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Expanded Newborn Screening ExpandedExpanded NewbornNewborn Screening:Screening: ChangingChanging thethe FaceFace ofof InbornInborn ErrorsErrors ofof MetabolismMetabolism AyeshaAyesha Ahmad,Ahmad, MDMD RobertRobert Grier,Grier, PhDPhD Division of Genetic and Metabolic Disorders Children’s Hospital of Michigan Sponsored by Wayne State University School of Medicine © 2006, Wayne State University School of Medicine ExpandedExpanded NewbornNewborn Screening:Screening: ChangingChanging thethe FaceFace ofof InbornInborn ErrorsErrors ofof MetabolismMetabolism All parties involved have no personal or financial relationship associated with this educational activity. The presentation is fair, balanced and free of commercial bias and fully supported by scientific evidence. For further information, please refer to: – Policy on privacy and confidentiality: www.wayne.edu/policies InbornInborn ErrorsErrors ofof MetabolismMetabolism (IEM)(IEM) OverOver thethe lastlast 2525 yearsyears thethe fieldfield ofof metabolicmetabolic diseasesdiseases hashas evolvedevolved fromfrom aa limitedlimited numbernumber ofof rare,rare, untreatable,untreatable, oftenoften fatalfatal disordersdisorders toto aa fieldfield ofof acutelyacutely lifelife--threateningthreatening but,but, forfor aa substantialsubstantial number,number, treatabletreatable diseases.diseases. InbornInborn ErrorsErrors ofof MetabolismMetabolism EarlyEarly recognitionrecognition andand promptprompt treatmenttreatment remainremain critical.critical. EarlyEarly signssigns andand symptomssymptoms areare oftenoften veryvery nonnon--specific.specific. EpisodesEpisodes ofof metabolicmetabolic decompensationdecompensation cancan leadlead toto irreversibleirreversible neurologicneurologic impairment.impairment. ExpandedExpanded NewbornNewborn Screening:Screening: ChangingChanging thethe FaceFace ofof InbornInborn ErrorsErrors ofof MetabolismMetabolism RobertRobert Grier,Grier, PhDPhD – History and Future of NBS in MI – Tandem Mass Spectrometry MichiganMichigan NewbornNewborn ScreeningScreening HistoryHistory 1965 1993 – Phenylketonuria – Congenital Adrenal Hyperplasia 1977 2003 – Congenital Hypothyroidism – Medium Chain Acyl-Coenzyme A Dehydrogenase Deficiency 1984 (MCAD) – Galactosemia 2004 1987 – Homocystinuria – Biotinidase Deficiency – Citrullinemia – Maple Syrup Urine Disease – Argininosuccinic Aciduria – Hemoglobinopathies – Tyrosinemia 2005 – Expanded Screening Pilot ScreeningScreening RecommendationsRecommendations InitialInitial screenscreen atat 2424--3636 hourshours ofof ageage TestTest beforebefore dischargedischarge oror transfertransfer regardlessregardless ofof ageage – Follow directions on Early Specimen letter from the State Laboratory regarding repeat specimens TestTest beforebefore transfusiontransfusion ofof redred bloodblood cellscells oror thethe administrationadministration ofof TPNTPN SpecificSpecific screeningscreening guidelinesguidelines forfor NICUNICU populationpopulation TandemTandem MassMass SpectrometrySpectrometry (MS/MS)(MS/MS) Molecules are detected by measuring their weight Can test for many disorders with a single blood spot Shorter run times per sample Additional disorders added at a relatively low cost NewbornNewborn ScreeningScreening TodayToday TandemTandem MassMass SpectrometrySpectrometry – Fatty Acid Disorders MCAD, VLCAD, LCHAD, GA 11, etc. – Amino Acid Disorders PKU, MSUD, TYR, CIT, ASA, etc. – Organic Acid Disorders PA, MMA, IVA, GA1, 3MCC, etc. TandemTandem MSMS ofof AminoAmino AcidsAcids Challenge:Challenge: – Analyze 9 amino acids from a few µL of blood that is dried on filter paper. – Analyze 500 specimens per instrument per day. – Minimize False Results No False Negative Results Minimal False Positive Results Diagnosis:Diagnosis: PKUPKU phe Phenylketonuria (PKU) NTL 102, full scan P/T ratio pro gln leu ala val glu met tyr gly asp 130 140 150 160 170 180 190 200 210 220 230 240 250 260 mass / charge TandemTandem MSMS ofof AcylcarnitinesAcylcarnitines Challenge:Challenge: – Analyze 40 + diagnostically important acylcarnitines from a few µL of dried blood on filter paper. – Analyze 500 specimens per instrument per day. – Minimize False Results No False Negative Results Minimal False Positive Results Diagnosis:Diagnosis: MCADMCAD DeficiencyDeficiency 20000 C8 MCAD Deficiency 19000 Homozygous A985G 18000 17000 16000 15000 14000 13000 12000 11000 10000 9000 8000 7000 C16 6000 5000 C10:1 4000 C10 C18:1 C18 C4 3000 C3 C6 2000 1000 C12 C14 280 300 320 340 360 380 400 420 440 460 480 500 mass / charge MS/MSMS/MS InterpretationInterpretation VisualVisual andand QuantitativeQuantitative InterpretationInterpretation – Analyze the abnormal printouts each day by Scientist at the Lansing NBS Lab with initial interpretation – Contact Dr. Grier or Children’s Hospital of MI Geneticist for confirmation of interpretation – Request repeat analysis for newborn specimens that may be borderline, suspicious or unsatisfactory – Determine interpretation for positive data, with referral to Geneticist on-call at Children’s Hospital of MI – Monitor internal standards and response of the MS/MS ExpandedExpanded NewbornNewborn Screening:Screening: ChangingChanging thethe FaceFace ofof InbornInborn ErrorsErrors ofof MetabolismMetabolism AyeshaAyesha Ahmad,Ahmad, MDMD – Process involved in screening and follow-up – Services offered by CHMMC – An overview of IEM’s MichiganMichigan NewbornNewborn ScreeningScreening LawLaw MCLMCL 333.5431333.5431 HighlightedHighlighted Features:Features: NoNo informedinformed consentconsent requiredrequired DepartmentDepartment maymay requirerequire thatthat thethe teststests bebe performedperformed byby thethe departmentdepartment ViolationViolation isis aa misdemeanormisdemeanor FeeFee forfor testingtesting Components of Program Hospitals Families Midwives Medical Home Newborn Screening Follow up Newborn Screening Medical Laboratory Management Services LaboratoryLaboratory ProceduresProcedures SpecimensSpecimens areare testedtested thethe dayday theythey areare receivedreceived – Up to 700 specimens each day PreliminaryPreliminary resultsresults samesame dayday forfor lifelife threateningthreatening disordersdisorders UnsatisfactoryUnsatisfactory specimensspecimens reportedreported thethe samesame dayday theythey areare receivedreceived – All tested and positives reported SpecimenSpecimen RetentionRetention andand DisposalDisposal SpecimensSpecimens areare storedstored forfor 21½21½ years,years, thenthen destroyeddestroyed Parents/legalParents/legal guardiansguardians maymay request:request: – Disposal of a specimen prior to the end of the retention schedule – Use of specimen for forensic, diagnostic or research purposes The Newborn Screening Laboratory screens all Michigan neonates for forty-eight disorders. NOTICE: Effective May 1, 2006, all disorders will be included on the notification of screening results. ACMG/HRSAACMG/HRSA ApprovedApproved NBSNBS PanelPanel Amino Acid Disorders: Phenylketonuria (PKU) Benign hyperphenylalaninemia (HYPER-PHE) Biopterin cofactor biosysnthesis (BIOPT (BS)) Defects of biopterin cofactor regeneration (BIOPT(REG)) Maple syrup disease (MSUD) Homocystinuria Hypermethioninemia (HCY/MET) Citrullinemia (CIT) Citrullinemia Type II (CIT II) Argininosuccinic acidemia (ASA) Tyrosinemia Type I (TYR I) Argininemia (ARG) ACMG/HRSAACMG/HRSA ApprovedApproved NBSNBS PanelPanel Fatty Acid Oxidation Disorders: Carnitine:acylcarnitine translocase deficiency (CACT) Carnitine palmitoyltransferase II deficiency (CPT II) Carnitine uptake defect (CUD) Carnitine palmitoyltransferase I def. (liver) (CPT 1A) Short-chain acyl-CoA dehydrogenase deficiency (SCAD) Glutaric academia type II (GA II) Med.-chain acyl-CoA dehydrogenase deficiency (MCAD) Long-chain L-3-OH acyl-CoA de hydrogenase deficiency (LCHAD) Trifunctional protein def.(LCHAD/TFP) Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) Med.-chain ketoacyl-CoA thiolase deficiency (MCKAT) Med./short-chain L-3-OH acyl-CoA dehydrogenase deficiency (M/SCHAD) Dienoyl-CoA reductase deficiency (DE RED) ACMG/HRSAACMG/HRSA ApprovedApproved NBSNBS PanelPanel Organic Acid Disorders: Isovaleric academia (IVA) 2-Methyl butyryrl-CoA dehydrogenase deficiency (2MBG) 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC) 3-OH 3-CH3 glutaric aciduria (HMG) 3-Methylglutaconic aciduria (3MGA) Beta-ketothiolase deficiency (BKT) Glutaric acidemia type I (GA I) Propionic academia (PA) Methylmalonic acidemia (mutase deficiency) (MUT) Methylmalonic acidemia (Cbl A,B) Methylmalonic acidemia (Cbl C,D) Multiple carboxylase deficiency (MCD) 2-Methyl 3-hydroxy butyric aciduria (2M3HBA) Malonic acidemia (MAL) Isobutyryl-CoA dehydrogenase deficiency (IBG) ACMG/HRSAACMG/HRSA ApprovedApproved NBSNBS PanelPanel Endocrine Disorders: Congenital Adrenal Hyperplasia (CAH) Congenital Hypothyroidism (CH) Enzyme Disorders: Galactosemia (GALT) Biotinidase Deficiency (BIOT) Hemoglobinopathies: Sickle cell anemia (Hb SS) Hb S/C Disease (Hb S/C) Hb S/Beta-thalassemia (Hb S/Beta-Th) Variant Hb-pathies (Var Hb) FollowFollow--UpUp PositivePositive resultsresults areare followedfollowed upup withwith aa repeatrepeat screeningscreening testtest oror promptprompt referralreferral toto medicalmedical managementmanagement Telephone/faxTelephone/fax notificationnotification withwith instructionsinstructions toto locallocal physicianphysician NegativeNegative resultsresults sentsent toto hospitalhospital – Hospital forwards the “Physician copy” to physician documented on the NBS card – Hospital places “Submitter copy” in the infant’s medical record MedicalMedical
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