25 Ene Glutaric Acidemia Type 1 GeneReview – False Positive and False Negative Results on Newborn Screening 2019
Glutaric Acidemia Type 1 GeneReview – False Positive and False NegativenResults on Newborn Screening
Title: Glutaric Acidemia Type 1 GeneReview – False Positive and False Negative
Results on Newborn Screening
Authors: Larson A, Goodman S
Initial posting: August 2019
False positive newborn screening (NBS) results (elevated C5DC levels in an infant
who does not have glutaric acidemia type 1 [GA-1]) can result from any one of the
following in descending order of likelihood:
Regional laboratory-specific variations in cutoff levels for C5DC
Renal insufficiency [Hennermann et al 2009]
Elevations in hydroxydecanoylcarnitine (C10-OH) due to multiple acyl-CoA
dehydrogenase (MADD) deficiency or medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Note: C10-OH and C5DC have almostidentical molecular weights and are indistinguishable on plasma acylcarnitine profiling (when the esters are usually butylated) in contrast to the dried blood spots used in NBS [Chace et al 2003]. Note that the addition of multiple analyte monitoring to tandem mass spectrometry (MS/MS) has increased the sensitivity of C5DC on NBS and reduced the rate of false-positive results[German Society for Newborn Screening 2015].
Maternal GA-1 is a consideration when both NBS and initial follow-up testing show increased C5DC and/or depleted free carnitine, but subsequent biochemical testing is normal. Note: When the mother has GA-1, the infant’s C5DC is expected to normalize in the first few weeks of life [Crombez et al 2008]. Confirmatory testing (GCDH molecular genetic testing or glutaryl-CoA dehydrogenase analysis) is normal in the infant and abnormal (diagnostic) in the mother.
False negative NBS results (i.e., normal or only slightly increased C5DC levels in an infant who has GA-1) can result when:
Infants have substantial residual enzyme activity (see Genotype-Phenotype Correlations);
Infants have extremely depleted carnitine reserves, such as in maternal or infantile carnitine transporter deficiency.