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Tandem MS Newborn Screening

Tandem MS Newborn Screening. Larry Sweetman, Ph.D. Paula Ashcraft, M.T. Institute of Metabolic Disease Baylor University Medical Center Dallas, TX, USA. Results Issues. Markers Ratios Sub-population Reference Ranges Detection of disorders Diagnostic confirmation . Markers.

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Tandem MS Newborn Screening

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  1. Tandem MS Newborn Screening Larry Sweetman, Ph.D.Paula Ashcraft, M.T.Institute of Metabolic DiseaseBaylor University Medical CenterDallas, TX, USA

  2. Results Issues • Markers • Ratios • Sub-population Reference Ranges • Detection of disorders • Diagnostic confirmation

  3. Markers • Consider pattern of multiple markers, rather than primary and secondary markers • Remember MS/MS doesn’t distinguish isobaric compounds • Remember MS/MS doesn’t distinguish structural isomers ex. C5 = isovaleryl plus 2-methylbutyryl

  4. Markers • Consider pattern of multiple markers, rather than primary and secondary markersex. MCAD: C6, C8, C10:1, and C10 acylcarnitinesex. MSUD: Leu (+Ile, allo-Ile, OH-Pro) and Val and Leu/Ala

  5. Ratios as Markers • Ratios of biochemical precursor/product ex. Phe / Tyr ex. MCAD: C8 / C2, C10:1 / C2 ex. VLCAD: C14:1 / C2 ex. CPT II or CACT: C16 / C2 • Other ratios based on altered metabolism ex. MSUD: Ile/Ala ex. CPT I: Free Carnitine / C16 Free carnitine / C18

  6. Age and Reference RangesSub-Populations

  7. C3 Acylcarnitine (uM) vs Age (days) NB cut off6.84 uM Baby cut off4.12 uM

  8. C16 Acylcarnitine (uM) vs Age (days) NB cut off9.53 uM Baby cut off6.47 uM

  9. Age Related Reference Ranges Case Study 1: MCAD First specimen: Two days old, 7lbs 4oz Results Analyte Value Newborn Reference Range (average of 3 extractions) (0 - 7 days old and >2000grams) C6 carnitine 0.51 < 0.86 C8 carnitine 2.84 VH < 0.40 C10:1 carnitine 0.49 H < 0.40 C10 carnitine 1.32 H < 0.72 C8/C2 ratio 0.09 VH < 0.02

  10. Case Study 1: MCAD Repeat specimen: 13days old Results Analyte(s) Value Newborn (average of 3 extractions) Reference Range C6 carnitine 0.57 < 0.86 C8 carnitine 0.53 H < 0.40 C10:1 carnitine 0.37 < 0.40 C10 carnitine 0.47 < 0.72 C8/C2 ratio 0.02 < 0.02 Baby Reference Range <0.95 <0.32 <0.34 <0.42 <0.03 H H

  11. Age Related Reference Ranges Case Study 3: GAI First specimen: Two days old, 3540grams Results Analyte Value Newborn Reference Range (average of 3 extractions) (0 - 7 days old and >2000grams) C5-DC 2.23 VH < 0.38

  12. Case Study 3: GAI Repeat specimen: 6 days old Results Analyte(s) Value Newborn (average of 3 extractions) Reference Range C5-DC 0.87 H < 0.38

  13. Age and Reference RangesSub-Populations

  14. Detection of DisordersAmino Acids • Detects disorders, fairly diagnostic Phe, Phe/Tyr = PKU or hyperPhe Ile and Val, Ile/Ala = MSUD Arg = Argininemia Orn = HHH syndrome 5-Oxoproline = 5-Oxoprolinuria

  15. Detection of DisordersAmino Acids • Detects disorders, needs differential Met: homocystinuria (cystathionine synthetase) vs Met adenosyltransferase Cit: Citrullinemia vs Argininosuccinic aciduria Tyr: Tyrosinemia I, II, III, transient neonatal, liver disease

  16. Detection of DisordersAcylcarnitines • Detects disorders, fairly diagnosticC6, C8, C10:1 C10 + ratios = MCADC14:1, C16, 18 +ratio C14:1/C2 = VLCADHigh free carnitine, free/C16, free/C18 = CPT IC5-dicarboxylic = GA IC3-dicarboxylic = malonic

  17. Detection of DisordersAcylcarnitines • Detects disorders, needs differential C16, C18:1 , C18; CPT II vs CACT C14-OH, C16-OH, C18:1-OH, C18-OH; LCHAD vs MTP C5; IVA vs 2MBCD C4: SCAD vs IBCD C3: PPA vs MMA vs cbl (B12) C4, C5 and/or longer chains = MADD?

  18. Detection of DisordersAcylcarnitines • Detects disorders, needs differential C5-OH; MCC vs maternal MCC C5-OH, C6-dicarboxylic; HMG vs 3-methylglutaconic C5:1; thiolase vs 2-methy-3- hydroxybutyryl-CoA dehydrogenase C3 + C5-OH; HCS vs biotinidase

  19. Confirmation of Screening Abnormalities • Repeat card for screenRequires age related cut offs Appropriate for Tyr (transient neonatal) • Recommend diagnostic testing Required when markers can suggest different disorders Recommended for most disorders

  20. Confirmation of DiagnosesDepends on the Disorder • Quantitative Amino Acids in Plasma • Quantitative Organic Acids in Urine • Acylcarnitine profile in plasma or DBS (DBS preferred for long-chain disorders) • Intact fibroblast metabolism studies, assay of enzyme activities in fibroblasts or lymphocytes • Mutations analysis of DNA

  21. Conclusion • Although interpretation and follow up of tandem MS newborn screening results is complex, • It can be done, and is of benefit to babies with a wide variety of inherited metabolic disorders.

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