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.
- movement disorders
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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Data sharing statement There are no additional unpublished data.
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