Clinical and genetic characterization of leukoencephalopathies in adults

David S. Lynch, Anderson Rodrigues Brandão De Paiva, Wei Jia Zhang, Enrico Bugiardini, Fernando Freua, Leandro Tavares Lucato, Lucia Inês Macedo-Souza, Rahul Lakshmanan, Justin A. Kinsella, Aine Merwick, Alexander M. Rossor, Nin Bajaj, Brian Herron, Paul McMonagle, Patrick J. Morrison, Deborah Hughes, Alan Pittman, Matilde Laurà, Mary M. Reilly, Jason D. WarrenCatherine J. Mummery, Jonathan M. Schott, Matthew Adams, Nick C. Fox, Elaine Murphy, Indran Davagnanam, Fernando Kok, Jeremy Chataway, Henry Houlden

Research output: Contribution to journalArticlepeer-review

81 Citations (Scopus)

Abstract

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 diseasecausing 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.

Original languageEnglish
Pages (from-to)1204-1211
Number of pages8
JournalBrain: a journal of neurology
Volume140
Issue number5
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

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