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.

Leukoencephalopathies are a diverse group of white matter disorders that can be difficult to diagnose. Using focused and whole-exome sequencing, Lynch et al. expand the known clinical and mutational spectrum of genetic leukoencephalopathy in adulthood, and describe the frequency and clinical and radiological phenotype of the most commonly mutated genes.

Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396) *Drs Rolfs, Fazekas and Grittner contributed equally to this work. Authors contributions: Dr Rolfs has conceptualized, initiated, and designed and organized the study, has been involved in the recruitment of the patients, and wrote significant parts of the manuscript. Dr Fazekas was involved in the study planning and has done together with Drs Enzinger and Schmidt the analysis of all MRI scans; this group was mainly involved in the statistical analysis of the MRI data. Drs Martus, Grittner, Holzhausen have taken responsibility for all statistical analysis and for the data structure of the total data bank. Drs Dichgans, Böttcher, Tatlisumak, Tanislav, Jungehulsing, Putaala, Huber, Bodechtel, Lichy, Hennerici, Kaps, Meyer, Kessler have been most active in the recruitment of the patients, drafting the manuscript and significantly influencing the scientific discussion. Dr Heuschmann was involved in drafting the manuscript and influencing the scientific discussion. Dr Norrving chaired the steering and publication committees of sifap, has written parts of the manuscript, and has significantly influenced the scientific discussions. Drs Lackner and Paschke, H. Mascher, Dr Riess have been involved in the laboratory analyses. Dr Kolodny has mostly contributed to the discussion of the Fabry cases. Dr Giese assisted in writing and editing the manuscript. All authors have reviewed, critically revised and approved the final version of the manuscript.The sponsors of the study had no role in the study design, data collection, data analysis, interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. The academic authors had unrestricted access to the derived dataset, and assume full responsibility for the completeness, integrity, and interpretation of the data, as well as writing the study report and the decision to submit for publication.†Listed in Appendix I in the online-only Data Supplement. Jeffrey L. Saver, MD, was guest editor for this article.