A Novel Citrin Deficiency Mutation in a Cholestatic Infant

To the Editor: Although certain causes of neonatal cholestasis, such as biliary atresia, are well known and promptly excluded, the cholestasis differential is vast, including numerous, less well-recognized genetic-metabolic disorders. Physicians need to be aware of this important disease category owing to significant health implications and potential interventions. As an example, we evaluated a cholestatic infant eventually found to have a novel citrin deficiency mutation. The patient, a term Chinese girl with elevated citrulline on the Quebec newborn urinary screen, was admitted at 2 months for progressive jaundice. Investigations revealed cholestasis, transaminitis, positive urinary reducing substances, coagulopathy, elevated ammonia and lactate, and low glucose. Plasma amino acid determination showed increased citrulline, threonine, serine (with elevated threonine-to-serine ratio), methionine, tyrosine, and arginine, with similar urinary elevations. Alpha-fetoprotein was measured only at 8 months (normal). SLC25A13 gene analysis revealed a paternally inherited known deleterious mutation reported in type II citrullinemia, c.1638_1660dup23 (p.A554GfsX16) (1), and 2 maternally inherited heterozygous novel unclassified variants, c.1046T>C (p.I349T) and c.1067T>A (p.M356K). The highly conserved nature of the amino acids in these variants suggested deleteriousness. The patient responded promptly to a galactose-free, low-carbohydrate, and protein-/lipid-rich diet; within 1 week, citrulline, bilirubin, and liver enzymes dropped substantially and normalized by 6 months. Although most common in east Asia, citrin deficiency is recognized to be panethnic. (2) It is an important consideration in the cholestatic infant, even in North America. Physicians need to include basic metabolic investigations, namely plasma amino acids, urine organic acids, and acylcarnitine profile in the evaluation of neonatal cholestasis. Acknowledgment The authors thank the patient's parents for allowing their child to be featured.