title: 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.
abstract: 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.
authors.affiliation: Starship Children's Hospital, Auckland, New Zealand.
authors.forename: Bryony
authors.initials: B
authors.lastname: Ryder
authors.affiliation: Newborn Metabolic Screening Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Detlef
authors.initials: D
authors.lastname: Knoll
authors.affiliation: Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Love
authors.affiliation: Auckland Uniservices Ltd Grafton, Auckland, New Zealand.
authors.forename: Phillip
authors.initials: P
authors.lastname: Shepherd
authors.affiliation: Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Love
authors.affiliation: Children's Research Centre, Starship Children's Health, Auckland, New Zealand.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reed
authors.affiliation: Newborn Metabolic Screening Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Mark
authors.initials: M
authors.lastname: de Hora
authors.affiliation: Newborn Metabolic Screening Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Dianne
authors.initials: D
authors.lastname: Webster
authors.affiliation: National Metabolic Service, Starship Children's Hospital, PO Box 92024, Auckland, New Zealand.
authors.forename: Emma
authors.initials: E
authors.lastname: Glamuzina
authors.affiliation: National Metabolic Service, Starship Children's Hospital, PO Box 92024, Auckland, New Zealand. callumw@adhb.govt.nz.
authors.forename: Callum
authors.initials: C
authors.lastname: Wilson
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000097:blood / Q000172:deficiency*; D002331:Carnitine / Q000097:blood*; D016022:Case-Control Studies; D000080984:Congenital Bone Marrow Failure Syndromes; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D008297:Male; D028361:Mitochondrial Diseases / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D009135:Muscular Diseases / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D015997:Neonatal Screening; D009520:New Zealand; D012189:Retrospective Studies
chemical_list: D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine