Direct Prediction of VLCADD Severity Using Newborn Screening Analyte Data

Area of Science:

• Biochemistry
• Genetics
• Neonatal Medicine

Background:

• Newborn screening (NBS) for very-long chain acyl-CoA dehydrogenase deficiency (VLCADD) faces challenges in predicting clinical outcomes.
• Accurate prediction of disease severity is crucial for timely and appropriate patient management.

Purpose of the Study:

• To investigate neonatal C18:2-carnitine concentrations as a predictor of VLCADD phenotype and clinical severity.
• To analyze the impact of sex, gestational age, sampling day, and birth weight on C18:2-carnitine levels.

Main Methods:

• Analysis of NBS-dried blood spots (DBS) from a large cohort of Dutch newborns (n=209,785) to assess C18:2-carnitine.
• Investigation of C18:2-carnitine in NBS-DBS and plasma of VLCADD patients (Dutch and German cohorts).
• Correlation of normalized C18:2-carnitine concentrations with clinical severity and diagnostic assays.

Main Results:

• C18:2-carnitine concentrations are influenced by gestational age, sampling day, birth weight, and sex.
• Normalized high C18:2-carnitine reliably identified VLCADD patients with severe phenotypes.
• Linoleylcarnitine was identified as the specific differentiating C18:2-carnitine marker.

Conclusions:

• Neonatal C18:2-carnitine concentrations serve as a reliable predictor of disease severity immediately following a positive NBS for VLCADD.
• High C18:2-carnitine identifies severe VLCADD cases requiring strict dietary management and monitoring.
• Low C18:2-carnitine suggests milder VLCADD cases amenable to preventive dietary measures.