Abstract
Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80% of them surpassed +3 SD (standard deviation), all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS.
Highlights
Citrin is an aspartate-glutamate carrier found in the mitochondrial membrane and a deficiency was initially found to cause adult-onset type II citrullinemia (CTLN2; OMIM #603471) [1]
Citrin is encoded by the SLC25A13 gene and its deficiency can manifest in newborns as neonatal intrahepatic cholestasis (NICCD; OMIM #605814) [2,3,4,5]
Since molecular diagnosis became feasible owing to the discovery of prevalent mutations in the SLC25A13 gene in Japan and East Asia [6,7,8], the clinical features are expanding in other pathogenic states in addition to CTLN2 and NICCD
Summary
Citrin is an aspartate-glutamate carrier found in the mitochondrial membrane and a deficiency was initially found to cause adult-onset type II citrullinemia (CTLN2; OMIM #603471) [1]. Citrin is encoded by the SLC25A13 gene (cytogenic location; 7q21.3) and its deficiency can manifest in newborns as neonatal intrahepatic cholestasis (NICCD; OMIM #605814) [2,3,4,5]. Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) is another recognized stage of the disease that is characterized by retarded growth and fatty liver in childhood [9]. The variety of symptoms associated with a lifelong citrin deficiency suggests a need for early diagnosis and treatment to prevent morbidity [11,12]
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