Citrullinemia is the earliest identifiable biochemical abnormality in neonates with\nintrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn\nscreening panels using tandem mass spectrometry. However, only one neonate was positive among\n600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated\n12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by\ntandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial\nNBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although\ntheir citrulline values exceeded the mean of the normal neonates and 80% of them surpassed +3 SD\n(standard deviation), all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino\nacids significantly elevated in patients with NICCD compared to the control. By evaluating two\nindicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an\nestimated index comprising citrulline values and citrulline to total amino acid ratios could assure\nNICCD detection by NBS.
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