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Neurogenetics
Review
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. 1Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  2. 2Department of Neurology, Royal Free Hospital, London, UK
  3. 3Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  4. 4Department of Neuroinflammation, UCL Institute of Neurology, London, UK
  5. 5Department of Neurology, St Vincent's University Hospital University College Dublin, Dublin, Ireland
  6. 6Department of Neurology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
  7. 7Memory 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. 8Dementia Research Centre, UCL Institute of Neurology, London, UK
  9. 9Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK
  10. 10Brain Repair & Rehabilitation, UCL Institute of Neurology, London, UK
  11. 11Charles 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}ucl.ac.uk

Abstract

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
https://creativecommons.org/licenses/by/4.0/

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: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/jnnp-2018-319481

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    Footnotes

    • 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.

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

    • Data sharing statement There are no additional unpublished data.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.