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

01. November, 2020

Dominic Lenz1, Desirée E C Smith2, Ellen Crushell3, Ralf A Husain4, Gajja S Salomons2, Bader Alhaddad5, Jonathan A Bernstein6,7, Alyssa Bianzano1, Saskia Biskup8,9, Heiko Brennenstuhl1, Dominique Caldari10, Nicola Dikow11, Tobias B Haack12,13, Andrea Hanson-Kahn14,15, Inga Harting16, Denise Horn17, Joanne Hughes3, Maya Huijberts18, Bertrand Isidor19,20, Simone Kathemann21, Robert Kopajtich5,22, Urania Kotzaeridou1, Sébastien Küry19,20, Elke Lainka21, Lucia Laugwitz12,23, James R Lupski24,25,26, Jennifer E Posey24, Claire Reynolds3, Jill A Rosenfeld24,27, Julian Schröter1, Fleur Vansenne28, Matias Wagner5,22,29, Claudia Weiß30, Bruce H R Wolffenbuttel18, Saskia B Wortmann5,22,31, Stefan Kölker1, Georg F Hoffmann1, Holger Prokisch5,22, Marisa I Mendes2,Christian Staufner32.


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.