Journal
BRAIN
Volume 140, Issue -, Pages 1204-1211Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx045
Keywords
leukodystrophy; neurodegeneration; white matter lesion; imaging
Categories
Funding
- Medical Research Council
- Leonard Wolfson Experimental Neurology Centre
- Wellcome Trust
- Brain Research Trust (BRT)
- National Institute for Health Research (NIHR), University College London Hospitals (UCLH)/UCL- Biomedical Research Centre (BRC)
- NIHR Queen Square Dementia Biomedical Research Unit
- Wellcome Trust [110043/Z/15/Z] Funding Source: Wellcome Trust
- MRC [G108/638, G1001253, MR/J004758/1, G0802760] Funding Source: UKRI
- Medical Research Council [G108/638, G1001253, MR/J004758/1, G0802760] Funding Source: researchfish
- Muscular Dystrophy UK [16GRO-PS36-0055] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10134, NF-SI-0515-10082, ACF-2014-18-009] Funding Source: researchfish
- Wellcome Trust [110043/Z/15/Z] Funding Source: researchfish
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Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.
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