Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1

Dominic Lenz, Desirée E.C. Smith, Ellen Crushell, Ralf A. Husain, Gajja S. Salomons, Bader Alhaddad, Jonathan A. Bernstein, Alyssa Bianzano, Saskia Biskup, Heiko Brennenstuhl, Dominique Caldari, Nicola Dikow, Tobias B. Haack, Andrea Hanson-Kahn, Inga Harting, Denise Horn, Joanne Hughes, Maya Huijberts, Bertrand Isidor, Simone KathemannRobert Kopajtich, Urania Kotzaeridou, Sébastien Küry, Elke Lainka, Lucia Laugwitz, James R. Lupski, Jennifer E. Posey, Claire Reynolds, Jill A. Rosenfeld, Julian Schröter, Fleur Vansenne, Matias Wagner, Claudia Weiß, Bruce H.R. Wolffenbuttel, Saskia B. Wortmann, Stefan Kölker, Georg F. Hoffmann, Holger Prokisch, Marisa I. Mendes, Christian Staufner*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

Original languageEnglish
Pages (from-to)1863-1873
Number of pages11
JournalGenetics in Medicine
Issue number11
Publication statusPublished - 1 Nov 2020

Cite this