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

Autor: Lenz D; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Smith DEC; Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands., Crushell E; National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street and Crumlin, Dublin, Ireland., Husain RA; Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, Jena, Germany., Salomons GS; Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands., Alhaddad B; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Bernstein JA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA.; Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA., Bianzano A; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Biskup S; CeGaT GmbH, Tübingen, Germany.; Praxis für Humangenetik Tübingen, Tübingen, Germany., Brennenstuhl H; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Caldari D; Service de pédiatrie, CHU Nantes, Nantes, France., Dikow N; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Haack TB; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany., Hanson-Kahn A; Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.; Lucile Packard Children's Hospital, Department of Pediatrics, Division of Medical Genetics, Palo Alto, CA, USA., Harting I; Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany., Horn D; Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany., Hughes J; National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street and Crumlin, Dublin, Ireland., Huijberts M; Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Isidor B; Service de Génétique Médicale, CHU Nantes, Nantes, France.; INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, France., Kathemann S; Children's Hospital, Department of Pediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany., Kopajtich R; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Kotzaeridou U; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Küry S; Service de Génétique Médicale, CHU Nantes, Nantes, France.; INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, France., Lainka E; Children's Hospital, Department of Pediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany., Laugwitz L; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Tübingen, Germany., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Reynolds C; National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street and Crumlin, Dublin, Ireland., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Baylor Genetics Laboratories, Houston, TX, USA., Schröter J; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Vansenne F; Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Wagner M; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany., Weiß C; Department of Neuropediatrics, Sozialpädiatrisches Zentrum (SPZ), Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Germany, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Wolffenbuttel BHR; Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Wortmann SB; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria., Kölker S; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Hoffmann GF; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Prokisch H; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Mendes MI; Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands., Staufner C; Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. Christian.Staufner@med.uni-heidelberg.de.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2020 Nov; Vol. 22 (11), pp. 1863-1873. Date of Electronic Publication: 2020 Jul 23.
DOI: 10.1038/s41436-020-0904-4
Abstrakt: 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.
Databáze: MEDLINE
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