title: RARS2 mutations in a sibship with infantile spasms.
abstract: Pontocerebellar hypoplasia is a group of heterogeneous neurodevelopmental disorders characterized by reduced volume of the brainstem and cerebellum. We report two male siblings who presented with early infantile clonic seizures, and then developed infantile spasms associated with prominent isolated cerebellar hypoplasia/atrophy on magnetic resonance imaging (MRI). Using whole exome sequencing techniques, both were found to be compound heterozygotes for one previously reported and one novel mutation in the gene encoding mitochondrial arginyl-tRNA synthetase 2 (RARS2). Mutations in this gene have been classically described in pontocerebellar hypoplasia type six (PCH6), a phenotype characterized by early (often intractable) seizures, profound developmental delay, and progressive pontocerebellar atrophy. The electroclinical spectrum of PCH6 is broad and includes a number of seizure types: myoclonic, generalized tonic-clonic, and focal clonic seizures. Our report expands the characterization of the PCH6 disease spectrum and presents infantile spasms as an associated electroclinical phenotype.
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Programme, UCL-Institute of Child Health, London, United Kingdom.|Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Adeline
authors.initials: A
authors.lastname: Ngoh
authors.affiliation: Department of Molecular Neuroscience, UCL-Institute of Neurology, London, United Kingdom.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.affiliation: Department of Molecular Neuroscience, UCL-Institute of Neurology, London, United Kingdom.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, U.S.A.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Programme, UCL-Institute of Child Health, London, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Programme, UCL-Institute of Child Health, London, United Kingdom.|Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: McTague
authors.affiliation: Department of Paediatric Neurology, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Dawson
authors.affiliation: Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Mankad
authors.affiliation: Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Roxana
authors.initials: R
authors.lastname: Gunny
authors.affiliation: Genetics and Genomic Medicine Programme, UCL-Institute of Child Health, London, United Kingdom.|Metabolic Medicine Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.affiliation: Genetics and Genomic Medicine Programme, UCL-Institute of Child Health, London, United Kingdom.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Department of Neurophysiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Thornton
authors.affiliation: Department of Neurophysiology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.
authors.forename: Ming
authors.initials: M
authors.lastname: Lai
authors.affiliation: Department of Paediatric Neurology, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.|Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0002-5657-4180
authors.initials: R
authors.lastname: Forsyth
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Programme, UCL-Institute of Child Health, London, United Kingdom.|Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
mesh_terms: D001126:Arginine-tRNA Ligase / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D035781:Siblings; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: D001126:Arginine-tRNA Ligase; C000604250:RARS2 protein, human
keywords: Infantile spasms; Pontocerebellar hypoplasia type 6; RARS2; Whole exome sequencing