- Email: [email protected]
75 The hunter outcome survey (HOS): A registry of mucopolysaccharidosis II patients
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Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34
clinical manifestations. We opted for the development of a biomarker filter paper method because in our Screening Program, newborn urine samples are collected by the parents on filter papers at 21 days of age. With technological advancements such as liquid chromatography-tandem mass spectrometry (LC–MS/MS), it is now feasible to analyze large molecules for treatable LSDs, such as globotriaosylceramide (GL-3) for Fabry disease. Total GL-3 analyses were carried out by positive electrospray ionization using a Waters Micromass Quattro micro tandem quadrupole system equipped with an Alliance 2795XE LC, while working with a two-step ammonium acetate-formic acid gradient. Validation (linearity, limit of detection and quantification, recovery) of the LC–MS/MS method was performed and the stability of GL-3 on filter paper established under different temperature conditions during 7 weeks (IS: C17:0-GL-3 isoform). This filter paper method eliminates lipid extraction, glycolipid isolation, centrifugation and evaporation steps. It is rapid, specific and highly sensitive for the analysis of total GL-3 isoforms, applicable to a forthcoming feasibility study. doi:10.1016/j.ymgme.2007.08.079
such as hematopoietic stem cell transplant and enzyme replacement therapy will affect long term outcomes. Second, age at which the treatment is applied will likely make a significant difference in outcome. Third, premorbid health status including orthopedic, sensory, central nervous system, and psychological status. Fourth, biomedical factors such as genotype, enzyme levels, and GAG levels. Finally, environmental factors such as psychological environment of the child, parental expectations, and life events may impact QOL, adaptive status, and psychosocial adjustment. We plan to measure QOL using various measures. The health outcome indices pilot study is to develop an objective rating of physician or health professional’s reported health status that can be used to assess the progress in several domains of functioning. The long term goal will be to correlate this with the parent and child’s rated quality-of-life. The measurement of children’s health outcomes and quality-of-life has assumed increased importance to determine whether the benefits accrued to the child after treatment sufficiently outweigh the risks, to analyze the factors contributing to benefits and risk to include the parent and child perception of whether a positive quality-of-life has been attained, and to study to factors contributing to health related quality-of-life and ways to improve it. doi:10.1016/j.ymgme.2007.08.081
75 The hunter outcome survey (HOS): A registry of mucopolysaccharidosis II patients Michael Beck, for the HOS Medical Advisory BoardChildrens Hospital University of Mainz, Mainz, Rhineland-Palatinat, Germany Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, progressive, X-linked disorder of glycosaminoglycan (GAG) metabolism that results in progressive GAG accumulation within multiple tissues and organs, due to a deficiency of iduronate-2-sulfatase (I2S). Idursulfase, a recombinant human I2S, is being developed as a treatment for MPS II. The Hunter Outcome Survey (HOS) is a global patient registry of MPS II patients sponsored by Shire Human Genetic Therapies, Inc. All MPS II patients are eligible regardless of treatment. The objectives of HOS are to enhance our understanding of the natural history of MPS II, to monitor the safety and efficacy of enzyme replacement therapy, and to provide the basis for the development of clinical management guidelines. The HOS database will capture clinical information obtained during the routine follow-up of MPS II patients, and these data will be transmitted electronically to the central database. HOS will benefit participating physicians by providing them with the opportunity to contribute to the study of the management of MPS II and by giving them the ability to review data on a larger population of MPS II patients. As of June 2006, over 60 patients from 15 sites in 7 countries have been enrolled into HOS. As enrollment increases, HOS will improve our understanding of MPS II, the long-term impact of enzyme replacement therapy and allow the development of evidence based clinical management guidelines. doi:10.1016/j.ymgme.2007.08.080
76 Quality-of-life and psychosocial outcomes in patients with MPS disorders who have undergone hematopoietic stem cell transplant Kendra Bjoraker, Elsa G. Shapiro, Lawrence Charnas, Paul Orchard, Kathleen Delaney, Cheryl K. Johnson, University of Minnesota, Minneapolis, MN, USA Advances in medical treatment have prolonged the lives of children with mucopolysaccharidosis (MPS I) and have necessitated increased attention to the assessment of their functioning and adaptation. Qualityof-life, adaptive skills, and psychosocial outcomes have not been systematically studied in children with MPS I. Our goal is to assess the factors that influence health outcomes and the quality-of-life, adaptive skills, and psychosocial adjustment in the developing child with MPS I, treated and untreated. Psychosocial adjustment, adaptive skills, and QOL are influenced by a number of factors. First, treatments and their side effects,
78 Mucolipidoses II and III: Clinical and molecular characterization Sara Cathey a, Michael Friez b, Karisa Draper b, Jules Leroy b, a Greenwood Genetic Center, Greenwood, SC, USA, b Ghent University Hospital, Department of Medical Genetics, Belgium Background: Mucolipidosis II and mucolipidosis III are allelic disorders of lysosomal enzyme targeting due to deficiency of GlcNAc-phosphotransferase. This alpha-2/beta-2/gamma-2 hexamer is encoded by two genes. The alpha and beta subunits are encoded by GNPTA, and the gamma subunit is encoded by GNPTG. Prior to molecular testing, ML II was distinguished from ML III by the severity of the clinical course. The goals of this project are to genotype individuals with clinical ML II or ML III and make genotype–phenotype correlations. Methods: Molecular analyses, which include sequencing the 21 exons of GNPTA in ML II and ML III probands and targeted sequencing in parents, have been completed in 29 of 40 participating families. Clinical data are obtained from medical records, questionnaire completed by parents of affected children, and physical exam when feasible. Results: Pathogenic changes have been found in GNPTA in every family. No mutations have been found in GNPTG. Patients with the most severe phenotype and clinical ML II have homozygous frameshifts, two different frameshifts, or one frameshift and one nonsense mutation. These patients have evidence of growth retardation at birth, dysmorphic features, and significant development delays. Individuals with clinical ML III have one missense or splice mutation with one frameshift. These individuals may not be diagnosed until mid-childhood, and limited joint mobility is often the presenting problem. Individuals ML II/III have mixed genotypes and phenotypes. doi:10.1016/j.ymgme.2007.08.083
79 Type II perinatal lethal Gaucher disease: Identification of a novel mutation, P332L, in a case study from Vancouver Island, British Columbia, Canada Francis Choy a, Agnes Zay b, Patrick MacLeod c, Cherrie R. Tan-Dy d, a University of Victoria, Victoria, BC, Canada, b Biology Department, UVic, c Division of Medical Genetics, d Department of Pediatrics, Victoria General Hospital, Victoria, BC, Canada Gaucher disease (GD) is the most prevalent lysosomal storage disorder and results from an inherited deficiency of the enzyme glucocerebrosidase. Three clinical forms of Gaucher disease have been described: Type 1, non-
Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34
clinical manifestations. We opted for the development of a biomarker filter paper method because in our Screening Program, newborn urine samples are collected by the parents on filter papers at 21 days of age. With technological advancements such as liquid chromatography-tandem mass spectrometry (LC–MS/MS), it is now feasible to analyze large molecules for treatable LSDs, such as globotriaosylceramide (GL-3) for Fabry disease. Total GL-3 analyses were carried out by positive electrospray ionization using a Waters Micromass Quattro micro tandem quadrupole system equipped with an Alliance 2795XE LC, while working with a two-step ammonium acetate-formic acid gradient. Validation (linearity, limit of detection and quantification, recovery) of the LC–MS/MS method was performed and the stability of GL-3 on filter paper established under different temperature conditions during 7 weeks (IS: C17:0-GL-3 isoform). This filter paper method eliminates lipid extraction, glycolipid isolation, centrifugation and evaporation steps. It is rapid, specific and highly sensitive for the analysis of total GL-3 isoforms, applicable to a forthcoming feasibility study. doi:10.1016/j.ymgme.2007.08.079
such as hematopoietic stem cell transplant and enzyme replacement therapy will affect long term outcomes. Second, age at which the treatment is applied will likely make a significant difference in outcome. Third, premorbid health status including orthopedic, sensory, central nervous system, and psychological status. Fourth, biomedical factors such as genotype, enzyme levels, and GAG levels. Finally, environmental factors such as psychological environment of the child, parental expectations, and life events may impact QOL, adaptive status, and psychosocial adjustment. We plan to measure QOL using various measures. The health outcome indices pilot study is to develop an objective rating of physician or health professional’s reported health status that can be used to assess the progress in several domains of functioning. The long term goal will be to correlate this with the parent and child’s rated quality-of-life. The measurement of children’s health outcomes and quality-of-life has assumed increased importance to determine whether the benefits accrued to the child after treatment sufficiently outweigh the risks, to analyze the factors contributing to benefits and risk to include the parent and child perception of whether a positive quality-of-life has been attained, and to study to factors contributing to health related quality-of-life and ways to improve it. doi:10.1016/j.ymgme.2007.08.081
75 The hunter outcome survey (HOS): A registry of mucopolysaccharidosis II patients Michael Beck, for the HOS Medical Advisory BoardChildrens Hospital University of Mainz, Mainz, Rhineland-Palatinat, Germany Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, progressive, X-linked disorder of glycosaminoglycan (GAG) metabolism that results in progressive GAG accumulation within multiple tissues and organs, due to a deficiency of iduronate-2-sulfatase (I2S). Idursulfase, a recombinant human I2S, is being developed as a treatment for MPS II. The Hunter Outcome Survey (HOS) is a global patient registry of MPS II patients sponsored by Shire Human Genetic Therapies, Inc. All MPS II patients are eligible regardless of treatment. The objectives of HOS are to enhance our understanding of the natural history of MPS II, to monitor the safety and efficacy of enzyme replacement therapy, and to provide the basis for the development of clinical management guidelines. The HOS database will capture clinical information obtained during the routine follow-up of MPS II patients, and these data will be transmitted electronically to the central database. HOS will benefit participating physicians by providing them with the opportunity to contribute to the study of the management of MPS II and by giving them the ability to review data on a larger population of MPS II patients. As of June 2006, over 60 patients from 15 sites in 7 countries have been enrolled into HOS. As enrollment increases, HOS will improve our understanding of MPS II, the long-term impact of enzyme replacement therapy and allow the development of evidence based clinical management guidelines. doi:10.1016/j.ymgme.2007.08.080
76 Quality-of-life and psychosocial outcomes in patients with MPS disorders who have undergone hematopoietic stem cell transplant Kendra Bjoraker, Elsa G. Shapiro, Lawrence Charnas, Paul Orchard, Kathleen Delaney, Cheryl K. Johnson, University of Minnesota, Minneapolis, MN, USA Advances in medical treatment have prolonged the lives of children with mucopolysaccharidosis (MPS I) and have necessitated increased attention to the assessment of their functioning and adaptation. Qualityof-life, adaptive skills, and psychosocial outcomes have not been systematically studied in children with MPS I. Our goal is to assess the factors that influence health outcomes and the quality-of-life, adaptive skills, and psychosocial adjustment in the developing child with MPS I, treated and untreated. Psychosocial adjustment, adaptive skills, and QOL are influenced by a number of factors. First, treatments and their side effects,
78 Mucolipidoses II and III: Clinical and molecular characterization Sara Cathey a, Michael Friez b, Karisa Draper b, Jules Leroy b, a Greenwood Genetic Center, Greenwood, SC, USA, b Ghent University Hospital, Department of Medical Genetics, Belgium Background: Mucolipidosis II and mucolipidosis III are allelic disorders of lysosomal enzyme targeting due to deficiency of GlcNAc-phosphotransferase. This alpha-2/beta-2/gamma-2 hexamer is encoded by two genes. The alpha and beta subunits are encoded by GNPTA, and the gamma subunit is encoded by GNPTG. Prior to molecular testing, ML II was distinguished from ML III by the severity of the clinical course. The goals of this project are to genotype individuals with clinical ML II or ML III and make genotype–phenotype correlations. Methods: Molecular analyses, which include sequencing the 21 exons of GNPTA in ML II and ML III probands and targeted sequencing in parents, have been completed in 29 of 40 participating families. Clinical data are obtained from medical records, questionnaire completed by parents of affected children, and physical exam when feasible. Results: Pathogenic changes have been found in GNPTA in every family. No mutations have been found in GNPTG. Patients with the most severe phenotype and clinical ML II have homozygous frameshifts, two different frameshifts, or one frameshift and one nonsense mutation. These patients have evidence of growth retardation at birth, dysmorphic features, and significant development delays. Individuals with clinical ML III have one missense or splice mutation with one frameshift. These individuals may not be diagnosed until mid-childhood, and limited joint mobility is often the presenting problem. Individuals ML II/III have mixed genotypes and phenotypes. doi:10.1016/j.ymgme.2007.08.083
79 Type II perinatal lethal Gaucher disease: Identification of a novel mutation, P332L, in a case study from Vancouver Island, British Columbia, Canada Francis Choy a, Agnes Zay b, Patrick MacLeod c, Cherrie R. Tan-Dy d, a University of Victoria, Victoria, BC, Canada, b Biology Department, UVic, c Division of Medical Genetics, d Department of Pediatrics, Victoria General Hospital, Victoria, BC, Canada Gaucher disease (GD) is the most prevalent lysosomal storage disorder and results from an inherited deficiency of the enzyme glucocerebrosidase. Three clinical forms of Gaucher disease have been described: Type 1, non-