The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment
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Very long chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM #201475) has been increasingly diagnosed since the advent of expanded newborn screening (NBS). Elevated levels of tetradecenoyl-L-carnitine (C14:1) in newborn screening blood spot samples are particularly common in New Zealand, however this has not translated into increased VLCADD clinical presentations. A high proportion of screen-positive cases in NZ are of Maori or Pacific ethnicity and positive for the c.1226C > T (p.Thr409Met) ACADVL gene variant. We performed a retrospective, blinded, case–control study of 255 cases, born between 2006 and 2013, with elevated NBS C14:1 levels between 0.9 and 2.4 μmol/L, below the NZ C14:1 notification cut-off of 2.5 μmol/L. Coded healthcare records were audited for cases and age- and ethnicity- matched controls. The clinical records of those with possible VLCADD-related symptoms were reviewed. The follow-up period was 6 months to 7 years. Two of 247 cases (0.8 %) had possible VLCADD-like symptoms while four of 247 controls (2 %) had VLCADD-like symptoms (p = 0.81). Maori were overrepresented (68 % of the cohort vs 15 % of population). Targeted analysis of the c.1226 locus revealed the local increase in screening C14:1 levels is associated with the c.1226C > T variant (97/152 alleles tested), found predominantly in Maori and Pacific people. There was no increase in clinically significant childhood disease, irrespective of ethnicity. The study suggests that children with elevated C14:1, between 0.9-2.4 μmol/L, on NBS are at very low risk of clinically significant childhood disease. A minimally interventional approach to managing these patients is indicated, at least in the New Zealand population.
This study was made possible by funding from the NZ Newborn Screening Unit and an ASIEM small project grant.
Compliance with ethical standards
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).
Conflict of interest
The study was anonymous and informed consent was not required. No identifying information about patients is included in the article. The study received approval from the NZ Ministry of Health National Screening Unit (NSU), the National Health and Disability Ethics Committee and the Auckland District Health Board Research Committee.
- Boneh A et al (2006) VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. Mol Genet and Metab 88:166–70Google Scholar
- Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet. 2.12.1-2.12.18Google Scholar
- Liebig M et al (2006) Neonatal screening for very long-chain acyl-CoA dehydrogenase deficiency: enzymatic and molecular evaluation of neonates with elevated C14:1-carnitine levels. Pediatrics 118:1065Google Scholar
- Ryder B et al (2014) Clinical, molecular and biochemical characteristics of patients with elevated tetradecenoylcarnitine (C14:1) detected by newborn screening in New Zealand: support for a common, likely benign mutation in the Pacific population. Poster (P035) presented at SSIEM 2014 Annual Symposium, September 2–5 Innsbruck, Austria. J Inherit Metab Dis 37(1):27–185Google Scholar
- Spiekerkoetter U et al (2010b) Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr 157:668–73Google Scholar
- Spiekerkoetter et al (2012) Lethal undiagnosed very long-chain acyl-CoA dehydrogenase deficiency with mild C14-acylcarnitine abnormalities on newborn screening. JIMD Reports 2:113–115Google Scholar