Retrospective review of positive newborn screening results for Isovaleric Acidemia and development of a strategy to improve the efficacy of newborn screening in the UK

Carling, Rachel S., Hedgethorne, Katy, Chakrapani, Anupam, Hall, Patricia L., Flynn, Nick, Greenfield, Toby, Moat, Stuart J., Ssali, Joshua, Shakespeare, Lynette, Taj, Nazia, Wu, Teresa H. Y., Anderson, Mark, Ghosh, Arunabha, Lemonde, Hugh, Pierre, Germaine, Sharrard, Mark, Sreekantam, Sreevidya and Bonham, James R. 2024. Retrospective review of positive newborn screening results for Isovaleric Acidemia and development of a strategy to improve the efficacy of newborn screening in the UK. International Journal of Neonatal Screening 10 (1) , 24. 10.3390/ijns10010024

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Abstract

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0–9.6) and 4.0 (1.8–>70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in ‘asymptomatic’ individuals (n = 17), demonstrating a median (range) C5C of 3.0 (1.8–7.1) whilst ‘clinically affected’ patients (n = 7), showed a median (range) C5C of 13.9 (7.7–70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and <5.0 µmol/L prompting second-tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	MDPI
Date of First Compliant Deposit:	8 April 2024
Date of Acceptance:	4 March 2024
Last Modified:	08 Apr 2024 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/167795

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