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Title: Infantile-onset Myoclonic Developmental and Epileptic Encephalopathy: a new RARS2 phenotype.
Austin Authors: de Valles-Ibáñez, Guillem;Hildebrand, Michael S ;Bahlo, Melanie;King, Chontelle;Coleman, Matthew;Green, Timothy E;Goldsmith, John;Davis, Suzanne;Gill, Deepak;Mandelstam, Simone;Scheffer, Ingrid E ;Sadleir, Lynette G
Affiliation: Departments of Paediatrics, University of Melbourne and Royal Children's Hospital, Melbourne, VIC, Australia
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Epilepsy Research Centre
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia
The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, Australia
Department of Medical Imaging, Royal Children's Hospital, Melbourne, VIC, Australia
Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Waikids Paediatric Service, Waikato District Health Board, Hamilton, New Zealand
Starship Children's Hospital, Auckland, New Zealand
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Austin Health
Issue Date: 2022
Date: 2021-10-30
Publication information: Epilepsia open 2022; 7(1): 170-180
Abstract: Recessive variants in RARS2, a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early-infantile (<12 weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2 epilepsy phenotypes and variants. Our novel cases had infantile-onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug-resistant generalized and focal seizures occurred with episodes of non-convulsive status epilepticus. Seizure types included absence, atonic, myoclonic and focal seizures. Electroencephalograms showed diffuse slowing, multifocal and generalised spike-wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense-mediated decay. We expand the RARS2 phenotypic spectrum to include infantile encephalopathy, and suggest this gene is enriched for pathogenic variants that disrupt splicing.
DOI: 10.1002/epi4.12553
ORCID: 0000-0001-5132-0774
Journal: Epilepsia Open
PubMed URL: 34717047
Type: Journal Article
Subjects: RARS2
developmental and epileptic encephalopathy
movement disorder
Appears in Collections:Journal articles

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