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A Review of Newborn Screening for VLCADD: The Wisconsin Experience
Breanna Mitchell1, Jessica Scott-Schwoerer2, Ashley Kuhl3
1Department of Clinical Genomics, Mayo Clinic Health System, Eau Claire, WI 54720, USA.
Insights
Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) screening in newborns is vital for early detection. New acylcarnitine markers show promise in improving accuracy and reducing false positives in newborn screening for VLCADD.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a metabolic disorder affecting fatty acid metabolism, posing risks of cardiomyopathy, hypoglycemia, and mortality in infants.
- Early detection through newborn screening (NBS) is critical for timely intervention, but challenges exist in differentiating affected infants from carriers due to overlapping biochemical markers.
Purpose of the Study:
- To evaluate the impact of an updated screening algorithm for VLCADD implemented in Wisconsin's NBS program.
- To identify specific acylcarnitine markers that can improve the distinction between true positive VLCADD cases and false positive results, particularly carrier states.
Main Methods:
- Retrospective analysis of VLCADD screen-positive cases from Wisconsin's NBS program between 2000 and 2021.
- Comparison of screening algorithm performance before and after algorithm modification.
- Statistical analysis of specific long-chain acylcarnitine levels (C14:1, C14:1/C16, C14:1/C2) to identify differentiating markers.
Main Results:
- Following algorithm changes, the false positive rate for VLCADD screening decreased from 25.3% to 20.4% between 2015 and 2021.
- The overall positive predictive value (PPV) decreased from 37.2% to 28%, attributed to a significant increase in identified carriers (from 27.5% to 51.8%).
- Three acylcarnitine elevations (C14:1, C14:1/C16, C14:1/C2) demonstrated statistically significant differences between true positive and false positive populations.
Conclusions:
- The updated screening algorithm has reduced false positives but also lowered PPV due to increased carrier detection.
- Specific acylcarnitine markers (C14:1, C14:1/C16, C14:1/C2) hold potential for enhancing the accuracy of VLCADD newborn screening.
- Further utilization of these markers could improve the distinction between affected infants and carriers, thereby increasing the PPV of the NBS for VLCADD.
Abstract:
Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is due to a defect in metabolism of long-chain fatty acids. Infants with VLCADD may experience cardiomyopathy, hypoglycemia, or even death; thus, early detection and intervention is crucial. The spectrum of disease and natural variation in newborn metabolism, however, lead to overlap in acylcarnitine values between affected and unaffected individuals, which contributes to the difficulty in identifying true positive cases while minimizing false positive cases. VLCADD was added to the state of Wisconsin's newborn screening (NBS) panel in 2000. A previous retrospective review of VLCADD screen positive cases identified between 2000 and 2014 resulted in a change to the screening algorithm. Following implementation, a reduction in the percentage of false positive screens from 25.3% to 20.4% was observed between 2015 and 2021. The overall PPV also decreased, from 37.2% to 28%, due to an increase in the number of carriers identified (27.5% of cases in 2000-2014 and 51.8% of cases in 2015-2021). A data review also identified three long-chain acylcarnitine elevations (C14:1, C14:1/C16, and C14:1/C2) that had statistically significant differences in concentrations in true positive populations versus false positive populations. Utilization of the C14:1, C14:1/C16, and C14:1/C2 values in newborn screening may provide clearer distinction between true positive and carrier populations and additionally increase the PPV of this screen.
