The diagnostic challenge of mild citrulline elevation at newborn screening

Mol Genet Metab. 2022 Apr;135(4):327-332. doi: 10.1016/j.ymgme.2022.02.008. Epub 2022 Feb 20.


Citrulline is a target analyte measured at expanded newborn screening (NBS) and its elevation represents a biomarker for distal urea cycle disorders and citrin deficiency. Altered ratios of citrulline with other urea cycle-related amino acids are helpful for the differential diagnosis. However, the use of cut-off values in screening programmes has raised the issue about the interpretation of mild elevation of citrulline levels detected at NBS, below the usual range observed in the "classical/severe" forms of distal urea cycle disorders and in citrin deficiency. Herein, we report ten subjects with positive NBS for a mild elevation of citrulline (<100 μmol/L), in whom molecular investigations revealed carriers status for argininosuccinate synthase deficiency, a milder form of argininosuccinate lyase deficiency and two other diseases, lysinuric protein intolerance and dihydrolipoamide dehydrogenase deficiency, not primarily affecting the urea cycle. To guide the diagnostic process, we have designed an algorithm for mild citrulline elevation (<100 μmol/L) at NBS, which expands the list of disorders to be included in the differential diagnosis.

Keywords: Citrulline; Dihydrolipoamide_dehydrogenase_deficiency; Expanded_Newborn_Screening; Lysinuric_Protein_Intolerance; Urea_Cycle_disorders.

MeSH terms

  • Citrulline*
  • Citrullinemia
  • Humans
  • Infant, Newborn
  • Neonatal Screening
  • Urea
  • Urea Cycle Disorders, Inborn* / diagnosis
  • Urea Cycle Disorders, Inborn* / genetics


  • Citrulline
  • Urea

Supplementary concepts

  • Adult-onset citrullinemia type 2