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

Abstract

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.

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Fig. 1: Localization of LARS1 variants and most prevalent clinical findings in the study cohort.
Fig. 2: Enzyme activity and protein expression of LARS1 at 37 °C and 40 °C.

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Acknowledgements

We thank all the individuals involved in the study for their participation. We thank Selina Wächter for excellent technical assistance as well as Ina Ellrichmann and Martina Kohl for supporting data collection. C.S. is supported by the Dietmar Hopp Foundation, St. Leon-Rot, Germany (grant number 23011235). D.L. is supported by the Deutsche Leberstiftung (grant number S163/10052/2018). Additionally, this work was supported by the German Federal Ministry of Education and Research (BMBF) through the E-Rare project GENOMIT (01GM1603 to H.P.). T.B.H. was supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, grant number 418081722). Furthermore, this work was supported in part by the National Institutes of Health, National Institute of Neurologic Disorders and Stroke (R35 NS105078) and a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor‐Hopkins Center for Mendelian Genomics (UM1 HG006542) to J.R.L. J.E.P. is supported by NHGRI (K08 HG008986).

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Correspondence to Christian Staufner MD.

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J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals and Novartis, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting, and is on the Scientific Advisory Board of Baylor Genetics (BG). The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical genomic sequencing offered at BG (http://bmgl.com). The other authors declare no conflicts of interest.

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Lenz, D., Smith, D.E.C., Crushell, E. et al. Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1. Genet Med (2020). https://doi.org/10.1038/s41436-020-0904-4

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Keywords

  • LARS1
  • infantile liver failure syndrome type 1
  • acute liver failure
  • aminoacyl-tRNA synthetase deficiency
  • metabolic stroke