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Newborn screening for Fabry disease: Is the A143T allele a pathogenic mutation or a pseudodeficiency allele?
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
10 Immunology of mucopolysaccharidosis Carolina Aranda, Dirceu Solé, Carmen Mendes, Maret Rand, Sandra Kyosen, Patricia Feliciano, Marco Curiati, Mariana Asato, Marcia Mallozi, Beatriz Costa-Carvalho, Vania D'Almeida, Ana Maria Martins, Universidade Federal de São Paulo, São Paulo, Brazil
OF
Recurrent infections, mainly respiratory, are reported in mucopolysaccharidosis (MPS) patients; therefore, immunological evaluation is important to understand the reasons for these infections. The immunity can be evaluated by the innate function (phagocytes, Toll-like receptors, complement system and nature killer (NK) cells), adaptive function (serum immunoglobulins, response to the proteins and polysaccharides antigens), cytokines and other components. The accumulation of glycosaminoglycans (GAG) in most of the cells results in the disruption of homeostasis. They can stimulate Toll-like receptor (as TLR4), similar to the lipopolysaccharides (LPS), through MyD88 and CD11 receptors leading to activation of inflammatory pathways such as NF-Kβ or the transcription factor STAT. GAG are an important biomarkers and the decrease in their urinary levels indicates treatment. The aim of this study is to begin immunological evaluation in MPS patients to clarify why they are prone to infections. Eighteen MPS patients (MPS type I = 5, II = 9 and VI = 4′ mean age 13 years, range 5–32 years) on enzyme replacement therapy (ERT), 88% male, were evaluated by measurement of complete blood count, quantitative/qualitative serum immunoglobulins (Ig; G, M and A), review of immunization (Bacillus Calmette–Guérin (BCG), hepatitis B and rubella), levels of urinary GAG (before and after ERT) and history of recurrent wheezing and pneumonia. The primary findings are that: Urinary GAG of all patients decreased after ERT to recommended levels (p b 0.001). All patients had history of wheezing and pneumonia before ERT. Thereafter, 6 patients (33%) still had episodes of wheezing and 8 (44%) had pneumonia. Only one patient (MPS II) had IgG serum levels lower than 3rd percentile. Three patients had IgM levels lower than 3rd percentile (2 MPS II and 1 MPS VI). All patients had normal numbers of lymphocytes, but two patients had neutrophil counts below the normal range. All patients were vaccinated for BCG, however one patient (MPS VI) had lymph node tuberculosis five years after that vaccine. Regarding the qualitative evaluation of immunoglobulins, 10 (55%) patients showed no response to hepatitis B vaccine and one (5.5%) patient (MPS VI) showed no response to rubella vaccine. The immunological evaluation of MPS patients is mandatory, especially for the high frequency of respiratory infections presented by them. The improvement in wheezing episodes and the number of pneumonias after ERT suggest decreased inflammation associated with a better immune response. In this group, the cell count was normal; however, the phagocyte function has not been evaluated. Some patients had serum immunoglobulin levels less than the third percentile which requires a reassessment. Regarding the response to protein antigens, there was little response to the hepatitis B vaccine. Antihepatitis B levels may decrease with age (seen in the general population), a factor that may confuse the outcome of this review. Regarding rubella, the lack of response suggests a qualitative antibody deficiency. More studies on the antibody and innate immunity are needed to understand the disease and improve the treatment of these complications.
UN
CO
RR
EC
TE
DP
type I (GD1) patients (3.5–12.5). The hypothesis is that deregulation of immune system resulting from glucocerebroside accumulation may influence the development of hematologic malignancies. However, the pathological mechanisms that influence MM development in GD1 patients are unknown. Cytokines produced in response to glucocerebroside accumulation, may be a critical factor to explain the pathogenesis of MM in GD1. This cytokine environment could trigger lymphocyte expansion and ultimately transformation. Objective: To analyze the proinflammatory cytokine profile among MGUS, MM from the Hematology Department and GD1 patients from the Spanish Registry (FEETEG) and controls. Methods: Between February and May, 2014 we have analyzed a panel of cytokines (IL4, IL6, IL7, IL10, IL13, MIP1α, MIP1β and TNF) by Luminex® 100 platform and Millipore cytokine kits. The analysis was performed in plasma samples stored at diagnosis in the Aragon Biobank. We studied three cohorts: 36 MGUS (58.3% women, mean age: 75 years, range 53–89), 11 IgGk; 6 IgGL; 5 IgAk; 8 IgAL; 3 IgMk; 3 doble IgG + IgA. 49 MM (42% women, mean age 68 years, range 39–89), 20 IgGk; 5 IgGL; 8 IgAk; 5 IgAL, 8 light chain disease and 3 double IgG + IgA. With reference to the ISS classification of these subjects, 44.0% MM patients had a score 1, 24.3% score 2 and 31.7% score 3. All patients with MGUS or MM and 38 GD1 patients (36.8% women, mean age 39.2 years, range: 17–79) and 71 healthy controls had been diagnosed consecutively during 2009 and followed up until now. Data were analyzed using non-parametric tests (Mann– Whitney-U and Kruskal–Wallis). Results: After 5 years of follow-up, 21 MM patients had died (42.8%) and 8 in the MGUS group (22.2%), 4 MGUS developed a MM (11.1%); of MM patients, 7 developed a second tumor (14.2%) and 8 in the MGUS group (22.2%). Among GD1 patients, one developed a MM and two a solid tumor. With respect to cytokine analysis, a significant difference (p b 0.05) was observed in IL4; MIP-1α; MIP-1β and TNFα values between controls. MGUS; MM and GD1 patients; and also IL13 in MM and GD1. MM and GD1 did not show differences in the median values of IL4 and IL13. These groups showed significant differences in MIP-1α, MIP-1β and TNFα values. In MM there are significant differences in IL4 (p = 0.012) and MIP-1α (p = 0.022) between ISS 1 and ISS 3. In addition there are significant differences in MIP-1α between IgGk vs IgAL and MGUS patients that will be transformed to MM (p = 0.018). There were no significant differences in cytokine profiles among patients that developed a second neoplasia (see Table 1). Conclusions: These results support the notion that GD1 and MM patients share similar proinflammatory profiles and that the abnormalities in the macrophage inflammatory environment among GD1 patients may be related to the development of malignancies in GD1 patients. GD1 and MM share skeletal complications, MIP-1α as osteoclast-activating factor could be a good biomarker during followup of GD1 or MGUS to detect patients at higher risk to develop bone complications. MIP-1α is described as significantly elevated in bone loss MGUS patients (Ng AC et al., 2011).
RO
S14
doi:10.1016/j.ymgme.2014.12.012
11 Newborn screening for Fabry disease: Is the A143T allele a pathogenic mutation or a pseudodeficiency allele?
doi:10.1016/j.ymgme.2014.12.011
Andrea M. Athertona, Dana Dohenyb, Dawn Peckc, Katherine Christensend, Kayla Smithe, Linda Manwaringe, Jami Kieslingf, Richard Hillmanc, Esperanza Font-Montgomeryc, Marwan Shinawie, Dorothy K. Grangee,
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
Robert J. Desnickb, Bryce A. Heesea, aChildren's Mercy Hospital, Kansas City, MO, USA, bIcahn School of Medicine at Mount Sinai, New York, NY, USA, c University of Missouri Children's Hospital, Columbia, MO, USA, dCardinal Glennon Children's Medical Center, St. Louis, MO, USA, eWashington University School of Medicine, St. Louis, MO, USA, fMissouri Department of Health and Senior Services, Jefferson City, MO, USA
S15
disease, Gaucher disease, Fabry disease and mucopolysaccharidosis type I (MPS I) in January 2013. We aim to provide a complete update on the first two years of experience related to Missouri's full population pilot newborn screening for LSD after screening ~ 160,000 infants between August 2012 and January 2015. doi:10.1016/j.ymgme.2014.12.014
13 Galabiosylceramide isoforms/analogues as biomarkers for Fabry disease patients
OF
Christiane Auray-Blais, Michel Boutin, Université de Sherbrooke, Sherbrooke, QC, Canada
RO
Fabry disease is an X-linked lysosomal disorder caused by alpha-galactosidase A deficiency and characterized by the accumulation of different substrates, globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3) and galabiosylceramide (Ga2) in biological fluids and tissues. Renal failure or a cardiac or cerebrovascular event can lead to premature death in Fabry patients. Urine samples from untreated Fabry males and healthy control males were fractionated by liquid–liquid extraction and analyzed by ultra-high performance liquid chromatography (UPLC) (Acquity, Waters Corp.) hyphenated to a time-of-flight (TOF) mass spectrometry system (Synapt, Waters). Molecules in the mass range corresponding to Ga2 (820–1020 Da) isoforms/analogues of the two sample groups were statistically compared by orthogonal partial least square discriminant analysis (OPLS-DA). A total of 19 different Ga2 isoforms/analogues were found to be significantly more abundant in Fabry samples compared to control samples, and were identified as Fabry disease biomarkers. These molecules were structurally elucidated by tandem mass spectrometry. For the first time, Ga2 analogues with a methylation of the amide linkage and a hydration of the sphingosine moiety are reported. The levels of Ga2 isoforms/analogues were compared to the levels of their Gb3 counterparts [1]. The relative abundance of the isoforms with hydroxylated fatty acids was 5 times higher for Ga2 compared to Gb3. These results suggest different biological pathways conducting to the synthesis and/or degradation of the two sphingolipid groups. Development and validation of a high sensitivity method for the analysis of 19 different Ga2 isoforms/analogues will allow the evaluation of these biomarkers as possible tools, complementary to Gb3 and Lyso-Gb3, for the diagnosis and monitoring of Fabry disease patients. [1] Auray-Blais, Boutin, Current Medicinal Chemistry, 2012, 19, 3241.
TE
DP
Missouri began a full population pilot utilizing a digital microfluidics multiplex enzymatic assay to rapidly screen newborns for four lysosomal disorders in January 2013 including Fabry disease. During the first 18 months of screening, over 115,000 newborns were screened at the Missouri State Public Health Laboratory. Of 89 referrals from the state NBS lab for Fabry disease, 40 newborns confirmed positive for Fabry disease with reduced enzyme activity and a mutation identified in the GLA gene. Based on current knowledge, the 40 confirmed cases have been categorized as classic Fabry disease (1), later onset form of Fabry disease (35) and Fabry disease with variants of unknown significance (4). The A143T allele was identified in 26/40 (approximately 65%) of the confirmed positive Fabry genotypes. Of the 40 families, a total of 58 additional family members who underwent genetic testing were identified to have Fabry disease. A few patients reported symptoms thought to be related to Fabry disease but only one of these individuals has begun treatment for Fabry disease. Based on Missouri newborn screening experience, the incidence of Fabry disease in the Missouri population is about 1 in 2875 which is significantly greater than predicted (1/40,000–1/60,000). The information gathered after 18 months of screening newborns for Fabry disease highlights the importance of genetic counseling and testing at risk family members. The high prevalence of the previously reported A143T allele in Missouri raises the question whether this mutation is truly a pathogenic mutation versus a pseudodeficiency allele. Future studies are needed to assess the frequency of the A143T mutation and to analyze functional data from unaffected family members who have this mutation.
EC
doi:10.1016/j.ymgme.2014.12.013
RR
12 The first two years of full population pilot newborn screening for lysosomal disorders: The Missouri experience
UN
CO
Andrea M. Athertona, Dawn Peckb, Katherine Christensenc, Kayla Smithd, Linda Manwaringd, Patrick Hopkinse, Sharmini Rogersf, Jami Kieslingf, Esperanza Font-Montgomeryb, Richard Hillmanb, Stephen Braddockc, Marwan Shinawid, Dorothy K. Granged, Bryce A. Heesea, a Children's Mercy Hospital, Kansas City, MO, USA, bUniversity of Missouri Children's Hospital, Columbia, MO, USA, cCardinal Glennon Children's Medical Center, St. Louis, MO, USA, dWashington University School of Medicine, St. Louis, MO, USA, eMissouri State Public Health Laboratory, Jefferson City, MO, USA, fMissouri Department of Health and Senior Services, Jefferson City, MO, USA Expanded newborn screening is an important public health initiative to screen for conditions for which interventions are available to significantly reduce the associated morbidity and mortality and is considered standard of care. While a recommended universal screening panel (RUSP) exists in the United States, the individual states decide which disorders are included on their newborn screening platform. There has been extensive discussion about the inclusion of lysosomal disorders on newborn screening panels and Missouri was the first state to implement newborn screening for five lysosomal diseases utilizing a rapid digital microfluidics assay. The state of MO began their full population pilot newborn screening for Krabbe disease in August 2012 and for Pompe
doi:10.1016/j.ymgme.2014.12.015
14 Mass spectrometry multiplex analysis of urinary glycosaminoglycans for mucopolysaccharidosis patients Christiane Auray-Blaisa, Shunji Tomatsub, Pamela Lavoiea, aUniversité de Sherbrooke, Sherbrooke, QC, Canada, bUniversity of Delaware, Wilmington, DE, USA Mucopolysaccharidoses (MPS) are the result of primary defects in lysosomal enzymes. Depending on the specific gene defect, the catabolism of one or more glycosaminoglycan (GAG) is blocked leading to the accumulation of substrates in tissues as well as in biological fluids of affected patients. The primary objective of this research project was to improve the diagnosis and monitoring of
10 Immunology of mucopolysaccharidosis Carolina Aranda, Dirceu Solé, Carmen Mendes, Maret Rand, Sandra Kyosen, Patricia Feliciano, Marco Curiati, Mariana Asato, Marcia Mallozi, Beatriz Costa-Carvalho, Vania D'Almeida, Ana Maria Martins, Universidade Federal de São Paulo, São Paulo, Brazil
OF
Recurrent infections, mainly respiratory, are reported in mucopolysaccharidosis (MPS) patients; therefore, immunological evaluation is important to understand the reasons for these infections. The immunity can be evaluated by the innate function (phagocytes, Toll-like receptors, complement system and nature killer (NK) cells), adaptive function (serum immunoglobulins, response to the proteins and polysaccharides antigens), cytokines and other components. The accumulation of glycosaminoglycans (GAG) in most of the cells results in the disruption of homeostasis. They can stimulate Toll-like receptor (as TLR4), similar to the lipopolysaccharides (LPS), through MyD88 and CD11 receptors leading to activation of inflammatory pathways such as NF-Kβ or the transcription factor STAT. GAG are an important biomarkers and the decrease in their urinary levels indicates treatment. The aim of this study is to begin immunological evaluation in MPS patients to clarify why they are prone to infections. Eighteen MPS patients (MPS type I = 5, II = 9 and VI = 4′ mean age 13 years, range 5–32 years) on enzyme replacement therapy (ERT), 88% male, were evaluated by measurement of complete blood count, quantitative/qualitative serum immunoglobulins (Ig; G, M and A), review of immunization (Bacillus Calmette–Guérin (BCG), hepatitis B and rubella), levels of urinary GAG (before and after ERT) and history of recurrent wheezing and pneumonia. The primary findings are that: Urinary GAG of all patients decreased after ERT to recommended levels (p b 0.001). All patients had history of wheezing and pneumonia before ERT. Thereafter, 6 patients (33%) still had episodes of wheezing and 8 (44%) had pneumonia. Only one patient (MPS II) had IgG serum levels lower than 3rd percentile. Three patients had IgM levels lower than 3rd percentile (2 MPS II and 1 MPS VI). All patients had normal numbers of lymphocytes, but two patients had neutrophil counts below the normal range. All patients were vaccinated for BCG, however one patient (MPS VI) had lymph node tuberculosis five years after that vaccine. Regarding the qualitative evaluation of immunoglobulins, 10 (55%) patients showed no response to hepatitis B vaccine and one (5.5%) patient (MPS VI) showed no response to rubella vaccine. The immunological evaluation of MPS patients is mandatory, especially for the high frequency of respiratory infections presented by them. The improvement in wheezing episodes and the number of pneumonias after ERT suggest decreased inflammation associated with a better immune response. In this group, the cell count was normal; however, the phagocyte function has not been evaluated. Some patients had serum immunoglobulin levels less than the third percentile which requires a reassessment. Regarding the response to protein antigens, there was little response to the hepatitis B vaccine. Antihepatitis B levels may decrease with age (seen in the general population), a factor that may confuse the outcome of this review. Regarding rubella, the lack of response suggests a qualitative antibody deficiency. More studies on the antibody and innate immunity are needed to understand the disease and improve the treatment of these complications.
UN
CO
RR
EC
TE
DP
type I (GD1) patients (3.5–12.5). The hypothesis is that deregulation of immune system resulting from glucocerebroside accumulation may influence the development of hematologic malignancies. However, the pathological mechanisms that influence MM development in GD1 patients are unknown. Cytokines produced in response to glucocerebroside accumulation, may be a critical factor to explain the pathogenesis of MM in GD1. This cytokine environment could trigger lymphocyte expansion and ultimately transformation. Objective: To analyze the proinflammatory cytokine profile among MGUS, MM from the Hematology Department and GD1 patients from the Spanish Registry (FEETEG) and controls. Methods: Between February and May, 2014 we have analyzed a panel of cytokines (IL4, IL6, IL7, IL10, IL13, MIP1α, MIP1β and TNF) by Luminex® 100 platform and Millipore cytokine kits. The analysis was performed in plasma samples stored at diagnosis in the Aragon Biobank. We studied three cohorts: 36 MGUS (58.3% women, mean age: 75 years, range 53–89), 11 IgGk; 6 IgGL; 5 IgAk; 8 IgAL; 3 IgMk; 3 doble IgG + IgA. 49 MM (42% women, mean age 68 years, range 39–89), 20 IgGk; 5 IgGL; 8 IgAk; 5 IgAL, 8 light chain disease and 3 double IgG + IgA. With reference to the ISS classification of these subjects, 44.0% MM patients had a score 1, 24.3% score 2 and 31.7% score 3. All patients with MGUS or MM and 38 GD1 patients (36.8% women, mean age 39.2 years, range: 17–79) and 71 healthy controls had been diagnosed consecutively during 2009 and followed up until now. Data were analyzed using non-parametric tests (Mann– Whitney-U and Kruskal–Wallis). Results: After 5 years of follow-up, 21 MM patients had died (42.8%) and 8 in the MGUS group (22.2%), 4 MGUS developed a MM (11.1%); of MM patients, 7 developed a second tumor (14.2%) and 8 in the MGUS group (22.2%). Among GD1 patients, one developed a MM and two a solid tumor. With respect to cytokine analysis, a significant difference (p b 0.05) was observed in IL4; MIP-1α; MIP-1β and TNFα values between controls. MGUS; MM and GD1 patients; and also IL13 in MM and GD1. MM and GD1 did not show differences in the median values of IL4 and IL13. These groups showed significant differences in MIP-1α, MIP-1β and TNFα values. In MM there are significant differences in IL4 (p = 0.012) and MIP-1α (p = 0.022) between ISS 1 and ISS 3. In addition there are significant differences in MIP-1α between IgGk vs IgAL and MGUS patients that will be transformed to MM (p = 0.018). There were no significant differences in cytokine profiles among patients that developed a second neoplasia (see Table 1). Conclusions: These results support the notion that GD1 and MM patients share similar proinflammatory profiles and that the abnormalities in the macrophage inflammatory environment among GD1 patients may be related to the development of malignancies in GD1 patients. GD1 and MM share skeletal complications, MIP-1α as osteoclast-activating factor could be a good biomarker during followup of GD1 or MGUS to detect patients at higher risk to develop bone complications. MIP-1α is described as significantly elevated in bone loss MGUS patients (Ng AC et al., 2011).
RO
S14
doi:10.1016/j.ymgme.2014.12.012
11 Newborn screening for Fabry disease: Is the A143T allele a pathogenic mutation or a pseudodeficiency allele?
doi:10.1016/j.ymgme.2014.12.011
Andrea M. Athertona, Dana Dohenyb, Dawn Peckc, Katherine Christensend, Kayla Smithe, Linda Manwaringe, Jami Kieslingf, Richard Hillmanc, Esperanza Font-Montgomeryc, Marwan Shinawie, Dorothy K. Grangee,
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
Robert J. Desnickb, Bryce A. Heesea, aChildren's Mercy Hospital, Kansas City, MO, USA, bIcahn School of Medicine at Mount Sinai, New York, NY, USA, c University of Missouri Children's Hospital, Columbia, MO, USA, dCardinal Glennon Children's Medical Center, St. Louis, MO, USA, eWashington University School of Medicine, St. Louis, MO, USA, fMissouri Department of Health and Senior Services, Jefferson City, MO, USA
S15
disease, Gaucher disease, Fabry disease and mucopolysaccharidosis type I (MPS I) in January 2013. We aim to provide a complete update on the first two years of experience related to Missouri's full population pilot newborn screening for LSD after screening ~ 160,000 infants between August 2012 and January 2015. doi:10.1016/j.ymgme.2014.12.014
13 Galabiosylceramide isoforms/analogues as biomarkers for Fabry disease patients
OF
Christiane Auray-Blais, Michel Boutin, Université de Sherbrooke, Sherbrooke, QC, Canada
RO
Fabry disease is an X-linked lysosomal disorder caused by alpha-galactosidase A deficiency and characterized by the accumulation of different substrates, globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3) and galabiosylceramide (Ga2) in biological fluids and tissues. Renal failure or a cardiac or cerebrovascular event can lead to premature death in Fabry patients. Urine samples from untreated Fabry males and healthy control males were fractionated by liquid–liquid extraction and analyzed by ultra-high performance liquid chromatography (UPLC) (Acquity, Waters Corp.) hyphenated to a time-of-flight (TOF) mass spectrometry system (Synapt, Waters). Molecules in the mass range corresponding to Ga2 (820–1020 Da) isoforms/analogues of the two sample groups were statistically compared by orthogonal partial least square discriminant analysis (OPLS-DA). A total of 19 different Ga2 isoforms/analogues were found to be significantly more abundant in Fabry samples compared to control samples, and were identified as Fabry disease biomarkers. These molecules were structurally elucidated by tandem mass spectrometry. For the first time, Ga2 analogues with a methylation of the amide linkage and a hydration of the sphingosine moiety are reported. The levels of Ga2 isoforms/analogues were compared to the levels of their Gb3 counterparts [1]. The relative abundance of the isoforms with hydroxylated fatty acids was 5 times higher for Ga2 compared to Gb3. These results suggest different biological pathways conducting to the synthesis and/or degradation of the two sphingolipid groups. Development and validation of a high sensitivity method for the analysis of 19 different Ga2 isoforms/analogues will allow the evaluation of these biomarkers as possible tools, complementary to Gb3 and Lyso-Gb3, for the diagnosis and monitoring of Fabry disease patients. [1] Auray-Blais, Boutin, Current Medicinal Chemistry, 2012, 19, 3241.
TE
DP
Missouri began a full population pilot utilizing a digital microfluidics multiplex enzymatic assay to rapidly screen newborns for four lysosomal disorders in January 2013 including Fabry disease. During the first 18 months of screening, over 115,000 newborns were screened at the Missouri State Public Health Laboratory. Of 89 referrals from the state NBS lab for Fabry disease, 40 newborns confirmed positive for Fabry disease with reduced enzyme activity and a mutation identified in the GLA gene. Based on current knowledge, the 40 confirmed cases have been categorized as classic Fabry disease (1), later onset form of Fabry disease (35) and Fabry disease with variants of unknown significance (4). The A143T allele was identified in 26/40 (approximately 65%) of the confirmed positive Fabry genotypes. Of the 40 families, a total of 58 additional family members who underwent genetic testing were identified to have Fabry disease. A few patients reported symptoms thought to be related to Fabry disease but only one of these individuals has begun treatment for Fabry disease. Based on Missouri newborn screening experience, the incidence of Fabry disease in the Missouri population is about 1 in 2875 which is significantly greater than predicted (1/40,000–1/60,000). The information gathered after 18 months of screening newborns for Fabry disease highlights the importance of genetic counseling and testing at risk family members. The high prevalence of the previously reported A143T allele in Missouri raises the question whether this mutation is truly a pathogenic mutation versus a pseudodeficiency allele. Future studies are needed to assess the frequency of the A143T mutation and to analyze functional data from unaffected family members who have this mutation.
EC
doi:10.1016/j.ymgme.2014.12.013
RR
12 The first two years of full population pilot newborn screening for lysosomal disorders: The Missouri experience
UN
CO
Andrea M. Athertona, Dawn Peckb, Katherine Christensenc, Kayla Smithd, Linda Manwaringd, Patrick Hopkinse, Sharmini Rogersf, Jami Kieslingf, Esperanza Font-Montgomeryb, Richard Hillmanb, Stephen Braddockc, Marwan Shinawid, Dorothy K. Granged, Bryce A. Heesea, a Children's Mercy Hospital, Kansas City, MO, USA, bUniversity of Missouri Children's Hospital, Columbia, MO, USA, cCardinal Glennon Children's Medical Center, St. Louis, MO, USA, dWashington University School of Medicine, St. Louis, MO, USA, eMissouri State Public Health Laboratory, Jefferson City, MO, USA, fMissouri Department of Health and Senior Services, Jefferson City, MO, USA Expanded newborn screening is an important public health initiative to screen for conditions for which interventions are available to significantly reduce the associated morbidity and mortality and is considered standard of care. While a recommended universal screening panel (RUSP) exists in the United States, the individual states decide which disorders are included on their newborn screening platform. There has been extensive discussion about the inclusion of lysosomal disorders on newborn screening panels and Missouri was the first state to implement newborn screening for five lysosomal diseases utilizing a rapid digital microfluidics assay. The state of MO began their full population pilot newborn screening for Krabbe disease in August 2012 and for Pompe
doi:10.1016/j.ymgme.2014.12.015
14 Mass spectrometry multiplex analysis of urinary glycosaminoglycans for mucopolysaccharidosis patients Christiane Auray-Blaisa, Shunji Tomatsub, Pamela Lavoiea, aUniversité de Sherbrooke, Sherbrooke, QC, Canada, bUniversity of Delaware, Wilmington, DE, USA Mucopolysaccharidoses (MPS) are the result of primary defects in lysosomal enzymes. Depending on the specific gene defect, the catabolism of one or more glycosaminoglycan (GAG) is blocked leading to the accumulation of substrates in tissues as well as in biological fluids of affected patients. The primary objective of this research project was to improve the diagnosis and monitoring of