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Newborn screening (NBS) for metachromatic leukodystrophy (MLD): results from a study of 100,000 deidentified NBS samples
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
Lysosomal acid lipase deficiency (LALD) is a life-threatening genetic disease caused by mutations in the lysosomal acid lipase (LIPA) gene with a clinical spectrum from infancy to adulthood, similar to other lysosomal disorders. Disease awareness is low and the number of known pathogenic mutations is small. Additional analysis is needed to better understand the underlying genetic architecture of the lysosomal acid lipase (LAL) enzyme and associated diminished activity resulting from the combined genetic mutations on each LIPA allele. As part of the ARISE study (NCT01757184, a multicenter, randomized, placebocontrolled study) and the CL06 study (NCT02112994, a multicenter, open-label, single-arm study) of sebelipase alfa, 97 children (N8 months of age) and adults with LALD had genetic analysis of the LIPA gene; they also had dried blood spot testing to show reduced LAL enzyme activity consistent with LALD. Isolation of DNA and genetic mutation analysis for allelic variants of the LIPA gene were performed (Prevention Genetics, Marshfield, WI, USA). Overall, 85% of subjects in the ARISE study had at least 1 copy of the c.894GNA common exon 8 splice junction mutation (E8SJM), 32% homozygotes and 53% compound heterozygotes, resulting in an E8SJM allele frequency of 58.3% in this study. Five novel LIPA mutations paired with c.894GNA were discovered (c.256CNT, c.309CNA, c.526GNA, c.538+5GNA, and c.931GNA) and 3 novel LIPA mutations were discovered in combination with pathogenic non-E8SJM LIPA mutations (c.417CNA, c.974CNT, and c.791TNC). Two additional novel pathogenic mutations, c.822+1GNC and c.377CNT, were discovered in study CL06. These 10 novel mutations from the ARISE and CL06 studies have been identified in patients diagnosed with LALD and represent a ~15% increase over the ~65 published pathogenic LIPA mutations. (Sponsored by Alexion Pharmaceuticals, Inc.)
doi:10.1016/j.ymgme.2016.11.294
286 Newborn screening (NBS) for metachromatic leukodystrophy (MLD): results from a study of 100,000 deidentified NBS samples Ross Ridsdalea, Charles Krolla, Karen Sandersa, Devin Olgesbeea, Piero Rinaldoa, John Hopwoodb, Fred Loreyc, Michael Gelbd, Kimiyo Raymonda, Dimitar Gavrilova, Silvia Tortorellia, Dietrich Materna, aMayo b Clinic, Rochester, MN, United States, SAHMRI, Adelaide, Australia, c California Department of Public Health, Rochester, CA, United States, d University of Washington, Seattle, WA, United States MLD, caused by arylsulfatase A (ARSA) deficiency, is a progressive demyelinating disorder with variable phenotype. Hematopoietic stem cell transplantation has shown promise and gene therapy is being investigated. Any treatment is expected to have greatest benefit when started before the onset of symptoms, making NBS for MLD desirable. Dried blood spot (DBS) based assays have been developed to measure either sulfatides that accumulate in MLD (Spacil Z et al. Clin Chem 2016; 62: 279-86) or the presence of the arylsulfatase A protein (Meikle PJ et al. Mol Genet Metab 2006; 88: 307-142). We pursued the latter approach by immunoassay in a screening study of nearly 100,000 deidentified NBS samples for MLD and 12 other lysosomal diseases, Wilson disease, and Friedreich ataxia by multiplex immunocapture assay. Of 95,163 NBS samples tested 73 samples had ARSA concentrations below a preliminary cut off corresponding to the 1st percentile of the study population. ARSA gene analysis of these cases found 51 individuals carrying mutations associated with ARSA pseudodeficiency, 20 carriers of a known mutation or a variant of uncertain significance, and homozygosity for a possibly pathogenic mutation (c.511GNA, p.D171N) in two cases. Measurement of sulfatides in the leftover DBS of one of the latter cases was normal indicating that c.511GNA is likely not a pathogenic mutation.
S115
Conclusions: The absence of an apparent MLD case in the study population may reflect the rarity of the disease in this population. Assuming 100% sensitivity of the high-throughput immunoassay, the screening performance could be optimized by (a) post-analytical use of a multivariate pattern recognition software (CLIR; available at https:// clir.mayo.edu) as has been done previously for other NBS tests (Hall PL et al. Genet Med 2014; 16: 889-93), and (b) application of the LC-MS/ MS based sulfatide assay as a 2nd tier NBS test.
doi:10.1016/j.ymgme.2016.11.295
287 Multi-stakeholder engagement leading to access to treatment for MPS IVA (Morquio syndrome type A), a model for the ultra rare disease community Charlotte Robertsa, Christine Laveryb, Nigel Nichollsc, Mohit Jainc, Christian J Hendrikszd, Sheela Upadhyayae, Edmund Jessopf, aMPS Commercial, Amersham, United Kingdom, bMPS Society, Amersham, United Kingdom, cBioMarin Europe Ltd., London, United Kingdom, dSalford Royal NHS Foundation Trust, Salford, United Kingdom, eNational Institute for Health Care Excellence (NICE), London, United Kingdom, fNational Health Service (NHS) England, London, United Kingdom The only treatment currently available for MPS IVA, elosulfase alfa, was licensed by the European Medicines Agency on 28th April 2014. The UK had been a major contributor to the Phase III clinical trial, and continued access to treatment was of major concern. NICE had introduced a new reimbursement decision process for highly specialised technologies (including ultra rare diseases) and its initial recommendation was not to fund elosulfase alfa. Patients together with the MPS Society, members of Parliament and clinicians canvassed NHS England and the Department of Health for equal access to therapies as for common disorders. As the NICE review process continued, the MPS Society suggested a Managed Access Agreement (MAA) and its development became a working partnership between NHS England, NICE, the MPS Society, BioMarin and a clinical expert. The MAA was designed to be inclusive for patients, ensuring response to treatment in a minimum of 4 out of 5 criteria through consistent clinical and quality of life monitoring. Treatment would stop for those not meeting treatment targets. On 16th December 2015, NICE approved the use of elosulfase alfa in England via the MAA. Wales and Northern Ireland have subsequently adopted the MAA for their patients. To date, 45 (48%) patients in England have entered the scheme and are receiving treatment. In an environment where health systems are having to choose between high cost drugs and the funding of other health resources, the MAA, with a confidential negotiated pricing scheme, offers all eligible patients access to therapy in the first 12 months. The MAA will be subject to annual review under the chairmanship of NICE and the data collected will be used to assess whether funding will continue after the 5 year term of the MAA.
doi:10.1016/j.ymgme.2016.11.296
288 Allosteric, non-inhibitory pharmacological chaperones for the treatment of lysosomal diseases Richard Robertsa, Laura Rodríguez-Pascaua, Ana María Garcíaa, Elena Cuberoa, Pilar Pizcuetaa, Aida Delgadoa, Marc Revésa, Natalia Péreza,
Lysosomal acid lipase deficiency (LALD) is a life-threatening genetic disease caused by mutations in the lysosomal acid lipase (LIPA) gene with a clinical spectrum from infancy to adulthood, similar to other lysosomal disorders. Disease awareness is low and the number of known pathogenic mutations is small. Additional analysis is needed to better understand the underlying genetic architecture of the lysosomal acid lipase (LAL) enzyme and associated diminished activity resulting from the combined genetic mutations on each LIPA allele. As part of the ARISE study (NCT01757184, a multicenter, randomized, placebocontrolled study) and the CL06 study (NCT02112994, a multicenter, open-label, single-arm study) of sebelipase alfa, 97 children (N8 months of age) and adults with LALD had genetic analysis of the LIPA gene; they also had dried blood spot testing to show reduced LAL enzyme activity consistent with LALD. Isolation of DNA and genetic mutation analysis for allelic variants of the LIPA gene were performed (Prevention Genetics, Marshfield, WI, USA). Overall, 85% of subjects in the ARISE study had at least 1 copy of the c.894GNA common exon 8 splice junction mutation (E8SJM), 32% homozygotes and 53% compound heterozygotes, resulting in an E8SJM allele frequency of 58.3% in this study. Five novel LIPA mutations paired with c.894GNA were discovered (c.256CNT, c.309CNA, c.526GNA, c.538+5GNA, and c.931GNA) and 3 novel LIPA mutations were discovered in combination with pathogenic non-E8SJM LIPA mutations (c.417CNA, c.974CNT, and c.791TNC). Two additional novel pathogenic mutations, c.822+1GNC and c.377CNT, were discovered in study CL06. These 10 novel mutations from the ARISE and CL06 studies have been identified in patients diagnosed with LALD and represent a ~15% increase over the ~65 published pathogenic LIPA mutations. (Sponsored by Alexion Pharmaceuticals, Inc.)
doi:10.1016/j.ymgme.2016.11.294
286 Newborn screening (NBS) for metachromatic leukodystrophy (MLD): results from a study of 100,000 deidentified NBS samples Ross Ridsdalea, Charles Krolla, Karen Sandersa, Devin Olgesbeea, Piero Rinaldoa, John Hopwoodb, Fred Loreyc, Michael Gelbd, Kimiyo Raymonda, Dimitar Gavrilova, Silvia Tortorellia, Dietrich Materna, aMayo b Clinic, Rochester, MN, United States, SAHMRI, Adelaide, Australia, c California Department of Public Health, Rochester, CA, United States, d University of Washington, Seattle, WA, United States MLD, caused by arylsulfatase A (ARSA) deficiency, is a progressive demyelinating disorder with variable phenotype. Hematopoietic stem cell transplantation has shown promise and gene therapy is being investigated. Any treatment is expected to have greatest benefit when started before the onset of symptoms, making NBS for MLD desirable. Dried blood spot (DBS) based assays have been developed to measure either sulfatides that accumulate in MLD (Spacil Z et al. Clin Chem 2016; 62: 279-86) or the presence of the arylsulfatase A protein (Meikle PJ et al. Mol Genet Metab 2006; 88: 307-142). We pursued the latter approach by immunoassay in a screening study of nearly 100,000 deidentified NBS samples for MLD and 12 other lysosomal diseases, Wilson disease, and Friedreich ataxia by multiplex immunocapture assay. Of 95,163 NBS samples tested 73 samples had ARSA concentrations below a preliminary cut off corresponding to the 1st percentile of the study population. ARSA gene analysis of these cases found 51 individuals carrying mutations associated with ARSA pseudodeficiency, 20 carriers of a known mutation or a variant of uncertain significance, and homozygosity for a possibly pathogenic mutation (c.511GNA, p.D171N) in two cases. Measurement of sulfatides in the leftover DBS of one of the latter cases was normal indicating that c.511GNA is likely not a pathogenic mutation.
S115
Conclusions: The absence of an apparent MLD case in the study population may reflect the rarity of the disease in this population. Assuming 100% sensitivity of the high-throughput immunoassay, the screening performance could be optimized by (a) post-analytical use of a multivariate pattern recognition software (CLIR; available at https:// clir.mayo.edu) as has been done previously for other NBS tests (Hall PL et al. Genet Med 2014; 16: 889-93), and (b) application of the LC-MS/ MS based sulfatide assay as a 2nd tier NBS test.
doi:10.1016/j.ymgme.2016.11.295
287 Multi-stakeholder engagement leading to access to treatment for MPS IVA (Morquio syndrome type A), a model for the ultra rare disease community Charlotte Robertsa, Christine Laveryb, Nigel Nichollsc, Mohit Jainc, Christian J Hendrikszd, Sheela Upadhyayae, Edmund Jessopf, aMPS Commercial, Amersham, United Kingdom, bMPS Society, Amersham, United Kingdom, cBioMarin Europe Ltd., London, United Kingdom, dSalford Royal NHS Foundation Trust, Salford, United Kingdom, eNational Institute for Health Care Excellence (NICE), London, United Kingdom, fNational Health Service (NHS) England, London, United Kingdom The only treatment currently available for MPS IVA, elosulfase alfa, was licensed by the European Medicines Agency on 28th April 2014. The UK had been a major contributor to the Phase III clinical trial, and continued access to treatment was of major concern. NICE had introduced a new reimbursement decision process for highly specialised technologies (including ultra rare diseases) and its initial recommendation was not to fund elosulfase alfa. Patients together with the MPS Society, members of Parliament and clinicians canvassed NHS England and the Department of Health for equal access to therapies as for common disorders. As the NICE review process continued, the MPS Society suggested a Managed Access Agreement (MAA) and its development became a working partnership between NHS England, NICE, the MPS Society, BioMarin and a clinical expert. The MAA was designed to be inclusive for patients, ensuring response to treatment in a minimum of 4 out of 5 criteria through consistent clinical and quality of life monitoring. Treatment would stop for those not meeting treatment targets. On 16th December 2015, NICE approved the use of elosulfase alfa in England via the MAA. Wales and Northern Ireland have subsequently adopted the MAA for their patients. To date, 45 (48%) patients in England have entered the scheme and are receiving treatment. In an environment where health systems are having to choose between high cost drugs and the funding of other health resources, the MAA, with a confidential negotiated pricing scheme, offers all eligible patients access to therapy in the first 12 months. The MAA will be subject to annual review under the chairmanship of NICE and the data collected will be used to assess whether funding will continue after the 5 year term of the MAA.
doi:10.1016/j.ymgme.2016.11.296
288 Allosteric, non-inhibitory pharmacological chaperones for the treatment of lysosomal diseases Richard Robertsa, Laura Rodríguez-Pascaua, Ana María Garcíaa, Elena Cuberoa, Pilar Pizcuetaa, Aida Delgadoa, Marc Revésa, Natalia Péreza,