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Prevalence of Fabry Disease in a High Risk U.S. Cohort with Hypertophic Cardiomyopathy and Other Cardiac Diagnoses
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Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69
MPS VI is a very rare condition, which was a relatively high incidence (13 cases identified so far) in the county of Monte Santo (50,000 inhabitants), in Bahia state, Northeast region of Brazil, where a common mutation (H178L) was found in all cases. As MPS VI could be treated with ERT and as there are indications that a better outcome may be expected in early treated cases, a newborn screening program for MPS VI was set up on this specific area. To the program already in place for PKU, hypothyroidism and hemoglobin disorders,a screening for MPS VI was added by ARSB activity assay and by the detection of the common mutation, both performed on DBS. The standardization of the techniques of enzyme assay, DNA extraction and mutation detection were already completed and the test on newborn samples has started on January 1st, 2011, and the results related to the first year of screening will be presented. The possibility of detecting carriers will help to estimate the frequency of this disease in the area, and will also be a tool to target genetic counseling to the more susceptible families.
The objective of this study is to establish the progression and phenotypic spectrum of lysosomal acid lipase deficient disorders, Wolman disease and Cholesteryl Ester Storage Disease (CESD). The protocol database includes a variety of clinical, biochemical, and pathologic data on affected individuals. In addition, genetic analyses of the causative mutations and/or detailed descriptions of the post-mortem findings will be analyzed. To date, the protocol is IRB approved at CCHMC and through the Rare Disease Networks, and is being registered as a national Clinical Trial. Four CESD patients’ data have been abstracted and another patient is undergoing evaluations currently. Several families with previous children affected by Wolman disease are being enrolled. The presentation will focus on the database structure, data collected, and overall design of the study. doi:10.1016/j.ymgme.2011.11.066
Liver-Directed Gene Therapy for Mucopolysaccharidosis Type I (MPS I)
doi:10.1016/j.ymgme.2011.11.064
Prevalence of Fabry Disease in a High Risk U.S. Cohort with Hypertophic Cardiomyopathy and Other Cardiac Diagnoses Kendrick Goss a, Matthew Taylor b, Martin Maron c, Barry Maron d, Danielle Metterville a, David Sweetser a, Katherine Sims a, e, aMassachub setts General Hospital, Boston, MA, USA, University of Colorado Denver, c Aurora, CO, Tufts Medical Center, Boston, MA, dHypertrophic Cardiomyopathy Center, Minneapolis Heart Inst, Minneapolis, MN, eInst Metabolic Disease, Baylor Res Inst, Dallas, TX Fabry disease is an X-linked lysosomal storage disorder which results in multi-system organ dysfunction including cardiac abnormalities. Because Fabry disease may manifest later in life and with variable severity, it may be underrecognized. In order to more accurately estimate the prevalence of Fabry, we have initiated a multicenter study to screen non-selected patients with hypertrophic cardiomyopathy (HCM). Fifty of the patients evaluated had cardiac dysfunction other than HCM, primarily supraventricular tachycardia and atrial fibrillation. We have screened all patients, male and female, for mutations in the alpha-galactosidase (GLA) gene, or measured alpha-galactosidase enzyme activity (α-Gal A) activity in dried blood spots (DBS), followed as appropriate by GLA sequencing. We have demonstrated the robustness of the DBS α-Gal A assay for disease screening. In addition to standard clinical methods, we found it productive to modify DBS sample collection to suit each center and particular patient care routines, including direct-mailing of DBS materials to primary care physicians and patients. We report a 1.2% incidence rate (5 females/ 1 male) of previously undiagnosed cases of Fabry in 487 patients (320 males/167 females). Extended populationbased screening holds promise for further calculation of the underlying prevalence of Fabry in selected populations. It also serves to identify patients for whom disease management is critical and for genetic risk assessment in their families. doi:10.1016/j.ymgme.2011.11.065
A Historical Chart Review and Longitudinal Follow-Up of Identified Patients with Wolman Disease or Cholesteryl Ester Storage Disease, Lysosomal Acid Lipase Deficiency Gregory A. Grabowski, Laurie Bailey, T. Andrew Burrow, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Brittney Gurda a, Peter Bell a, Yanqing Zhu a, Ping Wang b, Patty O'Donnell b, Julio Sanmiguel a, Luk Vandenberghe c, Mark Haskins b, James Wilson a, aUniversity of Pennsylvania, Gene Therapy Program, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA, bUniversity of Pennsylvania School of Veterinary Medicine, Department of Pathology and Medical Genetics, 3900 Delancey Street Philadelphia, PA 19104–6051, cFM Kirby Center for Molecular Ophthalmology Scheie Eye Institute, University of Pennsylvania 422 Curie Blvd, 310 Stellar-Chance Philadelphia PA 19104 – USA Mutations of the gene encoding for the lysosomal enzyme alphaL-iduronidase (IDUA; EC 3.2.1.76) lead to storage of the glycosaminoglycans (GAG) heparan and dermatan sulfates causing MPS I. A novel AAV serotype (AAV8) was isolated, which shows great promise in animal models and is currently being developed for clinical trials in hemophilia B patients. Two studies were initiated in MPS I dogs with IV injections of AAV8 containing the canine IDUA gene under a liverspecific promoter. One dog was injected at 3 months of age with 1x1012 GC/kg while seven dogs received 3x1012 GC/kg. Serum activity measurements indicated that IDUA peaked within the first 30 days post-injection (pi) with values ranging from 1.1- to 5.5-fold normal. Most dogs stabilized after about 3 months pi with persistent serum enzyme levels ranging from 0.15 to 2-fold normal over the next 6–12 months. Two dogs were euthanized due to signs of cervical spinal cord compression. The remaining dogs are still being followed with persistent serum activity at 12–20 months old. Histological analysis of liver at early time points indicated an absence of lesions compared to age-matched control animals. Analysis at later time points (days 289–381 pi) showed maintenance of correction with tissue IDUA activity levels at 10-12% of normal liver and 0.02-0.12 genome copies per cell. These studies highlight the persistence of transgene expression from an AAV8 vector and the therapeutic potential of low-level expression from the liver. doi:10.1016/j.ymgme.2011.11.067
A New Method for the Measurement of Lysosomal Acid Lipase in Dried Blood Spots using the Inhibitor Lalistat 2 John Hamilton, Iain W.D. Jones, Peter J. Galloway, Yorkhill Hospital, Glasgow, UK Background: A method for the measurement of Lysosomal Acid Lipase (LAL) in dried blood spots (DBS) would improve the ability to screen for Wolman Disease and CESD.
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69
MPS VI is a very rare condition, which was a relatively high incidence (13 cases identified so far) in the county of Monte Santo (50,000 inhabitants), in Bahia state, Northeast region of Brazil, where a common mutation (H178L) was found in all cases. As MPS VI could be treated with ERT and as there are indications that a better outcome may be expected in early treated cases, a newborn screening program for MPS VI was set up on this specific area. To the program already in place for PKU, hypothyroidism and hemoglobin disorders,a screening for MPS VI was added by ARSB activity assay and by the detection of the common mutation, both performed on DBS. The standardization of the techniques of enzyme assay, DNA extraction and mutation detection were already completed and the test on newborn samples has started on January 1st, 2011, and the results related to the first year of screening will be presented. The possibility of detecting carriers will help to estimate the frequency of this disease in the area, and will also be a tool to target genetic counseling to the more susceptible families.
The objective of this study is to establish the progression and phenotypic spectrum of lysosomal acid lipase deficient disorders, Wolman disease and Cholesteryl Ester Storage Disease (CESD). The protocol database includes a variety of clinical, biochemical, and pathologic data on affected individuals. In addition, genetic analyses of the causative mutations and/or detailed descriptions of the post-mortem findings will be analyzed. To date, the protocol is IRB approved at CCHMC and through the Rare Disease Networks, and is being registered as a national Clinical Trial. Four CESD patients’ data have been abstracted and another patient is undergoing evaluations currently. Several families with previous children affected by Wolman disease are being enrolled. The presentation will focus on the database structure, data collected, and overall design of the study. doi:10.1016/j.ymgme.2011.11.066
Liver-Directed Gene Therapy for Mucopolysaccharidosis Type I (MPS I)
doi:10.1016/j.ymgme.2011.11.064
Prevalence of Fabry Disease in a High Risk U.S. Cohort with Hypertophic Cardiomyopathy and Other Cardiac Diagnoses Kendrick Goss a, Matthew Taylor b, Martin Maron c, Barry Maron d, Danielle Metterville a, David Sweetser a, Katherine Sims a, e, aMassachub setts General Hospital, Boston, MA, USA, University of Colorado Denver, c Aurora, CO, Tufts Medical Center, Boston, MA, dHypertrophic Cardiomyopathy Center, Minneapolis Heart Inst, Minneapolis, MN, eInst Metabolic Disease, Baylor Res Inst, Dallas, TX Fabry disease is an X-linked lysosomal storage disorder which results in multi-system organ dysfunction including cardiac abnormalities. Because Fabry disease may manifest later in life and with variable severity, it may be underrecognized. In order to more accurately estimate the prevalence of Fabry, we have initiated a multicenter study to screen non-selected patients with hypertrophic cardiomyopathy (HCM). Fifty of the patients evaluated had cardiac dysfunction other than HCM, primarily supraventricular tachycardia and atrial fibrillation. We have screened all patients, male and female, for mutations in the alpha-galactosidase (GLA) gene, or measured alpha-galactosidase enzyme activity (α-Gal A) activity in dried blood spots (DBS), followed as appropriate by GLA sequencing. We have demonstrated the robustness of the DBS α-Gal A assay for disease screening. In addition to standard clinical methods, we found it productive to modify DBS sample collection to suit each center and particular patient care routines, including direct-mailing of DBS materials to primary care physicians and patients. We report a 1.2% incidence rate (5 females/ 1 male) of previously undiagnosed cases of Fabry in 487 patients (320 males/167 females). Extended populationbased screening holds promise for further calculation of the underlying prevalence of Fabry in selected populations. It also serves to identify patients for whom disease management is critical and for genetic risk assessment in their families. doi:10.1016/j.ymgme.2011.11.065
A Historical Chart Review and Longitudinal Follow-Up of Identified Patients with Wolman Disease or Cholesteryl Ester Storage Disease, Lysosomal Acid Lipase Deficiency Gregory A. Grabowski, Laurie Bailey, T. Andrew Burrow, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Brittney Gurda a, Peter Bell a, Yanqing Zhu a, Ping Wang b, Patty O'Donnell b, Julio Sanmiguel a, Luk Vandenberghe c, Mark Haskins b, James Wilson a, aUniversity of Pennsylvania, Gene Therapy Program, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA, bUniversity of Pennsylvania School of Veterinary Medicine, Department of Pathology and Medical Genetics, 3900 Delancey Street Philadelphia, PA 19104–6051, cFM Kirby Center for Molecular Ophthalmology Scheie Eye Institute, University of Pennsylvania 422 Curie Blvd, 310 Stellar-Chance Philadelphia PA 19104 – USA Mutations of the gene encoding for the lysosomal enzyme alphaL-iduronidase (IDUA; EC 3.2.1.76) lead to storage of the glycosaminoglycans (GAG) heparan and dermatan sulfates causing MPS I. A novel AAV serotype (AAV8) was isolated, which shows great promise in animal models and is currently being developed for clinical trials in hemophilia B patients. Two studies were initiated in MPS I dogs with IV injections of AAV8 containing the canine IDUA gene under a liverspecific promoter. One dog was injected at 3 months of age with 1x1012 GC/kg while seven dogs received 3x1012 GC/kg. Serum activity measurements indicated that IDUA peaked within the first 30 days post-injection (pi) with values ranging from 1.1- to 5.5-fold normal. Most dogs stabilized after about 3 months pi with persistent serum enzyme levels ranging from 0.15 to 2-fold normal over the next 6–12 months. Two dogs were euthanized due to signs of cervical spinal cord compression. The remaining dogs are still being followed with persistent serum activity at 12–20 months old. Histological analysis of liver at early time points indicated an absence of lesions compared to age-matched control animals. Analysis at later time points (days 289–381 pi) showed maintenance of correction with tissue IDUA activity levels at 10-12% of normal liver and 0.02-0.12 genome copies per cell. These studies highlight the persistence of transgene expression from an AAV8 vector and the therapeutic potential of low-level expression from the liver. doi:10.1016/j.ymgme.2011.11.067
A New Method for the Measurement of Lysosomal Acid Lipase in Dried Blood Spots using the Inhibitor Lalistat 2 John Hamilton, Iain W.D. Jones, Peter J. Galloway, Yorkhill Hospital, Glasgow, UK Background: A method for the measurement of Lysosomal Acid Lipase (LAL) in dried blood spots (DBS) would improve the ability to screen for Wolman Disease and CESD.