11First specimen: Two days old, 7lbs 4oz Age Related Reference RangesCase Study 1: MCADFirst specimen: Two days old, 7lbs 4ozResultsAnalyte Value Newborn Reference Range(average of 3 extractions) (0 - 7 days old and >2000grams)C6 carnitine < 0.86C8 carnitine VH < 0.40C10:1 carnitine H < 0.40C10 carnitine H < 0.72C8/C2 ratio VH < 0.02
12Repeat specimen: 13days old Case Study 1: MCADRepeat specimen: 13days oldResultsAnalyte(s) Value Newborn(average of 3 extractions) Reference RangeC6 carnitine < 0.86C8 carnitine H < 0.40C10:1 carnitine < 0.40C10 carnitine < 0.72C8/C2 ratio < 0.02BabyReference Range<0.95<0.32<0.34<0.42<0.03H
13First specimen: Two days old, 3540grams Age Related Reference RangesCase Study 3: GAIFirst specimen: Two days old, 3540gramsResultsAnalyte Value Newborn Reference Range(average of 3 extractions) (0 - 7 days old and >2000grams)C5-DC VH < 0.38
14Repeat specimen: 6 days old Case Study 3: GAIRepeat specimen: 6 days oldResultsAnalyte(s) Value Newborn(average of 3 extractions) Reference RangeC5-DC H < 0.38
18Detection 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
19Detection 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
20Detection 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
21Detection 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?
22Detection 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 hydroxybutyryl-CoA dehydrogenase C3 + C5-OH; HCS vs biotinidase
23Confirmation 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
24Confirmation of Diagnoses Depends on the Disorder Quantitative Amino Acids in PlasmaQuantitative Organic Acids in UrineAcylcarnitine profile in plasma or DBS (DBS preferred for long-chain disorders)Intact fibroblast metabolism studies, assay of enzyme activities in fibroblasts or lymphocytesMutations analysis of DNA
25ConclusionAlthough 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.