title: Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2.
abstract: Pontocerebellar hypoplasia type 6 (PCH6) (MIM #611523) is a recently described disorder caused by mutations in RARS2 (MIM *611524), the gene encoding mitochondrial arginyl-transfer RNA (tRNA) synthetase, a protein essential for translation of all mitochondrially synthesised proteins. This case confirms that progressive cerebellar and cerebral atrophy with microcephaly and complex epilepsy are characteristic features of PCH6. Additional features of PCH subtypes 2 and 4, including severe dystonia, optic atrophy and thinning of the corpus callosum, are demonstrated. Congenital lactic acidosis can be present, but respiratory chain dysfunction may be mild or absent, suggesting that disordered mitochondrial messenger RNA (mRNA) translation may not be the only mechanism of impairment or that a secondary mechanism exists to allow some translation. We report two novel mutations and expand the phenotypic spectrum of this likely underdiagnosed PCH variant, where recognition of the characteristic neuroradiological phenotype could potentially expedite genetic diagnosis and limit invasive investigations.
authors.affiliation: Department of Metabolic Medicine, Great Ormond Street Hospital for Children, London, UK. eglamuzina@adhb.govt.nz
authors.forename: Emma
authors.initials: E
authors.lastname: Glamuzina
authors.forename: Ruth
authors.initials: R
authors.lastname: Brown
authors.forename: Kieran
authors.initials: K
authors.lastname: Hogarth
authors.forename: Dawn
authors.initials: D
authors.lastname: Saunders
authors.forename: Isabelle
authors.initials: I
authors.lastname: Russell-Eggitt
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.forename: Carlos
authors.initials: C
authors.lastname: de Sousa
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Garry
authors.initials: G
authors.lastname: Brown
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grunewald
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D001126:Arginine-tRNA Ligase / Q000235:genetics*; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics; D002675:Child, Preschool; D004579:Electron Transport; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009849:Olivopontocerebellar Atrophies / Q000235:genetics*; D010641:Phenotype; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D000604:Amino Acyl-tRNA Synthetases; D001126:Arginine-tRNA Ligase
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