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Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
therapeutic decisions such as ERT dose alterations and pre-surgical planning to prevent excessive bleeding. Immune thrombocytopenia is additionally important in female patients of child bearing age, as antibodies cross the placenta.
doi:10.1016/j.ymgme.2016.11.318
310 Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease Jin-Song Shena, Erland Arninga, Michael L Westb, Taniqua S Daya, Seng H Chengc, Raphael Schiffmanna, Teodoro Bottiglieria, aBaylor Research Institute, Dallas, TX, United States, bDalhousie University, Halifax, NS, Canada, cSanofi Genzyme, Framingham, MA, United States Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to cardiovascular disease in Fabry patients. We hypothesized that decreased tetrahydrobiopterin (BH4) may play a role in the pathogenesis of Fabry disease. We found that in Fabry mice BH4 is decreased in the heart and kidney, but not in the liver and aorta. BH4 was also decreased in plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels inversely correlated with tissue levels of BH4 in Fabry mice and patients cultured cells. To investigate the role of BH4 deficiency in disease phenotypes, 12 months old Fabry mice were treated with AAV-mediated ERT or substrate reduction therapy (SRT) for 6 months. In Fabry mice receiving SRT, but not ERT, BH4 levels were restored concomitantly with reduction in cardiac and renal hypertrophy. Glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels closely correlated with glutathione levels, and inversely correlated with cardiac and kidney weights. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease.
doi:10.1016/j.ymgme.2016.11.319
311 ThinkGenetic: identification of misinformation and educational gaps using an innovative and interactive website Morgan F Simmons, Dawn A Laney, Emory University School of Medicine, Atlanta, GA, United States The availability and the ease of accessing health-related information on the Internet has transformed the way in which patients, caregivers, and family members obtain information about possible new diagnoses and learn more about genetic conditions such as lysosomal diseases. Unfortunately, the ease of accessing health related information through Google and similar search engines does not translate into an ease in finding accurate, up-to-date, and patient-directed information on the Internet. ThinkGenetic is a website and mobile app that taps into IBM Watson's cognitive technology to help people understand what questions to ask doctors in order to improve their medical care, and how to find resources to help them such as support groups and genetic
S123
professionals. Genetic counselors and other innovators in the field of genetics have been training Watson by writing a series of referenced questions and answers about specific genetic conditions in patientfriendly language. Individuals who visit the ThinkGenetic site are invited to participate in the study by allowing us to anonymously track which areas of the website they visited and the questions that they ask. These questions were categorized to identify misinformation and gaps in education for individuals living with an lysosomal disease, their caregivers, and healthcare providers. doi:10.1016/j.ymgme.2016.11.320
312 Evaluation of pentosan polysulfate in mucopolysaccharidosis type IIIA mice Calogera M. Simonaroa, Ningning Guoa, Victor DeAngelisa, Shunji Tomatsub, Edward H. Schuchmana, aIcahn School of Medicine at Mount Sinai, NY, NY, United States, bNemours - Alfred Dupont Hospital, Wilmington, DE, United States Purpose: Studies in murine models of Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) have revealed that neuroinflammation and neurodegeneration are significant phenotypes of the diseased brain. Our previous studies have shown that subcutaneous injections of the FDA/EMA approved drug, pentosan polysulfate (PPS), has potent anti-inflammatory and glycosaminoglycan (GAG) reducing properties in MPS animal models and patients, but it is not certain whether PPS crosses the blood brain barrier (BBB). We therefore evaluated the impact of PPS on neuroinflammation, neurodegeneration and neurobehavioral defects in MPS IIIA mice. Methodology: PPS was delivered through once weekly subcutaneous injections or intracerebroventricular infusion. Immunohistochemistry analyses were performed in brain sections to examine the effects of PPS on the neurodegenerative marker, tau protein, lysosomal integral membrane protein II, heparan sulfate, the ganglioside GM3, and markers of astrocyte/glial cell activation. The proinflammatory cytokines IL-1 alpha, IL-1 beta, MIP-1 alpha, MCP-1 and G-CSF also were measured in the plasma. Neurobehavior of the MPS mice was examined using a modified rotarod test to evaluate motor skill learning and memory. Results: Reduced neuroinflammation and P-tau expression was observed in the brains of the treated MPS IIIA mice following systemic administration. Inflammatory cytokines in the plasma also were reduced. Analyses of animals treated by intracerebroventricular infusion are ongoing, as is behavioral testing. Conclusion: To date this study has shown the systemically administered PPS can influence several neurodegenerative and neuroinflammatory markers in the CNS of MPS IIIA mice, suggetsing that it may cross the BBB and thus may be beneficial in ameliorating neurological fuctions of MPS. doi:10.1016/j.ymgme.2016.11.321
313 Improvement of Fabry disease pain with calcium gluconate infusions given at time of agalsidase beta therapy Cynthia A Smith, Renal Consultants, PLLC, South Charleston, WV, United States Neuropathic pain in Fabry disease (FD) can be a debilitating aspect of this disorder. Although enzyme replacement therapy has been
therapeutic decisions such as ERT dose alterations and pre-surgical planning to prevent excessive bleeding. Immune thrombocytopenia is additionally important in female patients of child bearing age, as antibodies cross the placenta.
doi:10.1016/j.ymgme.2016.11.318
310 Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease Jin-Song Shena, Erland Arninga, Michael L Westb, Taniqua S Daya, Seng H Chengc, Raphael Schiffmanna, Teodoro Bottiglieria, aBaylor Research Institute, Dallas, TX, United States, bDalhousie University, Halifax, NS, Canada, cSanofi Genzyme, Framingham, MA, United States Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to cardiovascular disease in Fabry patients. We hypothesized that decreased tetrahydrobiopterin (BH4) may play a role in the pathogenesis of Fabry disease. We found that in Fabry mice BH4 is decreased in the heart and kidney, but not in the liver and aorta. BH4 was also decreased in plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels inversely correlated with tissue levels of BH4 in Fabry mice and patients cultured cells. To investigate the role of BH4 deficiency in disease phenotypes, 12 months old Fabry mice were treated with AAV-mediated ERT or substrate reduction therapy (SRT) for 6 months. In Fabry mice receiving SRT, but not ERT, BH4 levels were restored concomitantly with reduction in cardiac and renal hypertrophy. Glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels closely correlated with glutathione levels, and inversely correlated with cardiac and kidney weights. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease.
doi:10.1016/j.ymgme.2016.11.319
311 ThinkGenetic: identification of misinformation and educational gaps using an innovative and interactive website Morgan F Simmons, Dawn A Laney, Emory University School of Medicine, Atlanta, GA, United States The availability and the ease of accessing health-related information on the Internet has transformed the way in which patients, caregivers, and family members obtain information about possible new diagnoses and learn more about genetic conditions such as lysosomal diseases. Unfortunately, the ease of accessing health related information through Google and similar search engines does not translate into an ease in finding accurate, up-to-date, and patient-directed information on the Internet. ThinkGenetic is a website and mobile app that taps into IBM Watson's cognitive technology to help people understand what questions to ask doctors in order to improve their medical care, and how to find resources to help them such as support groups and genetic
S123
professionals. Genetic counselors and other innovators in the field of genetics have been training Watson by writing a series of referenced questions and answers about specific genetic conditions in patientfriendly language. Individuals who visit the ThinkGenetic site are invited to participate in the study by allowing us to anonymously track which areas of the website they visited and the questions that they ask. These questions were categorized to identify misinformation and gaps in education for individuals living with an lysosomal disease, their caregivers, and healthcare providers. doi:10.1016/j.ymgme.2016.11.320
312 Evaluation of pentosan polysulfate in mucopolysaccharidosis type IIIA mice Calogera M. Simonaroa, Ningning Guoa, Victor DeAngelisa, Shunji Tomatsub, Edward H. Schuchmana, aIcahn School of Medicine at Mount Sinai, NY, NY, United States, bNemours - Alfred Dupont Hospital, Wilmington, DE, United States Purpose: Studies in murine models of Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) have revealed that neuroinflammation and neurodegeneration are significant phenotypes of the diseased brain. Our previous studies have shown that subcutaneous injections of the FDA/EMA approved drug, pentosan polysulfate (PPS), has potent anti-inflammatory and glycosaminoglycan (GAG) reducing properties in MPS animal models and patients, but it is not certain whether PPS crosses the blood brain barrier (BBB). We therefore evaluated the impact of PPS on neuroinflammation, neurodegeneration and neurobehavioral defects in MPS IIIA mice. Methodology: PPS was delivered through once weekly subcutaneous injections or intracerebroventricular infusion. Immunohistochemistry analyses were performed in brain sections to examine the effects of PPS on the neurodegenerative marker, tau protein, lysosomal integral membrane protein II, heparan sulfate, the ganglioside GM3, and markers of astrocyte/glial cell activation. The proinflammatory cytokines IL-1 alpha, IL-1 beta, MIP-1 alpha, MCP-1 and G-CSF also were measured in the plasma. Neurobehavior of the MPS mice was examined using a modified rotarod test to evaluate motor skill learning and memory. Results: Reduced neuroinflammation and P-tau expression was observed in the brains of the treated MPS IIIA mice following systemic administration. Inflammatory cytokines in the plasma also were reduced. Analyses of animals treated by intracerebroventricular infusion are ongoing, as is behavioral testing. Conclusion: To date this study has shown the systemically administered PPS can influence several neurodegenerative and neuroinflammatory markers in the CNS of MPS IIIA mice, suggetsing that it may cross the BBB and thus may be beneficial in ameliorating neurological fuctions of MPS. doi:10.1016/j.ymgme.2016.11.321
313 Improvement of Fabry disease pain with calcium gluconate infusions given at time of agalsidase beta therapy Cynthia A Smith, Renal Consultants, PLLC, South Charleston, WV, United States Neuropathic pain in Fabry disease (FD) can be a debilitating aspect of this disorder. Although enzyme replacement therapy has been