Tandem MS Newborn Screening

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Presentation transcript:

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 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

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

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

Age and Reference Ranges Sub-Populations

C3 Acylcarnitine (uM) vs Age (days) NB cut off 6.84 uM Baby cut off 4.12 uM

C16 Acylcarnitine (uM) vs Age (days) NB cut off 9.53 uM Baby cut off 6.47 uM

First specimen: Two days old, 7lbs 4oz 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

Repeat specimen: 13days old 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

First specimen: Two days old, 3540grams 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

Repeat specimen: 6 days old 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

Age and Reference Ranges Sub-Populations

Detection of Disorders Amino 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

Detection of Disorders Amino 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

Detection of Disorders Acylcarnitines Detects disorders, fairly diagnostic C6, C8, C10:1 C10 + ratios = MCAD C14:1, C16, 18 +ratio C14:1/C2 = VLCAD High free carnitine, free/C16, free/C18 = CPT I C5-dicarboxylic = GA I C3-dicarboxylic = malonic

Detection of Disorders Acylcarnitines 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?

Detection of Disorders Acylcarnitines 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

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

Confirmation of Diagnoses Depends 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

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.