Severe Neonatal Manifestations of Infantile Liver Failure Syndrome Type 1 Caused by Cytosolic Leucine-tRNA Synthetase Deficiency

Abstract

Background: Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24 months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented.

Case Report: We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient.

Conclusion: This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.

Appendices

Details of the Contributions of Individual Authors

Christina M. Peroutka, Jacqueline L. Salas, Juliet Bishop, and Jacquelyn F. Britton contributed to collection, analyses, and interpretation of data and drafting the article. W. Christopher Golden, Maureen M. Gilmore, Lisa Kratz, Jill A. Fahrner, and Tao Wang contributed to conception and design, data analysis and interpretation, and drafting the article or revising it critically for important intellectual content.

All authors read and approved the final manuscript.

Details of Funding

C.M.P. and J.C.B. are supported by NIH grant T32GM007471 awarded to the Johns Hopkins University.

Ethics Statement

This study is in accordance with the ethical standards of the responsible conduct on human subject research (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.

Parental Consent

The authors obtained parental consent to use protected health information presented in this report.

Synopsis

The triad of congenital anemia, prenatal and postnatal growth restriction, and severely impaired liver synthetic functions are early neonatal manifestation of infantile liver failure syndrome 1 caused by a deficiency of cytosolic leucine-tRNA synthetase.

Compliance with Ethics Guidelines

Christina Peroutka, Jacqueline Salas, Jacquelyn Britton, Juliet Bishop, Lisa Kratz, Maureen M. Gilmore, Jill Fahrner, W. Christopher Golden, and Tao Wang declare that they have no conflict of interest.