title: Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.
abstract: OBJECTIVE
  Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder.
  
  
  OBJECTIVE
  To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations.
  
  
  METHODS
  In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016.
  
  
  METHODS
  Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity.
  
  
  RESULTS
  Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP.
  
  
  CONCLUSIONS
  This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, England2The Leonard Wolfson Experimental Neurology Centre, University College London Institute of Neurology, London, England.
authors.forename: David S
authors.initials: DS
authors.lastname: Lynch
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, England3Department of Neurology, Royal Free Hospital, London, England.
authors.forename: Wei Jia
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Rahul
authors.initials: R
authors.lastname: Lakshmanan
authors.affiliation: Dementia Research Centre, Department of Neurodegeneration, The National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, England6University College Dublin, Department of Neurology, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Kinsella
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Günes Altiokka
authors.initials: GA
authors.lastname: Uzun
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Merih
authors.initials: M
authors.lastname: Karbay
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tüfekçioglu
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Hasmet
authors.initials: H
authors.lastname: Hanagasi
authors.affiliation: Department of Neurology, Queen Alexandra Hospital, Portsmouth, England9Wessex Neurological Centre, University Hospital Southampton, Southampton, England.
authors.forename: Georgina
authors.initials: G
authors.lastname: Burke
authors.affiliation: Wessex Clinical Genetics Services, Princess Anne Hospital, Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, England.
authors.forename: Nicola
authors.initials: N
authors.lastname: Foulds
authors.affiliation: Department of Neurology, Queen Alexandra Hospital, Portsmouth, England.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Hammans
authors.affiliation: Department of Neurology, Royal Free Hospital, London, England.
authors.forename: Anupam
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: Department of Neurology, Royal Free Hospital, London, England.
authors.forename: Heather
authors.initials: H
authors.lastname: Wilson
authors.affiliation: Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.affiliation: Clinical Neurosciences, Clinical & Experimental Sciences, University of Southampton, Department of Cellular Pathology, Southampton General Hospital, Southampton, England.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.affiliation: Clinical Neurosciences, Clinical & Experimental Sciences, University of Southampton, Department of Cellular Pathology, Southampton General Hospital, Southampton, England.
authors.forename: James A R
authors.initials: JA
authors.lastname: Nicoll
authors.affiliation: Department of Neuroinflammation, University College London Institute of Neurology, London, England.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chataway
authors.affiliation: Dementia Research Centre, Department of Neurodegeneration, The National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, England.
authors.forename: Nick
authors.initials: N
authors.lastname: Fox
authors.affiliation: Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Indran
authors.initials: I
authors.lastname: Davagnanam
authors.affiliation: Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, England.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: Department of Molecular Neuroscience, University College London Institute of Neurology, London, England14Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000328:Adult; D000412:Alanine-tRNA Ligase / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000473:pathology*; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D000412:Alanine-tRNA Ligase