Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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.

Rachel S Carling
* ,
Katy Hedgethorne
,
Anupam Chakrapani
,
Patricia L Hall
,
Nick Flynn
ORCID logo ,
Toby Greenfield
,
Stuart J. Moat
ORCID logo ,
Joshua Ssali
,
Lynette Shakespeare
,
Nazia Taj
,
Mark Anderson
,
Teresa H.Y. Wu
ORCID logo ,
Arunabha Ghosh
,
Hugh Lemonde
,
Germaine Pierre
,
Mark Sharrard
,
Sreevidya Sreekantam
,
James R Bonham
ORCID logo
Version 1 : Received: 23 January 2024 / Approved: 24 January 2024 / Online: 24 January 2024 (09:54:13 CET)

A peer-reviewed article of this Preprint also exists.

Carling, R.S.; Hedgethorne, K.; Chakrapani, A.; Hall, P.L.; Flynn, N.; Greenfield, T.; Moat, S.J.; Ssali, J.; Shakespeare, L.; Taj, N.; Wu, T.H.; Anderson, M.; Ghosh, A.; Lemonde, H.; Pierre, G.; Sharrard, M.; Sreekantam, S.; Bonham, J.R. 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. Int. J. Neonatal Screen. 2024, 10, 24. Carling, R.S.; Hedgethorne, K.; Chakrapani, A.; Hall, P.L.; Flynn, N.; Greenfield, T.; Moat, S.J.; Ssali, J.; Shakespeare, L.; Taj, N.; Wu, T.H.; Anderson, M.; Ghosh, A.; Lemonde, H.; Pierre, G.; Sharrard, M.; Sreekantam, S.; Bonham, J.R. 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. Int. J. Neonatal Screen. 2024, 10, 24.

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 2015-22 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 2nd tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder.

Keywords

isovaleric acidemia; false positive; newborn screening; inherited metabolic disease.

Subject

Medicine and Pharmacology, Pediatrics, Perinatology and Child Health

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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