title: Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.
abstract: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders.
  
  
  
  To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant.
  
  
  
  An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015.
  
  
  
  The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants.
  
  
  
  Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes.
  
  
  
  The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Ewen W
authors.initials: EW
authors.lastname: Sommerville
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Yi Shiau
authors.initials: YS
authors.lastname: Ng
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Gilberti
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Knowles
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Chin
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schaefer
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Gavin
authors.initials: G
authors.lastname: Falkous
authors.affiliation: Department of Cardiology, Queen Elizabeth University Hospital, Glasgow, Scotland.
authors.forename: David
authors.initials: D
authors.lastname: Murdoch
authors.affiliation: West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, Scotland.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.affiliation: Department of Neurology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.affiliation: Department of Clinical Medicine, Department of Clinical Medicine, University of Bergen, Bergen, Norway7Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.affiliation: Department of Medicine, University of Aberdeen, Aberdeen, Scotland (retired).
authors.forename: John M
authors.initials: JM
authors.lastname: Rawles
authors.affiliation: Department of Medical Genetics, Medical School Building, University of Aberdeen, Aberdeen, Scotland.
authors.forename: John C S
authors.initials: JCS
authors.lastname: Dean
authors.affiliation: Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, Scotland.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Petty
authors.affiliation: Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, Scotland.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Farrugia
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany12Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany12Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Donnini
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Gráinne S
authors.initials: GS
authors.lastname: Gorman
mesh_terms: D000140:Acidosis, Lactic / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D000756:Anemia, Sideroblastic / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D009202:Cardiomyopathies / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D004739:England / Q000208:ethnology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D018908:Muscle Weakness / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D011379:Prognosis; D012131:Respiratory Insufficiency / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D012606:Scotland / Q000208:ethnology; D014448:Tyrosine-tRNA Ligase / Q000235:genetics*
chemical_list: D014448:Tyrosine-tRNA Ligase