinical course in comparison to P2, which influenced function and quality of life. Therefore, in order to make the most of ERT, it may be more beneficial when initiated at a relatively young age.

An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan

Article

Full-text available

Oct 2019

Background: The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) and which eventually cause progressive damage to various tissues and organs. We developed a feasible MPS screening algorithm and established a cross-specialty collaboration platform between medical geneticists and other medical specialists based on at-risk criteria to allow for an earlier confirmative diagnosis of MPS. Methods: Children (<19 years of age) with clinical signs and symptoms compatible with MPS were prospectively enrolled from pediatric clinics between July 2013 and June 2018. Urine samples were collected for a non-specific total GAG analysis using the dimethylmethylene blue (DMB) spectrophotometric method, and the quantitation of three urinary GAGs (dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)) was performed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The subjects with elevated urinary GAG levels were recalled for leukocyte enzyme activity assay and genetic testing for confirmation. Results: Among 153 subjects enrolled in this study, 13 had a confirmative diagnosis of MPS (age range, 0.6 to 10.9 years-three with MPS I, four with MPS II, five with MPS IIIB, and one with MPS IVA). The major signs and symptoms with regards to different systems recorded by pediatricians at the time of the decision to test for MPS were the musculoskeletal system (55%), followed by the neurological system (45%) and coarse facial features (39%). For these 13 patients, the median age at the diagnosis of MPS was 2.9 years. The false negative rate of urinary DMB ratio using the dye-based method for these 13 patients was 31%, including one MPS I, two MPS IIIB, and one MPS IVA. However, there were no false negative results with urinary DS, HS and KS using the MS/MS-based method. Conclusions: We established an at-risk population screening program for MPS by measuring urinary GAG fractionation biomarkers using the LC-MS/MS method. The program included medical geneticists and other medical specialists to increase awareness and enable an early diagnosis by detecting MPS at the initial onset of clinical symptoms.

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance

Article

Full-text available

Dec 2019
ORPHANET J RARE DIS

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.

Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy

Article

Nov 2024

Therapy for Neuropathic Lysosomal Storage Diseases

Chapter

Nov 2024

Lysosomal storage diseases (LSDs) have phenotypic manifestations in multiple organ systems, most notably the central nervous system (CNS). LSDs can be classified broadly as sphingolipidosis (SL), mucopolysaccharidoses (MPS), mucolipidosis (ML), multiple enzyme deficiencies (MEDs), oligosaccharidoses (OS), and neuronal ceroid lipofuscinosis (NCF). Enzyme replacement therapy has shown positive outcomes in multiple diseases such as Fabry disease, Gaucher’s disease. Nanoparticle envelopes and liposomes are technological advances that stabilize recombinant enzymes, increase their half-life in the systemic circulation, and enhance their therapeutic effects. Many treatments for LSDs have completed clinical trials and received FDA approval. Despite the success of ERT in ameliorating non-CNS manifestations of LSDs, CNS manifestations are resistant to ERT, primarily because the BBB blocks the delivery of the replacement enzyme to the CNS. Using gene therapy delivered by CED of viral or nanoparticle vectors is also an area of research interest. Better treatments are required for the CNS involvement that accompanies many LSDs and often results in severe morbidity and early mortality.

Mucopolysaccharidoses

Chapter

Jan 2011

Marwan A.S. Bukhari

Evolução de indicadores antropométricos de portadores de mucopolissacaridoses: realidade de um centro de referência / Evolution of anthropometric indicators of mucopolysaccharidosis carriers: reality of a reference center

Article

Apr 2022

Objetivo: Avaliar a evolução dos parâmetros antropométricos de pacientes com mucopolissacaridoses (MPS) I, II e VI cadastrados no Centro de tratamento de Erros Inatos do Metabolismo em Pernambuco. Métodos: Estudo prospectivo com crianças, adolescentes e adultos em terapia de reposição enzimática, sendo avaliados: índice de massa corporal (IMC), circunferência do braço (CB), circunferência muscular do braço (CMB), área muscular do braço corrigida (AMBc) e prega cutânea tricipital (PCT) em dois momentos distintos, com intervalo médio de 15 meses. Resultados: participaram 29 indivíduos, sendo 2 portadores de MPS I, 6 de MPS II e 21 de MPS VI, com mediana de idade de 14,6 (3 - 40) anos na segunda entrevista. Em ambas as avaliações, houve uma frequência de eutrofia e excesso de peso pelo IMC e de déficit de estatura entre os participantes, com redução no percentual de desnutrição pela CMB. Houve uma variação positiva e significativa para peso, estatura, IMC, CB e CMB entre as crianças, e na estatura, CB, CMB e AMBc entre os adolescentes ao final do estudo. Conclusões: verificou-se uma prevalência de eutrofia e excesso de peso, e uma melhora dos parâmetros antropométricos, destacando àqueles relacionados ao compartimento muscular, com redução no percentual de desnutrição de acordo com a CMB.

Serebral Palsi ve Nöromusküler Hastalığı olan Çocuklarda Yürüyüş için Kullanılan Ayak ve Ayak Bileği Ortezlerinin Yürüme Performansı ve Enerji Harcamasına Etkilerinin İncelenmesi

Article

Full-text available

Dec 2021

Amaç: Bu çalışmanın amacı; serebral palsi (SP) ve nöromusküler hastalığı (NMH) olan çocuklarda yürüyüş için kullanılan ayak ve ayak bileği ortezlerinin (AFO) yürüme performansı ve enerji harcamasına etkilerinin incelenmesidir. Gereç ve Yöntem: Retrospektif tanımlayıcı bir araştırma dizaynı içerisinde hastalara, ortez kullanmaksızın ve ortez kullanılarak uygulanmış olan 6 Dakika Yürüme Testi (6DYT) ile elde edilen yürüme mesafesi, kalp atım hızı, solunum frekansı, dispne ve genel yorgunluk şiddetinin (Borg skalası ile) değerlendirme sonuçları SP ve NMH tanısı olan çocuklar arasında karşılaştırıldı. Ayrıca çocukların yürüme sırasındaki enerji tüketimlerinin hesaplanması amacıyla Fizyolojik Harcama İndeksi kullanıldı. Bulgular: Ocak 2018 –Aralık 2019 tarih aralığını kapsayan dosya taramaları sonucunda dahil edilme kriterlerine uygun olan çocukların 13’ü (%52) SP grubu olarak, 12’si (% 48) ise NMH grubu olarak gruplandırıldı. 6DYT kapsamında elde edilen kalp atım hızı, solunum frekansı, dispne ve yorgunluk şiddeti değerleri, kaydedilen yürüme mesafesindeki değişimler ve enerji tüketimleri her iki grup için de ortez kullanılmadığı ve kullanıldığı durumlarda benzer değişim gösterdi (p>0,05). Gruplar arası karşılaştırmalarda ortez kullanımı ile yürüyüş performansı ve enerji tüketimi açısından fark olmadığı sonucuna ulaşıldı (p>0,05). Sonuç: Bu retrospektif çalışmada AFO kullanımının SP ve NMH’li çocuklarda tanıdan bağımsız olarak yürüyüş performansını ve enerji tüketimini etkilediği sonucuna ulaşıldı. Her ne kadar konuya ilişkin genel bir bakış sağlamaya çalışılsa da, alanda biyomekanik etkilerin de dahil edildiği çok faktörlü etkileri inceleyen daha kapsamlı araştırmalara ihtiyaç duyulduğu görülmektedir.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): defining and measuring functional impacts in pediatric patients

Article

Full-text available

Dec 2021
ORPHANET J RARE DIS

Background Research about pediatric patients’ perspective on mucopolysaccharidosis type VI (MPS VI) and its impact on daily life is limited. We aimed to identify the disease concepts of interest that most impact function and day-to-day life of pediatric patients with MPS VI, and to consider clinical outcome assessments (COAs) that may potentially measure meaningful improvements in these concepts. Methods Potential focus group participants were identified by the National MPS Society (USA) and invited to participate if they self-reported a clinician-provided diagnosis of MPS VI and were 4 to 18 years, receiving enzyme replacement therapy (ERT), and available to attend a 1-day focus group with their caregiver in Dallas, TX, USA. The focus group consisted of a series of polling and open-ended concept elicitation questions and a cognitive debriefing session. The discussion was audio recorded, transcribed verbatim, and analyzed to identify disease concepts of interest and functional impacts most relevant to participants. Results Overall, caregivers (n = 9) and patients with MPS VI (n = 9) endorsed that although their children/they receive ERT, residual symptoms exist and impact health-related quality of life. The key disease concepts of interest identified were impaired mobility, upper extremity and fine motor deficits, pain, and fatigue. Pain was unanimously reported by all patients across many areas of the body and impacted daily activity. Key disease concepts were mapped to a selection of pediatric COAs including generic measures such as PROMIS®, PODCI, CHAQ, and PedsQL™. Caregivers endorsed the relevance of PODCI and PROMIS Upper Extremity, Mobility, and Pain items and all patients completed the NIH Toolbox Pegboard Dexterity Test. Additional COAs that aligned with the disease concepts included range of motion, the 2- and 6-min walk tests, timed stair climbs, Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition, grip strength, pain visual analog scale, and the Faces Pain Scale-Revised. Conclusion An MPS VI focus group of pediatric patients and their caregivers identified impaired mobility, upper extremity and fine motor deficits, pain, and fatigue as key disease concepts of interest. These disease concepts were mapped to existing pediatric COAs, which were provided to the group for endorsement of their relevance.

Thérapeutiques actuelles et perspectives

Article

Nov 2021

Nathalie Guffon

Résumé Malgré leur rareté, les maladies de surcharges lysosomales ont bénéficié de nombreuses avancées thérapeutiques. Plusieurs approches existent. La première vise à apporter l’enzyme manquante par thérapie cellulaire (transplantation de cellules souches hématopoïétiques), ou par l’apport hebdomadaire ou tous les quinze jours, par voie intraveineuse, de l’enzyme déficitaire sous la forme d’une protéine recombinante parfois modifiée (traitement enzymatique substitutif) ou encore en agissant directement sur le gène pour corriger des anomalies délétères (translecture de codons stop, modulation de l’épissage…), ou enfin par thérapie génique soit in vivo par transfert direct de gène à l’aide de vecteurs viraux recombinants soit ex vivo avec réinjection de cellules du malade génétiquement modifiées. La deuxième approche consiste à empêcher l’accumulation des composés non dégradés : il s’agit de la thérapie par réduction de substrat. La troisième approche est d’agir sur les conséquences physiopatho-logiques de l’accumulation excessive de substrat : inflammation, stress oxydatif, auto-immunité, autophagie, apoptose. Les limitations actuelles des différentes thérapeutiques sont les difficultés de ciblage de certains tissus ainsi qu’au rôle du système immunitaire qui peut restreindre l’efficacité de certains traitements et nécessiter des traitements adjuvants.

Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI

Article

Sep 2021

Background: Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is a rare genetic disorder caused by the deficiency of arylsulphatase B. The resultant accumulation of dermatan sulphate causes lysosomal damage. The clinical symptoms are related to skeletal dysplasia (i.e. short stature and degenerative joint disease). Other manifestations include cardiac disease, impaired pulmonary function, ophthalmological complications, hepatosplenomegaly, sinusitis, otitis, hearing loss and sleep apnea. Intellectual impairment is generally absent. Clinical manifestation is typically by two or three years of age; however, slowly progressive cases may not present until adulthood. Enzyme replacement therapy (ERT) with galsulfase is considered a new approach for treating MPS VI. Objectives: To evaluate the effectiveness and safety of treating MPS VI by ERT with galsulfase compared to other interventions, placebo or no intervention. Search methods: Eletronic searches were performed on the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Date of the latest search: 09 June 2021. Further searches of the following databases were also performed: CENTRAL, MEDLINE, LILACS, the Journal of Inherited Metabolic Disease, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Date of the latest search: 20 August 2021. Selection criteria: Randomized and quasi-randomized controlled clinical studies of ERT with galsulfase compared to other interventions or placebo. Data collection and analysis: Two authors independently screened the studies, assessed the risk of bias, extracted data and assessed the certainty of the the evidence using the GRADE criteria. Main results: One study was included involving 39 participants who received either ERT with galsulfase (recombinant human arylsulphatase B) or placebo. This small study was considered overall to have an unclear risk of bias in relation to the design and implementation of the study, since the authors did not report how both the allocation generation and concealment were performed. Given the very low certainty of the evidence, we are uncertain whether at 24 weeks there was a difference between groups in relation to the 12-minute walk test, mean difference (MD) of 92.00 meters (95% confidence interval (CI) 11.00 to 172.00), or the three-minute stair climb, MD 5.70 (95% CI -0.10 to 11.50). In relation to respiratory tests, we are uncertain whether galsulfase makes any difference as compared to placebo in forced vital capacity in litres (FVC (L) (absolute change in baseline), given the very low certainty of the evidence. Cardiac function was not reported in the included study. We found that galsulfase, as compared to placebo, may decrease urinary glycosaminoglycan levels at 24 weeks, MD -227.00 (95% CI -264.00 to -190.00) (low-certainty evidence). We are uncertain whether there are differences between the galsulfase and placebo groups in relation to adverse events (very low-certainty evidence). In general, the dose of galsulfase was well tolerated and there were no differences between groups. These events include drug-related adverse events, serious and severe adverse events, those during infusion, drug-related adverse events during infusion, and deaths. More infusion-related reactions were observed in the galsulfase group and were managed with interruption or slowing of infusion rate or administration of antihistamines or corticosteroids drugs. No deaths occurred during the study. AUTHORS' CONCLUSIONS: The results of this review are based only on one small study (a 24-week randomised phase of the study and prior to the open-label extension). We are uncertain whether galsulfase is more effective than placebo, for treating people with MPS VI, in relation to the 12-minute walk test or the three-minute stair climb, as the certainty of the evidence has been assessed as very low. We found that galsulfase may reduce urinary glycosaminoglycans levels. We are also uncertain whether there are any differences between treatment groups in relation to cardiac or pulmonary functions, liver or spleen volume, overnight apnea-hypopnea, height and weight, quality of life and adverse effects. Further studies are needed to obtain more information on the long-term effectiveness and safety of ERT with galsulfase.

Deep intronic variant in the ARSB gene as the genetic cause for Maroteaux–Lamy syndrome (MPS VI)

Article

Aug 2021

Maroteaux–Lamy syndrome (MPS‐VI) is a rare autosomal‐recessive disorder with a wide spectrum of clinical manifestations, ranging from an attenuated to a rapidly progressive disease. It is caused by variants in ARSB, which encodes the lysosomal arylsulfatase B (ARSB) enzyme, part of the degradation process of glycosaminoglycans in lysosomes. Over 220 variants have been reported so far, with a majority of missense variants. We hereby report two siblings of Bedouin origin with a diagnosis of MPS‐VI. Western blots in patient fibroblasts revealed total absence of ARSB protein production. Complete sequencing of the coding region of ARSB did not identify a candidate disease‐associated variant. However, deep sequencing of the noncoding region of ARSB by whole genome sequencing (WGS) revealed a c.1142+581A to G variant. The variant is located within intron 5 and fully segregated with the disease in the family. Determination of the genetic cause for these patients enabled targeted treatment by enzyme replacement therapy, along with appropriate genetic counseling and prenatal diagnosis for the family. These results highlight the advantage of WGS as a powerful tool, for improving the diagnostic rate of rare disease‐causing variants, and emphasize the importance of studying deep intronic sequence variation as a cause of monogenic disorders.

The Mucopolysaccharidoses: Prenatal Diagnosis, Neonatal Screening and Emerging Therapies

Chapter

Apr 2021

Lorne Clarke

The rapid emergence and integration of effective therapies for many of the mucopolysaccharidoses (MPSs) has fueled a resurgence in the establishment of strategies leading to early diagnosis, including newborn screening and prenatal diagnosis as well as delineation of the precise pathogenic mechanisms underlying disease symptoms and natural history. The insights gained from the success of enzyme replacement strategies in altering somatic disease in the MPSs has led to the recent development and evaluation of alternative therapies for the MPSs, including those that specifically target the central nervous system as well as gene‐based therapeutics. The emergence of molecular genetic techniques, including chromosome microarray analysis, Sanger sequencing, and next‐generation sequencing methodologies providing accurate, single‐gene, gene‐panel, whole‐exome, and whole‐genome sequencing, has largely replaced enzymatic‐based prenatal diagnosis for the MPSs. Prior to the elucidation of the biochemical and molecular bases of MPS I, Scheie syndrome was initially thought to represent a distinct disorder and was termed MPS V.

Long-term outcomes of patients with mucopolysaccharidosis VI treated with galsulfase enzyme replacement therapy since infancy

Article

Mar 2021

Objective Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated. Methods 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. Results 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. Conclusion 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.

Mucopolysaccharidoses

Chapter

Jan 2021

Roberto Giugliani

The mucopolysaccharidoses (MPSs) are inherited disorders of the metabolism of the glycosaminoglycans (GAGs), caused by the deficiency of enzymes involved in the stepwise degradation of these compounds. Being the GAGs a major component of the extracellular matrix of the connective tissue, its storage leads to a multisystem disorder. Eleven subtypes of MPS have been described so far, being all chronic and progressive, having a wide range of clinical manifestations and a broad spectrum of severity in each type. The disease generally presents in one of the three ways depending on the specific enzyme that is defective: (1) A dysmorphic syndrome (e.g., MPS types I, II, VI, or VII); (2) behavioral disturbances, neurodegeneration, and dementia (MPS III); (3) a severe bone dysplasia (MPS IV). In most cases, diagnosis initially depends on clinical suspicion, followed by demonstration of increased levels and/or abnormal pattern of GAGs in urine. The clinical picture combined with the pattern of urinary GAG excretion usually guides the laboratory to define which specific enzymes should be analyzed in order to identify the deficiency and elucidate the diagnosis. Mutation analyses are recommended to pinpoint the specific genetic defects causing the disorder. Although no cure exists for the MPSs, several treatment approaches are available or under investigation. Management is multidisciplinary and includes palliative care, surgeries, cell-based therapy (bone marrow or umbilical cord blood transplantation) and enzyme replacement therapy (ERT). Manifestations involving the skeleton and particularly the central nervous system (CNS) are the most challenging to treat, but newer therapeutic approaches (e.g., substrate reduction, Trojan horse ERT, intrathecal (IT)/ intracerebroventricular ERT, stop codon read-through, gene therapy, gene editing, etc.) are in development and may change the outcome of these disorders in a near future. Carrier identification and prenatal diagnosis are available for all of these disorders, and newborn screening (NBS) is already being conducted as part of regular programs for MPS I and MPS II in some places, and is under investigation for other treatable MPSs.

A Generic Assay to Detect Aberrant ARSB Splicing and mRNA Degradation for the Molecular Diagnosis of MPS VI

Article

Full-text available

Dec 2020

Identification and characterization of disease-associated variants in monogenic disorders is an important aspect of diagnosis, genetic counseling, prediction of disease severity, and development of therapy. However, the effects of disease-associated variants on pre-mRNA splicing and mRNA degradation are difficult to predict and often missed. Here we present a generic assay for unbiased identification and quantification of arylsulfatase B (ARSB) mRNA for molecular diagnosis of patients with mucopolysaccharidosis VI (MPS VI). We found that healthy control individuals have inefficient ARSB splicing because of natural skipping of exon 5 and inclusion of two pseudoexons in introns 5 and 6. Analyses of 12 MPS VI patients with 10 different genotypes resulted in identification of a 151-bp intron inclusion caused by the c.1142+2T>C variant and detection of low ARSB expression from alleles with the c.629A>G variant. A special case showed skipping of exon 4 and low ARSB expression. Although no disease-associated DNA variant could be identified in this patient, the molecular diagnosis could be made based on RNA. These results highlight the relevance of RNA-based analyses to establish a molecular diagnosis of MPS VI. We speculate that inefficient natural splicing of ARSB may be a target for therapy based on promotion of canonical splicing. Broeders et al. present a generic assay for unbiased identification and quantification of arylsulfatase B mRNA for molecular diagnosis of MPS VI. Aberrantly spliced and degraded products were identified in MPS VI patients and healthy control individuals, highlighting the relevance of RNA-based analyses.

Lysosomal Storage Diseases

Chapter

Jan 2012

Gregory M. Pastores

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

Article

Full-text available

Apr 2020
INT J MOL SCI

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

Evolução natural em uma paciente com Mucopolissacaridose tipo VI

Article

Full-text available

Mar 2001

Introdução. A mucopolissacaridose tipo VI é causada pela deficiência da n-acetilgalactosamina-4-sulfatase, uma das onze enzimas lisossomais responsáveis pela degradação de glicosaminoglicanos, e estas, ao se acumularem causam dano ao lisossomo, morte celular e disfunção orgânica. Objetivo. Apresentar a evolução natural da deposição dos glicosaminoglicanos em uma paciente sem tratamento prévio e relacionar as dificuldades na conduta e diagnóstico desta rara doença no Brasil. Relato do Caso. Paciente apresentando quadro multissistêmico devido à mucopolissacaridose tipo VI após quatorze anos da doença, sem tratamento ou acompanhamento. Conclusão. O diagnóstico precoce e a terapêutica correta são juntos indispensáveis para uma qualidade de vida a esses pacientes.

Enzyme replacement therapy in a feline model of Maroteaux-Lamy syndrome

Article

Full-text available

May 1996

We report studies that suggest enzyme replacement therapy will result in a significant reduction in disease progression and tissue pathology in patients with Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). A feline model for MPS VI was used to evaluate tissue distribution and clinical efficacy of three forms of recombinant human N-acetylgalactosamine-4-sulfatase (rh4S, EC 3.1.6.1). Intravenously administered rh4S was rapidly cleared from circulation. The majority of rh4S was distributed to liver, but was also detected in most other tissues. Tissue half-life was approximately 2-4 d. Three MPS VI cats given regular intravenous infusions of rh4S for up to 20 mo showed variable reduction of storage vacuoles in Kupffer cells and connective tissues, however cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in two MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy.

A Qualitative Systematic Overview of the Measurement Properties of Functional Walk Tests Used in the Cardiorespiratory Domain*

Article

Full-text available

Feb 2001

To perform a qualitative systematic overview of the measurement properties of the most commonly utilized walk tests in the cardiorespiratory domain: the 2-min walk test (2MWT), 6-min walk test (6MWT), 12-min walk test (12MWT), self-paced walk test (SPWT), and shuttle walk test (SWT). MEDLINE (1966 to January 2000) and CINAHL (1982 to December 1999) electronic databases were searched. Bibliographies of the retrieved articles were reviewed. Clinical trials and observational studies were included if they reported data on the validity, reliability, interpretability, or responsiveness of the 2MWT, 6MWT, 12MWT, SPWT, or SWT. Only studies conducted on patients with cardiac and/or respiratory involvement were included. Fifty-two studies examining measurement properties of the various walk tests were found: 5 studies on the 2MWT, 29 studies on the 6MWT, 13 studies on the 12MWT, 6 studies on the SPWT, and 4 studies on the SWT. Measurement properties were most strongly demonstrated for the 6MWT. Correlations of 6MWT distance and maximal oxygen consumption ranged from 0.51 to 0.90. A change in distance walked of at least 54 m was found to be clinically significant for the 6MWT. Reliability was shown to be optimized when the administration of walk tests was standardized and at least two practice walks were performed. Patients with increased likelihood of postoperative complications, hospitalization, and death were identified by analysis of distance walked. Measurement properties of the 6MWT have been the most extensively researched and established. In addition, the 6MWT is easy to administer, better tolerated, and more reflective of activities of daily living than the other walk tests. Therefore, the 6MWT is currently the test of choice when using a functional walk test for clinical or research purposes.

Management Guidelines for Mucopolysaccharidosis VI

Article

Full-text available

Sep 2007
Pediatrics

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.

Part 12: 78. The mucopolysaccharidoses

Article

Jan 2001

The six-minute walking test in children with cystic fibrosis: Reliability and validity

Article

Aug 1996
PEDIATR PULM

There is a need to judge general exercise tolerance in children with cystic fibrosis (CF) under normal daily activity conditions and—when more extensive testing is required—in an exercise laboratory in a specialized center. We investigated the reproducibility, validity, and criterion for a 6-minute walking test, which simulates normal childhood activities. In Part A, we evaluated the reproducibility of a 6-minute walking test in 23 children (12 girls and 11 boys; ages 11.1 ± 2.2 years; range, 8.2 15.6 years) with mild symptoms of CF [forced expiratory volume in 1 second (FEV1) 94.4 ± 16.5% of predicted values (range, 60.6–129.7); body weight Z-score −0.71 ± 0.81 (range, −1.73–0.93)]. The subjects performed two standardized 6-minute walking tests with 1 week between tests. There was no significant difference between the two walking distances reached (737 ± 85 versus 742 ± 90 meters; P = 0.56), and there was a strong correlation between the two walking distances reached by the individuals (r = 0.90, P < 0.0001).

Enzyme replacement therapy in mucopolysaccaridosis VI (Maroteaux-Lamy Syndrome)

Article

Jun 2004
J Pediatr

To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI). An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks. No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking <100 meters at baseline. Shoulder range of motion improved in all patients at week 48 and joint pain improved in patients with significant pain at baseline. rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux–Lamy syndrome)

Article

May 2005

A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (>200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.

Replacement therapy in Mucopolysaccharidosis type VI: Advantages of early onset of therapy

Article

Mar 2003

This study evaluates the immunological response following weekly 2h infusions of recombinant human N-acetylgalactosamine 4-sulfatase (rh4S) in Mucopolysaccharidosis VI (MPS VI) cats. The results of three trials (Trial "A": 9 month duration with onset at 3-5 months of age, n = 5; and Trials "B" and "C": 6 month duration starting at birth, n = 9) were compared. No detrimental effects were noted throughout Trials B and C. Temporary hypersensitivity reactions (e.g., vomiting, diarrhoea) occurred in four cats in Trial A and were alleviated by increasing the dose of antihistamine premedication and the duration of infusion. All cats in Trial A developed antibodies to rh4S (range of final titres: 1041-134,931). All cats treated from birth showed negligible titres (range: < 50-598). In vitro inhibition of rh4S activity (up to 47%) was demonstrated with plasma from four cats with elevated titres. Significant reduction of urinary glycosaminoglycan concentration in all cats indicated the ability of rh4S to metabolize stored substrates regardless of the presence of circulating antibodies. Similarly, lysosomal storage in reticuloendothelial cells and fibroblasts of kidney interstistium, dura and skin was reduced in all cats irrespective of their antibody titre although cats with elevated titre had less beneficial effect on cardiovascular tissues (aorta smooth muscle cells, heart valve fibroblasts). Overall improvement in the disease condition (at physical, neurological, and skeletal levels) was most pronounced for cats treated from birth compared with cats treated at a later age.

Direct Comparison of Measures of Endurance, Mobility, and Joint Function During Enzyme-Replacement Therapy of Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): Results After 48 Weeks in a Phase 2 Open-Label Clinical Study of Recombinant Human N-Acetylgalactosamine 4-Sulfatase

Article

Jun 2005
Pediatrics

Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients. This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals. After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion (<10 degrees ) and in the time taken to stand, walk, and turn starting from a seated position (Expanded Timed Get-Up and Go test). Improvement in pulmonary function based on forced vital capacity and forced expiratory volume at 1 minute in the absence of growth was observed in 3 of 6 patients, and the observed gains occurred in the 24- to 48-week treatment interval. A mean decrease of 76% in urinary excretion of glycosaminoglycans indicated that a satisfactory biochemical response was achieved and the ERT was well tolerated. The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.

Physiologic response of the 6-minute walk test in children with juvenile idiopathic arthritis

Article

Jun 2005

To determine the physiologic response of the 6-minute walk test (6-mwt) in children with juvenile idiopathic arthritis (JIA). Eighteen children with JIA (age 7-17 years; 6 boys, 12 girls) performed a 6-mwt and a maximal exercise test. The physiologic response of the 6-mwt was on average between 80% and 85% of the peak values of heart rate and oxygen uptake (VO2peak) during the maximal exercise test, except for the minute ventilation, which had a mean percentage of 68.5%. Backward regression analysis showed that height and distance walked were the best predictors of VO2peak during cycling (R2 = 0.883, P < 0.001). During the 6-mwt, the difference between the first and second minute was significant in every variable, except for heart rate. The range of walking distance of children with JIA was comparable with that of healthy elderly people. The physiologic response of the 6-mwt is at a submaximal, intense level of exercise. The course of the responses during the 6-mwt was normal. The 6-mwt can be regarded as a good test for measuring functional exercise capacity.

Six-Minute Walking Test to Assess Exercise Tolerance and Cardiorespiratory Responses During Training Program in Children With Congenital Heart Disease

Article

Nov 2005

This study assessed the exercise tolerance and the cardiorespiratory responses to a training program by the six-minute walk test (6'WT) in children with congenital heart disease (CHD). Seventeen cardiac and 14 healthy children performed maximal cardiopulmonary exercise test (CPET) and 6'WT. Reliability of 6'WT was assessed in all subjects (test-retest) by Bland-Altman plots. Cardiac subjects were randomly divided in training (T-CHD) and control groups (C-CHD). T-CHD underwent an individualized training exercise at the ventilatory threshold (VT) intensity during 12 weeks. We found that the 6'WT is a reliable and reproducible test. CHD children walked a lower distance than healthy children before training (472.5 +/- 18.1 vs. 548.8 +/- 7.7 m, respectively, p < 0.001). Likewise, power output, oxygen uptake (V.O (2)), and heart rate (HR) at the maximum and the VT levels, were significantly lower in patients (p < 0.001). After training, a significant improvement of walking distance (WD) was shown in T-CHD (529.6 +/- 15.3 vs. 467.7 +/- 17.1 m, p < 0.001). The power output, VO2, HR, and V.E increased slightly (6 to 10 %, p > 0.05) at peak exercise and significantly at ventilatory threshold level (p < 0.05) in T-CHD. Significant relationships between WD and VO2max as well as VO2 at VT were founded (p < 0.05). We concluded that the 6'WT is a useful and reliable tool in the assessment and follow-up of functional capacity during rehabilitation program in children with CHD.

Enzyme replacement therapy for mucopolysaccharidosis VI: A Phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study

Article

May 2006
J Pediatr

The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p=.025) and 5.7 stairs per minute more 3MSC (p=.053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227+/-18 microg/mg more with rhASB than placebo (p<.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.

Six-Minute Walk Test in Children and Adolescents

Article

May 2007

To evaluate the 6-minute walking distance (6MWD) for healthy Caucasian children and adolescents of a population-based sample from the age of 3 to 18 years. Two hundred and eighty boys and 248 girls completed a modified test, using a measuring wheel as incentive device. Median 6MWD increased from the age of 3 to 11 years in boys and girls alike and increased further with increasing age in boys (from 667.3 m to 727.6 m), whereas it essentially plateaued in girls (655.8 m to 660.9 m). After adjusting for age, height (P = .001 in boys and P < .001 in girls) remained independently correlated with the 6MWD. In the best fitting and most efficient linear and quadratic regression models, the variables age and height explained about 49% of the variability of the 6MWD in boys and 50% in girls. This modified 6-minute walk test (6MWT) proved to be safe, easy to perform, and highly acceptable to children. It provides a simple and inexpensive means to measure functional exercise capacity in children, even of young age, and might be of value when conducting comparable studies.

Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of acetylgalactosamine 4-sulfatase

Jan 2005
681-689

P Harmatz
D Ketteridge
R Giugliani
N Guffon
E L Teles
M C Miranda
Z F Yu
S J Swiedler
J J Hopwood

P. Harmatz, D. Ketteridge, R. Giugliani, N. Guffon, E.L. Teles, M.C. Miranda, Z.F. Yu, S.J. Swiedler, J.J. Hopwood, Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of acetylgalactosamine 4-sulfatase, Pediatrics 115 (2005) e681–e689.

The mucopolysaccharidoses The Metabolic and Molecular Bases of Inherited Disease

Jan 2001
3421-3452

E Neufeld
J Muenzer

E. Neufeld, J. Muenzer, The mucopolysaccharidoses, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle (Eds.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 3421–3452.

RN Department of Genetic Medicine, Women's and Children's Hospital Adelaide

Jan 2008
469-475

Mps The
Vi
John Study
Waterson
Md
Elio Phd
Gizzi
Center Md
Oakland
Oakland
Amraoui
Hosp Md
Pediatrí
Caceres
D N Spain
Bennett-Jones
Md
Physician
Whitehaven
Philippe Uk
Bernard
Centre Md
Hospitalier
Arras
Arras
France
Prof
Billette
Michel Villemeur
Kretz
Md
Civil
Le Colmar
Centre
Enfant
Colmar
France
Shuan-Pei Lin
Ana Md
Maria Martins
Md
Unifesp
Oncologia Instituto
Graacc Pediátrica
Unifesp
Departamento
São Pediatria
Paulo
Brazil
O Anne
Meara
Md
Lady Our
Lorenzo Pavone
Rita Md
Barone
Agata Md
Fiumara
Md
Prof
Giovanni
Sorge

The MPS VI Study Group co-investigators are: John Waterson, MD, PhD and Elio Gizzi, MD, Children's Hospital & Research Center Oakland, Oakland, California; Yasmina Amraoui, MD, Children's Hosp, University of Mainz, Germany; Ana Cecí Azevedo, MD, Servic ßo de Genética Médica, Hospital de Clí nicas de Porto Alegre, Porto Alegre, Brazil; Bonito Victor, MD, Unidade de Doenc ßas Metabólicas, Departamento Pediatria, Hospital de Sao João, Porto, Portugal; Javier Arroyo, MD, Hospital San Pedro de Alcantara, Hospital de dí a de Pediatrí, Caceres, Spain; D.N. Bennett-Jones, MD, Consultant General & Renal Physician, Whitehaven, UK; Philippe Bernard, MD, Centre Hospitalier d'Arras, Arras, France; Prof. Billette de Villemeur, Hôpital Trousseau, Paris, France; Raquel Boy, MD, Hospital Universitário Pedro Ernesto, Rio de Janeiro, Brazil; Eduardo Coopman, MD, Hospital del Cobre De. Salvador, Calama, Chile; Prof. Rudolf Korinthenberg, Universitätsklinikum Freiburg, Zentrum für Kinderheilkunde und Jugendmedizin, Klinik II Neuropädiatrie und Muskelerkrankungen, Freiburg, Germany; Michel Kretz, MD, Hôpital Civil de Colmar, Le Parc Centre de la Mère et de l'Enfant, Colmar, France; Shuan-Pei Lin, MD, MacKay Memorial Hospital, Department of Genetics, Taipei, Taiwan; Ana Maria Martins, MD, UNIFESP, Instituto de Oncologia Pediátrica, GRAACC/UNIFESP, Departamento de Pediatria, São Paulo, Brazil; Anne O'Meara, MD, Our Lady's Hospital for Sick Children, Dublin, Ireland; Gregory Pastores, MD, PhD, NYU Medical Center, Rusk Institute, New York, New York; Lorenzo Pavone, MD, Rita Barone, MD, Agata Fiumara, MD, and Prof. Giovanni Sorge, Department of Pediatrics, University of Catania, Catania, Italy; Silvio Pozzi, MD, Ospedale Vito Fazzi, UO Pediatria, Lecce, Italy; Uwe Preiss, MD, Universitaetsklinik und Poliklinik fuer Kinder, Halle, Germany; Emerson Santana Santos, MD, Fundac ßão Universidade de Ciências da Saúde de Alagoas Governador,Departamento de Pediatria, Maceió, Brazil; Isabel Cristina Neves de Souza, MD and Luiz Carlos Santana da Silva, PhD, Universidade Federal do Pará, Centro de Ciências Biológicas, Hospital Universitário João de Barros Barreto, Belém, Brazil; Eugênia Ribeiro Valadares, MD, PhD, Hospital das Clí nicas, Faculdade de Medicina da Universidade Federal de Minas Gerais-UFMG, Avenida Professor Alfredo Balena, Belo Horizonte-Minas Gerais, Brazil; Laura Keppen, MD, Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, SD; David Sillence, MD, Children's Hospital, Westmead, Australia; Lionel Lubitz, MD, Royal Children's Hospital, Melbourne, Australia; William Frischman, MD, The Townsville Hospital, Townsville, Australia; Julie Simon, RN, Children's Hospital & Research Center Oakland, Oakland, California; Claudia Lee, MPH, Children's Hospital & Research Center Oakland, Oakland, California; Stephanie Oates, RN Department of Genetic Medicine, Women's and Children's Hospital Adelaide, North Adelaide, Australia; Lewis Waber, MD, PhD, Pediatric Genetics and Metabolism, University of Texas Southwest Medical Center, Dallas, TX; Ray Pais, MD, Pediatric Hematology/Oncology, East Tennessee Children's Hospital, Knoxville, TN. Molecular Genetics and Metabolism 94 (2008) 469–475 References

Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase

Abstract

No full-text available

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