title: Redefining the phenotype of ALSP andAARS2mutation-related leukodystrophy.
abstract: OBJECTIVE
  To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L), and highlight key differentiating features.
  
  
  METHODS
  ALSP andAARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database.
  
  
  RESULTS
  A combined total of 74 cases of ALSP and 10 cases ofAARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years inAARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive toAARS2-L, present in all known female cases. Both ALSP andAARS2-L showed a confluent, asymmetric, predominantly frontoparietal, periventricular pattern of white matter disease with subcortical U-fiber sparing; pyramidal tract and corpus callosum involvement; and diffusion changes in the white matter which we have termed "deep white matter diffusion dots." Central atrophy and corpus callosal thinning were prominent in ALSP and disproportionately mild inAARS2-L when present. ALSP also occasionally showed ventricular abnormalities and calcifications in the frontal periventricular white matter, features not seen inAARS2-L.AARS2-L demonstrates white matter rarefaction which suppresses on fluid-attenuated inversion recovery MRI sequences, a feature not seen in ALSP.
  
  
  CONCLUSIONS
  ALSP andAARS2-L share similar clinical, imaging, and pathologic characteristics with key differentiating features that we have highlighted.
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Lakshmanan
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Adams
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Lynch
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Kinsella
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chataway
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Lysholm Department of Neuroradiology (R.L., M.E.A., I.D.), the National Hospital for Neurology and Neurosurgery; Department of Molecular Neuroscience (D.S.L., H.H.), UCL Institute of Neurology; the Leonard Wolfson Experimental Neurology Centre (D.S.L., J.A.K.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology; Dementia Research Centre (J.A.K., J.M.S., J.D.R., N.C.F.), Department of Neurodegeneration, UCL Institute of Neurology, UK; Department of Neurology (J.A.K.), St Vincent's University Hospital, University College Dublin, Ireland; Division of Neuropathology and Department of Neurodegenerative Disease (R.P.), Charles Dent Metabolic Unit (E.M.), Department of Neuroinflammation (J.C.), Neurogenetics Laboratory (H.H.), and Department of Brain Repair and Rehabilitation (I.D.), the National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, UK.
authors.forename: Indran
authors.initials: I
authors.lastname: Davagnanam