Article Text

Download PDFPDF

Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era
  1. David S Lynch1,2,
  2. Charles Wade2,
  3. Anderson Rodrigues Brandão de Paiva3,
  4. Nevin John4,
  5. Justin A Kinsella5,
  6. Áine Merwick6,
  7. Rebekah M Ahmed7,
  8. Jason D Warren8,
  9. Catherine J Mummery8,
  10. Jonathan M Schott8,
  11. Nick C Fox8,
  12. Henry Houlden1,
  13. Matthew E Adams9,
  14. Indran Davagnanam9,10,
  15. Elaine Murphy11,
  16. Jeremy Chataway4
  1. 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  2. 2 Department of Neurology, Royal Free Hospital, London, UK
  3. 3 Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  4. 4 Department of Neuroinflammation, UCL Institute of Neurology, London, UK
  5. 5 Department of Neurology, St Vincent's University Hospital University College Dublin, Dublin, Ireland
  6. 6 Department of Neurology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
  7. 7 Memory and Cognition Clinic, Department of Clinical Neurosciences, Royal Prince Alfred Hospital and the Brain and Mind Centre, University of Sydney, Camperdown, New South Wales, Australia
  8. 8 Dementia Research Centre, UCL Institute of Neurology, London, UK
  9. 9 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK
  10. 10 Brain Repair & Rehabilitation, UCL Institute of Neurology, London, UK
  11. 11 Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery Queen Square, London, UK
  1. Correspondence to Dr David S Lynch, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK; david.lynch.13{at}


Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R, AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.

  • neurogenetics
  • neuroradiology
  • dementia
  • adrenoleukodystrophy
  • movement disorders

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

View Full Text

Statistics from


  • Contributors DSL, CW, ARBdP, NJ ciritically reviewed the literature and drafted the manuscript. JAM, AM, RMA, CJM, JDW, JMS, NCF, HH, MEA, ID, EM, JC critically reviewed and edited the manuscript. DSL, JC devised and oversaw the study.

  • Funding We would like to gratefully acknowledge our funders, which include the Leonard Wolfson Experimental Neurology Centre, the UK NIHR UCL/UCLH Biomedical Research Centre, the Wellcome Trust and the Medical Research Council.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Ethical approval was not required for this study, which did not involve human participants or their data.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement There are no additional unpublished data.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.