Helman G1 2, Mendes MI3, Nicita F4, Darbelli L5 6 7 8, Sherbini O9, Moore T5 6, Derksen A5 6, Pizzino A9, Carrozzo R4, Torraco A4, Catteruccia M4, Aiello C4, Goffrini P10, Figuccia S10, Smith DEC3, Hadzsiev K11, Hahn A12, Biskup S13, Brösse I14, Kotzaeridou U14, Gauck D15, Grebe TA16, Elmslie F17, Stals K18, Gupta R19, Bertini E4, Thiffault I20 21 22, Taft RJ23, Schiffmann R24, Brandl U25, Haack TB15, Salomons GS3, Simons C1 2, Bernard G5 6 7 8, van der Knaap MS26 27, Vanderver A28 29, Husain RA30
Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.
Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts.
Results: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes.
Conclusion: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.
- Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, VIC, Australia.
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
- Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
- Department of Pediatrics, McGill University, Montreal, QC, Canada.
- Department of Human Genetics, McGill University, Montreal, QC, Canada.
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
- Department of Medical Genetics, University of Pécs, Pécs, Hungary.
- Department of Child Neurology, Justus-Liebig-University, Giessen, Germany.
- Praxis fuer Humangenetik and CeGaT GmbH, Tuebingen, Germany.
- Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
- Division of Genetics and Metabolism, Department of Child Health, Phoenix Children’s Hospital, University of Arizona College of Medicine, Phoenix, AZ, USA.
- South West Thames Regional Genetics Service, St George’s University Hospital, London, UK.
- Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
- Department of Neurology, Birmingham Children’s Hospital, Birmingham, UK.
- Children’s Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, MO, USA.
- Department of Pathology and Laboratory Medicine, Children’s Mercy Hospitals, Kansas City, MO, USA.
- School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
- Illumina, Inc, San Diego, CA, USA.
- Baylor Scott & White Research Institute, Dallas, TX, USA.
- Department of Neuropediatrics, Jena University Hospital, Jena, Germany.
- Department of Child Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands.
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. email@example.com.
- Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. firstname.lastname@example.org.
- Department of Neuropediatrics, Jena University Hospital, Jena, Germany. Ralf.Husain@med.uni-jena.de.