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Consensus recommendation on a diagnostic guideline for acid sphingomyelinase deficiency
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Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
treatment, consistent with reduced immunogenicity and induced tolerance during PRX-102 treatment. Impact on PK: PRX-102 has a favorable PK profile [maximum concentration (Cmax) and overall enzyme amount (AUC)] with higher amount of active enzyme available throughout the 2-week treatment intervals. The 2 ADA+ patients in Cohort 1 exhibited a distinct and reversible effect on PK profile resulting in decreased Cmax and AUC at 3 and 6 months compared to Day 1, with improvement back to the baseline profile after 12 months of treatment, suggesting that the ADA impact on PRX-102 activity was transient. The ADA + patient in Cohort 2 had a low ADA titer and had stable PK parameters throughout the study. In summary, it appears that the reduced immunogenicity of PRX-102 is associated with improved PK profiles that may reflect longer term induction of tolerance in previously seroconverted patients.
357 Consensus recommendation on a diagnostic guideline for acid sphingomyelinase deficiency Melissa Wassersteina, Carlo Dionisi-Vicib, Roberto Giuglianic, Paul Hwud, Olivier Lidovee, Zoltan Lukacsf, Eugen Mengelg, Pramod Mistryh, Edward Schuchmani, Margaret McGovernj, aChildren’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, United States, b Hospital Bambino Gesu, Rome, Italy, cMedical Genetics Service, HCPA, Porto Alegre, Brazil, dNational Taiwan University Hospital, Taipei, Taiwan, e Hopital de la Croix St Simon, Paris, France, fUniversity Medical Center Hamburg-Eppendorf, Hamburg, Germany, gMedical Center of the Johannes Gutenberg University, Mainz, Germany, hYale University School of Medicine, New Haven, CT, United States, iIcahn School of Medicine at Mt. Sinai, New York, NY, United States, jStony Brook University School of Medicine, Stony Brook, NY, United States
doi:10.1016/j.ymgme.2016.11.364
356 The New York pilot newborn screen for lysosomal diseases: 40 month data Melissa Wassersteina, Sean Baileyb, Michele Cagganac, Robert J Desnickd, Ian Holzmand, Nicole Kellya, Gabriel Kupchike, Monica Martinc, Randi Wassermanf, Amy Yangd, Joseph J Orsinic, aChildren's Hospital at Montefiore, Bronx, NY, United States, bNew York University Medical Center, New York, NY, United States, cNew York State Department of Health, Albany, NY, United States, dIcahn School of Medicine at Mount Sinai, New York, NY, United States, eMaimonides Medical Center, Brooklyn, NY, United States, fElmhurst Hospital Center, Queens, NY, United States A prospective, consented pilot study is currently underway at four New York City hospitals in order to assess the utility of newborn screening for lysosomal diseases, to define the pre-symptomatic natural history, and to evaluate the ethical, legal, and social issues associate with such screening. Between May 2013 and September 1, 2016, 49,996 of 68, 094 (73%) approached parents verbally consented to participate. Lysosomal disease testing is performed at the NYS NBS LSD Lab using tandem MS-MS to measure enzyme activity with referral cutoffs set to 15% of daily mean activity for GAA, IDUA, ABG, ASM, and 25% for GLA. 19,197 specimens were screened for Pompe between May 2013 and October 2014. Of 6 referred infants, 1 has genotype consistent with lateronset disease and 5 have pseudodeficiency alleles (PPV=0.17). 20,320 were screened for MPS I since it was added in May 2015. 5 of 5 referred infants are unaffected based on genotype (PPV=0). Of 49,996 infants screened for Fabry, Gaucher and Niemann-Pick disease type A/B: 10 of 16 referred Fabry disease infants have later-onset genotypes, 3 are negative, 1 was lost to follow-up and 2 results are pending (PPV=0.77); 9 of 11 infants who underwent confirmatory testing for Gaucher have genotypes consistent with later-onset disease, 1 is negative and 1 result is pending (PPV=0.9), and the 2 infants referred for Niemann-Pick disease type A/B have genotypes consistent with later-onset disease (PPV=1.0). In summary, we have detected only later-onset lysosomal diseases, which challenges traditional NBS criteria. NBS using enzyme activity alone results in a wide range of PPVs as defined by genotypes. Gaucher and Niemann-Pick disease type A/B have the highest PPVs, whereas MPS I and Pompe disease, the only two lysosomal diseases currently on the RUSP, have the lowest. Concurrent molecular analysis to reduce the number of false positives is recommended.
doi:10.1016/j.ymgme.2016.11.365
Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, multiorgan lysosomal disease historically known as Niemann-Pick disease types A (NPD A) and B (NPD B). ASMD results in the progressive accumulation of sphingomyelin in reticuloendothelial organs (liver, spleen, bone marrow, and lung), hepatocytes, and in severe cases, brain. ASMD manifests as a clinical spectrum ranging from a rapidly progressive infantile neurovisceral form (NPD A) which is uniformly fatal by age 3, to chronic neurovisceral (NPD B variant) and visceral (NPD B) forms that have variable ages of onset, slower progression, and longer lifespans. Disease management is aimed at mitigating symptoms and regular assessments for multisystem involvement. An international panel of laboratory and clinical ASMD experts gathered to review the evidence base and develop guidelines for the diagnosis, nomenclature, and management of ASMD. During a meeting at which published material and personal experience were reviewed, the panel members discussed the best approach for diagnosis and developed a diagnostic guideline and new recommended nomenclature to better capture the clinical spectrum of ASMD. The diagnosis of ASMD is based on ASMD enzyme activity and SMPD1 gene sequencing. Because of symptom overlap between ASMD and Gaucher disease, it is recommended that, whenever possible, parallel enzyme testing for Gaucher disease and ASMD is performed. Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers since it is important that primary care providers (e.g., pediatricians) and specialists (e.g., pulmonologists, hepatologists, and hematologists) be able to recognize ASMD in order to provide the appropriate patient care and referrals. Early diagnosis is essential for effective disease and symptom management. (Supported by Sanofi Genzyme.)
doi:10.1016/j.ymgme.2016.11.366
358 Genistein: a lysosomal stimulator for treatment of various lysosomal diseases Grzegorz Wegrzyna, Karolina Pierzynowskaa, Aleksandra Haca, Magdalena Gabig-Ciminskab, Joanna Jakobkiewicz-Baneckaa, aUniversity of Gdansk, Gdansk, Poland, bInstitute of Biochemistry and Biophysics of Polish Academy of Sciences, Gdansk, Poland The use of genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1benzopyran-4-one) has been proposed as a putative treatment for lysosomal diseases, particularly mucopolysaccharidoses (MPS). This proposal was based on findings that this isoflavone can inhibit
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
treatment, consistent with reduced immunogenicity and induced tolerance during PRX-102 treatment. Impact on PK: PRX-102 has a favorable PK profile [maximum concentration (Cmax) and overall enzyme amount (AUC)] with higher amount of active enzyme available throughout the 2-week treatment intervals. The 2 ADA+ patients in Cohort 1 exhibited a distinct and reversible effect on PK profile resulting in decreased Cmax and AUC at 3 and 6 months compared to Day 1, with improvement back to the baseline profile after 12 months of treatment, suggesting that the ADA impact on PRX-102 activity was transient. The ADA + patient in Cohort 2 had a low ADA titer and had stable PK parameters throughout the study. In summary, it appears that the reduced immunogenicity of PRX-102 is associated with improved PK profiles that may reflect longer term induction of tolerance in previously seroconverted patients.
357 Consensus recommendation on a diagnostic guideline for acid sphingomyelinase deficiency Melissa Wassersteina, Carlo Dionisi-Vicib, Roberto Giuglianic, Paul Hwud, Olivier Lidovee, Zoltan Lukacsf, Eugen Mengelg, Pramod Mistryh, Edward Schuchmani, Margaret McGovernj, aChildren’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, United States, b Hospital Bambino Gesu, Rome, Italy, cMedical Genetics Service, HCPA, Porto Alegre, Brazil, dNational Taiwan University Hospital, Taipei, Taiwan, e Hopital de la Croix St Simon, Paris, France, fUniversity Medical Center Hamburg-Eppendorf, Hamburg, Germany, gMedical Center of the Johannes Gutenberg University, Mainz, Germany, hYale University School of Medicine, New Haven, CT, United States, iIcahn School of Medicine at Mt. Sinai, New York, NY, United States, jStony Brook University School of Medicine, Stony Brook, NY, United States
doi:10.1016/j.ymgme.2016.11.364
356 The New York pilot newborn screen for lysosomal diseases: 40 month data Melissa Wassersteina, Sean Baileyb, Michele Cagganac, Robert J Desnickd, Ian Holzmand, Nicole Kellya, Gabriel Kupchike, Monica Martinc, Randi Wassermanf, Amy Yangd, Joseph J Orsinic, aChildren's Hospital at Montefiore, Bronx, NY, United States, bNew York University Medical Center, New York, NY, United States, cNew York State Department of Health, Albany, NY, United States, dIcahn School of Medicine at Mount Sinai, New York, NY, United States, eMaimonides Medical Center, Brooklyn, NY, United States, fElmhurst Hospital Center, Queens, NY, United States A prospective, consented pilot study is currently underway at four New York City hospitals in order to assess the utility of newborn screening for lysosomal diseases, to define the pre-symptomatic natural history, and to evaluate the ethical, legal, and social issues associate with such screening. Between May 2013 and September 1, 2016, 49,996 of 68, 094 (73%) approached parents verbally consented to participate. Lysosomal disease testing is performed at the NYS NBS LSD Lab using tandem MS-MS to measure enzyme activity with referral cutoffs set to 15% of daily mean activity for GAA, IDUA, ABG, ASM, and 25% for GLA. 19,197 specimens were screened for Pompe between May 2013 and October 2014. Of 6 referred infants, 1 has genotype consistent with lateronset disease and 5 have pseudodeficiency alleles (PPV=0.17). 20,320 were screened for MPS I since it was added in May 2015. 5 of 5 referred infants are unaffected based on genotype (PPV=0). Of 49,996 infants screened for Fabry, Gaucher and Niemann-Pick disease type A/B: 10 of 16 referred Fabry disease infants have later-onset genotypes, 3 are negative, 1 was lost to follow-up and 2 results are pending (PPV=0.77); 9 of 11 infants who underwent confirmatory testing for Gaucher have genotypes consistent with later-onset disease, 1 is negative and 1 result is pending (PPV=0.9), and the 2 infants referred for Niemann-Pick disease type A/B have genotypes consistent with later-onset disease (PPV=1.0). In summary, we have detected only later-onset lysosomal diseases, which challenges traditional NBS criteria. NBS using enzyme activity alone results in a wide range of PPVs as defined by genotypes. Gaucher and Niemann-Pick disease type A/B have the highest PPVs, whereas MPS I and Pompe disease, the only two lysosomal diseases currently on the RUSP, have the lowest. Concurrent molecular analysis to reduce the number of false positives is recommended.
doi:10.1016/j.ymgme.2016.11.365
Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, multiorgan lysosomal disease historically known as Niemann-Pick disease types A (NPD A) and B (NPD B). ASMD results in the progressive accumulation of sphingomyelin in reticuloendothelial organs (liver, spleen, bone marrow, and lung), hepatocytes, and in severe cases, brain. ASMD manifests as a clinical spectrum ranging from a rapidly progressive infantile neurovisceral form (NPD A) which is uniformly fatal by age 3, to chronic neurovisceral (NPD B variant) and visceral (NPD B) forms that have variable ages of onset, slower progression, and longer lifespans. Disease management is aimed at mitigating symptoms and regular assessments for multisystem involvement. An international panel of laboratory and clinical ASMD experts gathered to review the evidence base and develop guidelines for the diagnosis, nomenclature, and management of ASMD. During a meeting at which published material and personal experience were reviewed, the panel members discussed the best approach for diagnosis and developed a diagnostic guideline and new recommended nomenclature to better capture the clinical spectrum of ASMD. The diagnosis of ASMD is based on ASMD enzyme activity and SMPD1 gene sequencing. Because of symptom overlap between ASMD and Gaucher disease, it is recommended that, whenever possible, parallel enzyme testing for Gaucher disease and ASMD is performed. Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers since it is important that primary care providers (e.g., pediatricians) and specialists (e.g., pulmonologists, hepatologists, and hematologists) be able to recognize ASMD in order to provide the appropriate patient care and referrals. Early diagnosis is essential for effective disease and symptom management. (Supported by Sanofi Genzyme.)
doi:10.1016/j.ymgme.2016.11.366
358 Genistein: a lysosomal stimulator for treatment of various lysosomal diseases Grzegorz Wegrzyna, Karolina Pierzynowskaa, Aleksandra Haca, Magdalena Gabig-Ciminskab, Joanna Jakobkiewicz-Baneckaa, aUniversity of Gdansk, Gdansk, Poland, bInstitute of Biochemistry and Biophysics of Polish Academy of Sciences, Gdansk, Poland The use of genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1benzopyran-4-one) has been proposed as a putative treatment for lysosomal diseases, particularly mucopolysaccharidoses (MPS). This proposal was based on findings that this isoflavone can inhibit