Sabrina Malvagia1, Christopher A Haynes2, Laura Grisotto3, Daniela Ombrone1, Silvia Funghini1, Elisa Moretti4, Kathleen S McGreevy5, Annibale Biggeri3, Renzo Guerrini6, Raquel Yahyaoui7, Uttam Garg8, Mary Seeterlin9, Donald Chace10, Victor R De Jesus2, Giancarlo la Marca11. 1. Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy. 2. Newborn Screening and Molecular Biology Branch, Centers for Disease Control and Prevention, Atlanta, GA USA. 3. Department of Statistics, Computer Science and Applications 'G. Parenti' University of Florence, Florence, Italy. 4. Analytics and Early Formulations Department, Chiesi Farmaceutici S.P.A., Parma, Italy. 5. Research, Innovation and International Relations Office, Meyer Children's University Hospital, Florence, Italy. 6. Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Viale Pieraccini 24, 50139 Florence, Italy. 7. Newborn Screening and Clinical Laboratory, Málaga Regional Hospital, Málaga, Spain. 8. Department of Pathology and laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, USA. 9. Newborn Screening Section, Michigan Department of Community Health, Bureau of Laboratories, Chemistry and Toxicology, Lansing, MI, USA. 10. The Pediatrix Center for Research, Education and Quality Pediatrix Medical Group, Concord Terrace Sunrise, FL, USA. 11. Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy. Electronic address: g.lamarca@meyer.it.
Abstract
BACKGROUND: 3-Hydroxypalmitoleoyl-carnitine (C16:1-OH) has recently been reported to be elevated in acylcarnitine profiles of patients with propionic acidemia (PA) or methylmalonic acidemia (MMA) during expanded newborn screening (NBS). High levels of C16:1-OH, combined with other hydroxylated long chain acylcarnitines are related to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and trifunctional protein (TFP) deficiency. METHODS: The acylcarnitine profile of two LCHADD patients was evaluated using liquid chromatography-tandem mass spectrometric method. A specific retention time was determined for each hydroxylated long chain acylcarnitine. The same method was applied to some neonatal dried blood spots (DBSs) from PA and MMA patients presenting abnormal C16:1-OH concentrations. RESULTS: The retention time of the peak corresponding to C16:1-OH in LCHADD patients differed from those in MMA and PA patients. Heptadecanoylcarnitine (C17) has been identified as the novel biomarker specific for PA and MMA patients through high resolution mass spectrometry (Orbitrap) experiments. We found that 21 out of 23 neonates (22 MMA, and 1PA) diagnosed through the Tuscany region NBS program exhibited significantly higher levels of C17 compared to controls. Twenty-three maternal deficiency (21 vitamin B12 deficiency, 1 homocystinuria and 1 gastrin deficiency) samples and 82 false positive for elevated propionylcarnitine (C3) were also analyzed. CONCLUSIONS: We have characterized a novel biomarker able to detect propionate disorders during expanded newborn screening (NBS). The use of this new biomarker may improve the analytical performances of NBS programs especially in laboratories where second tier tests are not performed.
BACKGROUND:3-Hydroxypalmitoleoyl-carnitine (C16:1-OH) has recently been reported to be elevated in acylcarnitine profiles of patients with propionic acidemia (PA) or methylmalonic acidemia (MMA) during expanded newborn screening (NBS). High levels of C16:1-OH, combined with other hydroxylated long chain acylcarnitines are related to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and trifunctional protein (TFP) deficiency. METHODS: The acylcarnitine profile of two LCHADD patients was evaluated using liquid chromatography-tandem mass spectrometric method. A specific retention time was determined for each hydroxylated long chain acylcarnitine. The same method was applied to some neonatal dried blood spots (DBSs) from PA and MMApatients presenting abnormal C16:1-OH concentrations. RESULTS: The retention time of the peak corresponding to C16:1-OH in LCHADD patients differed from those in MMA and PA patients. Heptadecanoylcarnitine (C17) has been identified as the novel biomarker specific for PA and MMApatients through high resolution mass spectrometry (Orbitrap) experiments. We found that 21 out of 23 neonates (22 MMA, and 1PA) diagnosed through the Tuscany region NBS program exhibited significantly higher levels of C17 compared to controls. Twenty-three maternal deficiency (21 vitamin B12deficiency, 1 homocystinuria and 1 gastrin deficiency) samples and 82 false positive for elevated propionylcarnitine (C3) were also analyzed. CONCLUSIONS: We have characterized a novel biomarker able to detect propionate disorders during expanded newborn screening (NBS). The use of this new biomarker may improve the analytical performances of NBS programs especially in laboratories where second tier tests are not performed.
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