Newborn screening and disease variants predict neurological outcome in isovaleric aciduria
Open Access
- 7 February 2021
- journal article
- research article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 44 (4), 857-870
- https://doi.org/10.1002/jimd.12364
Abstract
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean +/- SD, 90.7 +/- 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 +/- 7.1) compared to those without crises (IQ 94.7 +/- 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 +/- 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.Funding Information
- Dietmar Hopp Stiftung (2311221, DH2011117)
- Medizinischen Fakultät Heidelberg, Universität Heidelberg (F.206852)
- Nutricia Research Foundation
This publication has 24 references indexed in Scilit:
- Aspects of Newborn Screening in Isovaleric AcidemiaInternational Journal of Neonatal Screening, 2018
- Newborn Screening Programmes in Europe, Arguments and Efforts Regarding Harmonisation: Focus on Organic AciduriasJIMD Reports, 2016
- Impact of age at onset and newborn screening on outcome in organic aciduriasJournal of Inherited Metabolic Disease, 2015
- The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotypeJournal of Inherited Metabolic Disease, 2015
- Current status of newborn screening worldwide: 2015Seminars in Perinatology, 2015
- Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1 – From blood spot to screening resultJournal of Inherited Metabolic Disease, 2012
- Clinical and neurocognitive outcome in symptomatic isovaleric acidemiaOrphanet Journal of Rare Diseases, 2012
- Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *Orphanet Journal of Rare Diseases, 2011
- Expanded Newborn Screening for Inborn Errors of Metabolism by Electrospray Ionization-Tandem Mass Spectrometry: Results, Outcome, and ImplicationsPEDIATRICS, 2003
- Isovaleric acidemia: a new genetic defect of leucine metabolism.Proceedings of the National Academy of Sciences of the United States of America, 1966