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Newborn Screening with Acylcarnitines Lynette Shakespeare Clinical - - PowerPoint PPT Presentation
Newborn Screening with Acylcarnitines Lynette Shakespeare Clinical - - PowerPoint PPT Presentation
Newborn Screening with Acylcarnitines Lynette Shakespeare Clinical Scientist February 20 th 2013 Newborn Screening in England l Bloodspot sample at 5 days l PKU l Congenital Hypothyroidism l Cystic Fibrosis l Sickle Cell Disease l MCADD l Pilot
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Expanded Panel
lIVA lGA-1 lLCHADD lMSUD lHomocystinuria
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Expanded Panel
lIVA lGA-1 lLCHADD lMSUD lHomocystinuria
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lLooking at healthy population lWell babies, no clinical suspicions lNot crisis samples
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Screening Acylcarnitine Methodology
l3mm punch from dried bloodspot lElute into methanolic internal standard lUnderivatised MRM for target analytes
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Acylcarnitines by MRM for:
C16:OH (416→85) LCHADD C5DC (276→85) GA-1 C5 (246→85) IVA C10 (316→85) C8 (288→85) MCADD Secondary analyte Primary analyte Condition
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Screening cut-offs
lMaximise case detection lMinimise false positives lCut-offs much higher than population normal values
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Population and screening values
0.05 0.15 0.01 C16OH 0.3 n/a 0.07 C10 0.3 0.50* + ratio >1.0 0.06 C8 0.1 0.70 0.11 C5DC 0.6 1.00 0.10 C5 Metabolic lab ULN Screen cut-off Population mean Analyte * Local variation – all C8 >1.0 referred
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Positive sample follow up
lRepunch in duplicate (underiv MRM) lElevated result refuted
¡Investigate cause of spurious elevation
lElevated result confirmed
¡Full acylcarnitine scan (underiv) ¡Clinical referral – screening specialist nurse involvement
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Diagnostic testing
ACCRN, OA, DNA if biochem normal/equiv GA1 ACCRN, OA, DNA (G1528C), enzyme LCHADD ACCRN, OA, benign mutation IVA ACCRN, OA, DNA (G985) MCADD Diagnostic Testing Disorder
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Positive predictive values
100% 100% 100% Sensitivity 50% LCHADD 42% GA1 30% IVA 80%* MCADD PPV Screen * 2005 value before ratio included in protocol
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MCADD screening
lScreen pilot began 2004 l6 centres covering 300,000 births lInitially C8 and C0 lNow C8 and C10 – ratio involved in referral decision lFull implementation in England from 2009
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MCADD: what we’ve learnt
lCarriers lMAD (GA2) l288 interference lEarly samples lAsymptomatic patients lUncertain significance of screening- associated mutations
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Expanded Panel
lPilot began in July 2012 l6 labs included
- lApprox. 430,000 babies
lRuns until July 2013 lAnticipate 18-20 true positives lExtension until March 2014 to allow evaluation to be completed lStill a learning curve
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IVA
l4 referrals so far lPotential pitfalls:
¡Antibiotics ¡SBCAD ¡GA2
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GA1
lNo referrals so far lC6-OH interference - confirm elevated level by derivatised scan
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LCHADD
l1 case so far – sib identified before screening lNormal values on treatment
¡(Screen C16:OH 0.13 – cut-off at time was slightly higher)
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lhttp://www.expandedscreening.org/home/ disorder-lchadd-video.asp
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