The Experts below are selected from a list of 240 Experts worldwide ranked by ideXlab platform
Patrick A. Meere - One of the best experts on this subject based on the ideXlab platform.
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Musculoskeletal complications associated with lysosomal storage disorders: Gaucher disease and Hurler-Scheie Syndrome (mucopolysaccharidosis type I)
Current Opinion in Rheumatology, 2005Co-Authors: Gregory M. Pastores, Patrick A. MeereAbstract:PURPOSE OF REVIEW: Enzyme therapy for lysosomal storage disorders directed at correcting the underlying cause of disease represents the most significant recent advance in patient management. This review focuses on two disease groups: glycosphingolipidoses and mucopolysaccharidoses. Specifically, Gaucher disease and Hurler-Scheie Syndrome have been selected as the prototypical disorder for each respective class.\n\nRECENT FINDINGS: Musculoskeletal complications are encountered in several of the lysosomal storage disorders and often represent a major source of extraneurologic morbidity, particularly in the subacute or chronic variants. Enzyme therapy has led to improvements in physical and functional well-being. However, bone involvement remains a recalcitrant feature, especially among patients with established disease before institution of therapy.\n\nSUMMARY: Early diagnosis and appropriate timely intervention are critical in achieving the best therapeutic results. A better understanding of the fundamental mechanisms of bone pathology may enable the identification of complementary approaches (eg, the use of bisphosphonates for severe osteopenia) for optimized outcomes. Symptomatic care and rigorous physical and occupational therapy remain critical components of a comprehensive management approach.
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musculoskeletal complications associated with lysosomal storage disorders gaucher disease and hurler Scheie Syndrome mucopolysaccharidosis type i
Current Opinion in Rheumatology, 2005Co-Authors: Gregory M. Pastores, Patrick A. MeereAbstract:Purpose of reviewEnzyme therapy for lysosomal storage disorders directed at correcting the underlying cause of disease represents the most significant recent advance in patient management. This review focuses on two disease groups: glycosphingolipidoses and mucopolysaccharidoses. Specifically, Gauch
Gregory M. Pastores - One of the best experts on this subject based on the ideXlab platform.
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Musculoskeletal complications associated with lysosomal storage disorders: Gaucher disease and Hurler-Scheie Syndrome (mucopolysaccharidosis type I)
Current Opinion in Rheumatology, 2005Co-Authors: Gregory M. Pastores, Patrick A. MeereAbstract:PURPOSE OF REVIEW: Enzyme therapy for lysosomal storage disorders directed at correcting the underlying cause of disease represents the most significant recent advance in patient management. This review focuses on two disease groups: glycosphingolipidoses and mucopolysaccharidoses. Specifically, Gaucher disease and Hurler-Scheie Syndrome have been selected as the prototypical disorder for each respective class.\n\nRECENT FINDINGS: Musculoskeletal complications are encountered in several of the lysosomal storage disorders and often represent a major source of extraneurologic morbidity, particularly in the subacute or chronic variants. Enzyme therapy has led to improvements in physical and functional well-being. However, bone involvement remains a recalcitrant feature, especially among patients with established disease before institution of therapy.\n\nSUMMARY: Early diagnosis and appropriate timely intervention are critical in achieving the best therapeutic results. A better understanding of the fundamental mechanisms of bone pathology may enable the identification of complementary approaches (eg, the use of bisphosphonates for severe osteopenia) for optimized outcomes. Symptomatic care and rigorous physical and occupational therapy remain critical components of a comprehensive management approach.
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musculoskeletal complications associated with lysosomal storage disorders gaucher disease and hurler Scheie Syndrome mucopolysaccharidosis type i
Current Opinion in Rheumatology, 2005Co-Authors: Gregory M. Pastores, Patrick A. MeereAbstract:Purpose of reviewEnzyme therapy for lysosomal storage disorders directed at correcting the underlying cause of disease represents the most significant recent advance in patient management. This review focuses on two disease groups: glycosphingolipidoses and mucopolysaccharidoses. Specifically, Gauch
Tracey Remmington - One of the best experts on this subject based on the ideXlab platform.
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enzyme replacement therapy with laronidase aldurazyme for treating mucopolysaccharidosis type i
Cochrane Database of Systematic Reviews, 2016Co-Authors: Elisabeth Jameson, Simon A Jones, Tracey RemmingtonAbstract:Background Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler Syndrome, Hurler-Scheie Syndrome and Scheie Syndrome, with the scale of severity being such that Hurler Syndrome is the most severe and Scheie Syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler Syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie Syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler Syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane review published in 2013. Objectives To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase. Date of most recent search: 05 October 2015. Selection criteria Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo. Data collection and analysis Two authors independently screened the identified studies. The authors then appraised and extracted data. Main results One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation. Authors' conclusions The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive and of good quality, although there were few participants. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.
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The Cochrane Library - Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I
Cochrane Database of Systematic Reviews, 2016Co-Authors: Elisabeth Jameson, Simon A Jones, Tracey RemmingtonAbstract:Background Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler Syndrome, Hurler-Scheie Syndrome and Scheie Syndrome, with the scale of severity being such that Hurler Syndrome is the most severe and Scheie Syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler Syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie Syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler Syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane review published in 2013. Objectives To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase. Date of most recent search: 05 October 2015. Selection criteria Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo. Data collection and analysis Two authors independently screened the identified studies. The authors then appraised and extracted data. Main results One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation. Authors' conclusions The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive and of good quality, although there were few participants. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.
Doug A. Brooks - One of the best experts on this subject based on the ideXlab platform.
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α-L-Iduronidase and enzyme replacement therapy for mucopolysaccharidosis I
Expert Opinion on Biological Therapy, 2020Co-Authors: Doug A. BrooksAbstract:Mucopolysaccharidosis I (McKusick 25280, Hurler Syndrome, Scheie Syndrome) is caused by a deficiency in the lysosomal hydrolase, α-L-iduronidase (EC 3.2.1.76) and results in a failure to degrade the glycosaminoglycans, dermatan sulfate and heparan sulfate. Mucopolysaccharidosis I patients present within a spectrum of clinical phenotypes, where Hurler and Scheie Syndromes represent the two extremes. In the 80 or more years since the discovery of mucopolysaccharidosis I, the molecular defect has been defined, the α-L-iduronidase protein purified and characterised, the α-L-iduronidase (IDUA) gene cloned, molecular genetic studies performed and expression systems developed. These advances have allowed the development of α-L-iduronidase enzyme replacement therapy as a treatment strategy for mucopolysaccharidosis I patients. Using animal models of mucopolysaccharidosis I, the efficacy of α-L-iduronidase replacement therapy has been evaluated and justified the initiation of human clinical trials in mucopolysacch...
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Laronidase Treatment of Mucopolysaccharidosis I
BioDrugs, 2005Co-Authors: Ed J. Wraith, John J. Hopwood, Maria Fuller, Peter J. Meikle, Doug A. BrooksAbstract:The lysosomal storage disorder (LSD) mucopolysaccharidosis type I (MPS I, McKusick 25280, Hurler Syndrome, Hurler-Scheie Syndrome, Scheie Syndrome) is caused by a deficiency in the lysosomal enzyme, α-L-iduronidase (EC 3.2.1.76). MPS I patients can present within a diverse clinical spectrum, ranging from classical Hurler Syndrome to attenuated Scheie Syndrome. Laronidase (Aldurazyme®) enzyme replacement therapy has been developed as a treatment strategy for MPS I patients and has been approved for clinical practice. Here we review the pre-clinical studies and clinical trials that have been used to demonstrate that intravenous laronidase therapy is well tolerated and effective for treating MPS I patients who do not have neuronal pathology. Current challenges for a viable treatment strategy for all MPS I patients include development of an early screening protocol that identifies patients before the onset of irreversible pathology, methods to predict disease severity, appropriate treatment for neuropathology, and an effective patient monitoring regimen.
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The α-L-iduronidase mutations R89Q and R89W result in an attenuated mucopolysaccharidosis type I clinical presentation
Biochimica et Biophysica Acta, 2003Co-Authors: Leanne K. Hein, John J. Hopwood, Peter R. Clements, Doug A. BrooksAbstract:Abstract Mucopolysaccharidosis type I (MPS I; McKusick 25280; Hurler Syndrome, Hurler–Scheie Syndrome and Scheie Syndrome) is caused by a deficiency in the lysosomal hydrolase, α- l -iduronidase (EC 3.2.1.76). MPS I patients present within a clinical spectrum bounded by the extremes of Hurler and Scheie Syndromes. The α- l -iduronidase missense mutations R89Q and R89W were investigated and altered an important arginine residue proposed to be a nucleophile activator in the catalytic mechanism of α- l -iduronidase. The R89Q α- l -iduronidase mutation was shown to result in a reduced level of α- l -iduronidase protein (≤10% of normal control) compared to a normal control level of α- l -iduronidase protein that was detected for the R89W α- l -iduronidase mutation. When taking into account α- l -iduronidase specific activity, the R89W mutation had a greater effect on α- l -iduronidase activity than the R89Q mutation. However, overall the R89W mutation produced more residual α- l -iduronidase activity than the R89Q mutation. This was consistent with MPS I patients, with an R89W allele, having a less severe clinical presentation compared to MPS I patients with either a double or single allelic R89Q mutation. The effects of the R89Q and R89W mutations on enzyme activity supported the proposed role of R89 as a nucleophile activator in the catalytic mechanism of α- l -iduronidase.
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Identification of mutations in the alpha-L-iduronidase gene (IDUA) that cause Hurler and Scheie Syndromes.
American Journal of Human Genetics, 1993Co-Authors: Hamish S. Scott, Doug A. Brooks, John J. Hopwood, Tom Litjens, Paul V. Nelson, P R Thompson, C. P. MorrisAbstract:Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive genetic disease caused by a deficiency of the lysosomal glycosidase [alpha]-L-iduronidase. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) Syndromes are clinical subtypes of MPS-I, but it is difficult to distinguish between these subtypes by biochemical measurements. Mutation analysis was undertaken to provide a molecular explanation for the clinical variation seen in MPS-I. Using chemical cleavage and direct PCR sequencing, the authors have defined four previously undescribed mutations for MPS-I (delG[sub 1702], 1060 + 2t [yields] c, R[sub 89]Q, and 678-7g [yields] a). R[sub 89]Q and 678-7g [yields] a were found to be present in 40% of Scheie Syndrome alleles. Expression of R[sub 89]Q demonstrated reduced stability and activity of the mutant protein. The deleterious effect of R[sub 89]Q may be potentiated by a polymorphism (A[sub 361]T) to produce an intermediate phenotype. 678-7g [yields] a was found to be a mild mutation, since it was present in an index Scheie Syndrome patient in combination with a severe allele (W[sub 402]X). This mutation appears to allow a very small amount of normal mRNA to be produced from the allele which is likely to be responsible for the mild clinical phenotype observed. Both the 5[prime]more » and 3[prime] splice site mutations (1060 + 2t [yields] c and 678-7g [yields] a, respectively) result in high proportions of mature mRNAs containing introns, which has not been observed for other splicing mutations. The frameshift mutation (delG[sub 1702]) and the 5[prime] splice site mutation (1060 + 2t [yields] c) are both thought to be associated with severe MPS-I. The identification of these MPS-I mutations begins to document the expected genetic heterogeneity in MPS-I and provides the first molecular explanations for the broad range of clinical phenotypes observed. 38 refs., 11 figs., 5 tabs.« less
Simon A Jones - One of the best experts on this subject based on the ideXlab platform.
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enzyme replacement therapy with laronidase aldurazyme for treating mucopolysaccharidosis type i
Cochrane Database of Systematic Reviews, 2016Co-Authors: Elisabeth Jameson, Simon A Jones, Tracey RemmingtonAbstract:Background Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler Syndrome, Hurler-Scheie Syndrome and Scheie Syndrome, with the scale of severity being such that Hurler Syndrome is the most severe and Scheie Syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler Syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie Syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler Syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane review published in 2013. Objectives To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase. Date of most recent search: 05 October 2015. Selection criteria Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo. Data collection and analysis Two authors independently screened the identified studies. The authors then appraised and extracted data. Main results One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation. Authors' conclusions The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive and of good quality, although there were few participants. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.
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The Cochrane Library - Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I
Cochrane Database of Systematic Reviews, 2016Co-Authors: Elisabeth Jameson, Simon A Jones, Tracey RemmingtonAbstract:Background Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler Syndrome, Hurler-Scheie Syndrome and Scheie Syndrome, with the scale of severity being such that Hurler Syndrome is the most severe and Scheie Syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler Syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie Syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler Syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane review published in 2013. Objectives To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase. Date of most recent search: 05 October 2015. Selection criteria Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo. Data collection and analysis Two authors independently screened the identified studies. The authors then appraised and extracted data. Main results One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation. Authors' conclusions The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive and of good quality, although there were few participants. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.
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early treatment with laronidase improves clinical outcomes in patients with attenuated mps i a retrospective case series analysis of nine sibships
Orphanet Journal of Rare Diseases, 2015Co-Authors: Nouriya Alsannaa, Ana Maria Martins, Simon A Jones, Luisa Bay, Deborah S Barbouth, Youssef Benhayoun, Cyril Goizet, Norberto Guelbert, Sandra Obikawa Kyosen, Chanika PhornphutkulAbstract:Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie Syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.
