- Email: [email protected]
94. The UBDRS predicts rate of JCNL (CLN3) disease progression
Abstracts/Molecular Genetics and Metabolism 99 (2010) S8–S41 92. First steps towards determination of the most efficient and effective newborn screening (NBS) approach for LSD Dietrich Matern, Jean Lacey, Karen Sanders, Mark Magera, Giselle Bentz Pino, Elyse Grycki, Elisabeth Wooley, Kimiyo Raymond, Biochemical Genetics Lab, Department of Laboratory Medicine, Mayo Clinic College of Medicine Several methods for the detection of a few LSD in dried blood spots (DBS) have been described in recent years. To date, a tandem mass spectrometry (MS/MS) approach has found acceptance in several NBS programs and is supported by the CDCs Newborn Screening Quality Assurance Program (NSQAP) which provides calibrators and QC samples. Our laboratory has implemented the MS/MS based assay for Pompe, Fabry, Gaucher, Krabbe, and Niemann-Pick A/B diseases and enzyme-specific fluorometric assays for Pompe, Fabry and Gaucher diseases. We aim to determine a NBS approach for LSD that is characterized by highest sensitivity and specificity. A first step towards this goal is the implementation and comparison of the various screening methods proposed. Here we report such comparison of the aforementioned methods in DBS samples of confirmed cases of Pompe (n = 13), Fabry (n = 12 males, 7 females), and Gaucher (n = 13) diseases. Determination of alpha-glucosidase, alpha-galactosidase, and beta-glucosidase activities by both methods in normal controls (n = 125, 123, and 74, respectively) revealed regression coefficients of 0.92, 0.69, and 0.80, respectively. Enzyme activities determined by both methods and compared against normal control ranges revealed abnormal results in all patients with confirmed diagnoses. Alpha-galactosidase activities for carrier females were higher than in affected males but below their respective control range. This comparison indicates that both enzyme assays allow identification of affected patients and that the fluorometric methods can be used as second tier assays to confirm abnormal results of the multiplex MS/MS analysis, thereby improving NBS specificity. doi:10.1016/j.ymgme.2009.10.109
93. A Phase2 clinical trial to assess the safety and tolerability of the pharmacological chaperone AT 2101 in treatment-nave adult patients with type I Gaucher disease Atul Mehta, Derralynn Hughes, Eugene Schneider, Quinn Dinh, Royal Free & University College Medical School, Amicus Therapeutics Background: AT 2101 (afegostat tartrate) is an orally administered small molecule pharmacological chaperone designed to selectively bind and stabilize glucocerebrosidase (GCase), thereby increasing GCase trafficking to the lysosome and cellular activity. The first clinical trial of AT 2101 in Type 1 Gaucher disease (GD) was conducted in 30 participants at 11 U.S. sites. AT 2101 was generally well-tolerated at all doses evaluated with no reported serious adverse events. Leukocyte GCase activity was increased in 20 of the 26 evaluable subjects, with higher doses of AT 2101 producing more consistent elevations of GCase. Treatment with AT 2101 for 4 weeks was not associated with changes in hematologic parameters or biological markers of disease progression in stable subjects with Type 1 GD who suspended enzyme replacement therapy (ERT) for 7 weeks. We now report preliminary results of the second clinical trial of AT 2101 in patients with Type 1 GD. Study design: This was a randomized, open-label study to assess the safety and tolerability of AT 2101 in treatment-naive adult patients with Type 1 GD. Objectives: (1) to evaluate the safety and tolerability of 2 dose regimens of orally administered AT 2101; (2) to assess pharmacodynamic (PD) effects of these 2 dose regimens. Methods: The study consisted of a screening period of up to 21 days, followed by randomization, a 24-week treatment period, and a 14-day post-treatment follow-up period. Study participants were randomized to one of two AT 2101 treatment cohorts: (1) one cycle of 225 mg once daily for 7 days on and 7 days off then continue on 3 days on and 4 days off regimen for 22 weeks; (2) 225 mg once daily for 7 days on and 7 days off for 24 weeks. Patient Demographics and Baseline Characteristics: 19 patients were enrolled across 10 study centers worldwide. Subjects average age was 43 years (range: 17 years 10 mo to 69 years), 15 were males and 4 females, 18 out of 19 were Caucasian. The subjects relevant clinical characteristics at baseline were as follows: average hemoglobin concentration was 13 g/dL (range: 11–15.9 g/dL), average platelet count was 73 109/L (range: 41123 109/L), average spleen volume was 12 multiples of normal (MN) (range: 3–64 MN), average liver volume was 1.5 MN (range: 1–3.6 MN). Preliminary results and conclusions: Pending at time of abstract submission. doi:10.1016/j.ymgme.2009.10.110
94. The UBDRS predicts rate of JCNL (CLN3) disease progression Jonathan Mink, Jennifer M. Kwon, Frederick J. Marshall, Heather R. Adams, Paul G. Rothberg, Elisabeth A. deBlieck, Amy Vierhile, Nicole J. Newhouse, Erika J. Levy, Erika F. Augustine, Denia Ramirez-Montealegre, University of Rochester, Rochester, NY, USA
S27
We developed the Unified Batten Disease Rating Scale (UBDRS) to measure physical, behavioral and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL), a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002 during which the scale and has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in assessing clinical outcomes in research trials. We administered the UBDRS to nearly 100 patients with Batten disease over 8 years. The majority of these subjects have CLN3 mutations and have had serial annual research evaluations. From these data, the rate of physical and motor decline has been calculated in subjects with known CLN3 mutations. The rate of decline over time was quantified using multivariate linear regression and repeated measures analysis. Of 99 subjects, 82 had JNCL with known CLN3 mutations. Fourty-two subjects were seen more than once at least annually. The UBDRS physical subscale shows decline over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This decline correlates with functional capability and is not influenced by gender or CLN3 genotype. The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to predict the rate of decline in juvenileonset NCL (JNCL) in clinical trials. doi:10.1016/j.ymgme.2009.10.111
95. Developmental and functional surveillance in preschool children with lysosomal storage diseases Michael Msalla, Duffner Patriciab, Nancy Lyona, Elsa Shapiroc, aWomen and Childrens Hospital, University of Chicago, Buffalo, NY, USA, bHunter James Kelly Research Institute, Center on Excellence in Bioinformatics, University of Chicago, Buffalo, NY, USA, cUniversity of Minnesota, Minneapolis, MN, USA Background: New treatments for children with lysosomal storage diseases (LSD) are being developed and applied to treatment. However, there are several barriers in assessing their effectiveness. Objective: (1) To develop a phone-based surveillance system for capturing health, developmental, and functional outcomes. (2) To use validated tools for assessing health and developmental status, behavior, and adaptive competencies in early childhood. (3) Link these scores to standard neuropsychological testing of cognitive and adaptive skills at ages 2 and 5 years. Methods: Four initial preschool cohorts will be enrolled. (1) Children with confirmed Krabbe disease (2) Children with Metachromatic Leukodystrophy (3) Children with mucopolysaccharidosis (MPS) Type I Parent/caregiver of our cohorts will be interviewed every 6 months via phone when their child is between 6 and 72 months. The following standardized assessments will be used to measure the childs progress and family supports: Ages and Stages Questionnaires (ASQ); Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEAFS); Pediatric Evaluation of Disability Inventory Caregiver Assistance (PEDICA); Strengths and Difficulties Questionnaire; Health Status SF-12; Center for Epidemiologic Studies Depression Scale (CES-D); Support Function Scale (SFS); Family Activity Scale (FAS) Outcomes will be analyzed using the following categories: (1) Children who received enzyme replacement by infusion. (2) Children who received stem cell transplantation. (3) Children who received specific metabolic therapies. (4) Children who received combination of attenuation 1 through 3 listed above. (5) Children with early onset Lysosomal disorders who did not receive any of the above interventions. doi:10.1016/j.ymgme.2009.10.112
96. Natural history and structural–functional relationships (SFR) in Fabry nephropathy (FN) Behzad Najafianb, Marie-Claire Gublera, Chester Whitleyb, Einar Svarstadc, Leif Bostadc, Michael Mauerb, aUniversit Ren Descartes, Hpital Necker-Enfants Malades APHP, Paris, France, bDepartment of Pediatrics, University of Minnesota, Minneapolis, MN, USA, cMedical Department, and Departments of Pediatrics, and Pathology, Haukland University Hospital, Bergen, Norway Background: Most male and about 20% of female Fabry patients eventually develop end stage renal disease (ESRD). However, pathophysiology of FN is not well-understood. SFR studies can lead to the discovery of FN progression predictors. Aim: To study FN natural history and renal function and structure in 50–60 Fabry patients with a broad range of age from childhood to adulthood before starting enzyme replacement therapy. Preliminary data: We have so far studies renal biopsies from 20 (male/female = 2/ 1) Fabry patients, age 4–44 years; Glomerular structural parameters, including volume fraction of globotriaosylceramide (GL3) inclusions in podocytes [Vv(Inc/PC)],
93. A Phase2 clinical trial to assess the safety and tolerability of the pharmacological chaperone AT 2101 in treatment-nave adult patients with type I Gaucher disease Atul Mehta, Derralynn Hughes, Eugene Schneider, Quinn Dinh, Royal Free & University College Medical School, Amicus Therapeutics Background: AT 2101 (afegostat tartrate) is an orally administered small molecule pharmacological chaperone designed to selectively bind and stabilize glucocerebrosidase (GCase), thereby increasing GCase trafficking to the lysosome and cellular activity. The first clinical trial of AT 2101 in Type 1 Gaucher disease (GD) was conducted in 30 participants at 11 U.S. sites. AT 2101 was generally well-tolerated at all doses evaluated with no reported serious adverse events. Leukocyte GCase activity was increased in 20 of the 26 evaluable subjects, with higher doses of AT 2101 producing more consistent elevations of GCase. Treatment with AT 2101 for 4 weeks was not associated with changes in hematologic parameters or biological markers of disease progression in stable subjects with Type 1 GD who suspended enzyme replacement therapy (ERT) for 7 weeks. We now report preliminary results of the second clinical trial of AT 2101 in patients with Type 1 GD. Study design: This was a randomized, open-label study to assess the safety and tolerability of AT 2101 in treatment-naive adult patients with Type 1 GD. Objectives: (1) to evaluate the safety and tolerability of 2 dose regimens of orally administered AT 2101; (2) to assess pharmacodynamic (PD) effects of these 2 dose regimens. Methods: The study consisted of a screening period of up to 21 days, followed by randomization, a 24-week treatment period, and a 14-day post-treatment follow-up period. Study participants were randomized to one of two AT 2101 treatment cohorts: (1) one cycle of 225 mg once daily for 7 days on and 7 days off then continue on 3 days on and 4 days off regimen for 22 weeks; (2) 225 mg once daily for 7 days on and 7 days off for 24 weeks. Patient Demographics and Baseline Characteristics: 19 patients were enrolled across 10 study centers worldwide. Subjects average age was 43 years (range: 17 years 10 mo to 69 years), 15 were males and 4 females, 18 out of 19 were Caucasian. The subjects relevant clinical characteristics at baseline were as follows: average hemoglobin concentration was 13 g/dL (range: 11–15.9 g/dL), average platelet count was 73 109/L (range: 41123 109/L), average spleen volume was 12 multiples of normal (MN) (range: 3–64 MN), average liver volume was 1.5 MN (range: 1–3.6 MN). Preliminary results and conclusions: Pending at time of abstract submission. doi:10.1016/j.ymgme.2009.10.110
94. The UBDRS predicts rate of JCNL (CLN3) disease progression Jonathan Mink, Jennifer M. Kwon, Frederick J. Marshall, Heather R. Adams, Paul G. Rothberg, Elisabeth A. deBlieck, Amy Vierhile, Nicole J. Newhouse, Erika J. Levy, Erika F. Augustine, Denia Ramirez-Montealegre, University of Rochester, Rochester, NY, USA
S27
We developed the Unified Batten Disease Rating Scale (UBDRS) to measure physical, behavioral and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL), a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002 during which the scale and has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in assessing clinical outcomes in research trials. We administered the UBDRS to nearly 100 patients with Batten disease over 8 years. The majority of these subjects have CLN3 mutations and have had serial annual research evaluations. From these data, the rate of physical and motor decline has been calculated in subjects with known CLN3 mutations. The rate of decline over time was quantified using multivariate linear regression and repeated measures analysis. Of 99 subjects, 82 had JNCL with known CLN3 mutations. Fourty-two subjects were seen more than once at least annually. The UBDRS physical subscale shows decline over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This decline correlates with functional capability and is not influenced by gender or CLN3 genotype. The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to predict the rate of decline in juvenileonset NCL (JNCL) in clinical trials. doi:10.1016/j.ymgme.2009.10.111
95. Developmental and functional surveillance in preschool children with lysosomal storage diseases Michael Msalla, Duffner Patriciab, Nancy Lyona, Elsa Shapiroc, aWomen and Childrens Hospital, University of Chicago, Buffalo, NY, USA, bHunter James Kelly Research Institute, Center on Excellence in Bioinformatics, University of Chicago, Buffalo, NY, USA, cUniversity of Minnesota, Minneapolis, MN, USA Background: New treatments for children with lysosomal storage diseases (LSD) are being developed and applied to treatment. However, there are several barriers in assessing their effectiveness. Objective: (1) To develop a phone-based surveillance system for capturing health, developmental, and functional outcomes. (2) To use validated tools for assessing health and developmental status, behavior, and adaptive competencies in early childhood. (3) Link these scores to standard neuropsychological testing of cognitive and adaptive skills at ages 2 and 5 years. Methods: Four initial preschool cohorts will be enrolled. (1) Children with confirmed Krabbe disease (2) Children with Metachromatic Leukodystrophy (3) Children with mucopolysaccharidosis (MPS) Type I Parent/caregiver of our cohorts will be interviewed every 6 months via phone when their child is between 6 and 72 months. The following standardized assessments will be used to measure the childs progress and family supports: Ages and Stages Questionnaires (ASQ); Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEAFS); Pediatric Evaluation of Disability Inventory Caregiver Assistance (PEDICA); Strengths and Difficulties Questionnaire; Health Status SF-12; Center for Epidemiologic Studies Depression Scale (CES-D); Support Function Scale (SFS); Family Activity Scale (FAS) Outcomes will be analyzed using the following categories: (1) Children who received enzyme replacement by infusion. (2) Children who received stem cell transplantation. (3) Children who received specific metabolic therapies. (4) Children who received combination of attenuation 1 through 3 listed above. (5) Children with early onset Lysosomal disorders who did not receive any of the above interventions. doi:10.1016/j.ymgme.2009.10.112
96. Natural history and structural–functional relationships (SFR) in Fabry nephropathy (FN) Behzad Najafianb, Marie-Claire Gublera, Chester Whitleyb, Einar Svarstadc, Leif Bostadc, Michael Mauerb, aUniversit Ren Descartes, Hpital Necker-Enfants Malades APHP, Paris, France, bDepartment of Pediatrics, University of Minnesota, Minneapolis, MN, USA, cMedical Department, and Departments of Pediatrics, and Pathology, Haukland University Hospital, Bergen, Norway Background: Most male and about 20% of female Fabry patients eventually develop end stage renal disease (ESRD). However, pathophysiology of FN is not well-understood. SFR studies can lead to the discovery of FN progression predictors. Aim: To study FN natural history and renal function and structure in 50–60 Fabry patients with a broad range of age from childhood to adulthood before starting enzyme replacement therapy. Preliminary data: We have so far studies renal biopsies from 20 (male/female = 2/ 1) Fabry patients, age 4–44 years; Glomerular structural parameters, including volume fraction of globotriaosylceramide (GL3) inclusions in podocytes [Vv(Inc/PC)],