Clinical and genetic characterization of leukoencephalopathies in adults.

David S Lynch,Enrico Bugiardini,Deborah Hughes,Nick C Fox,Matthew Adams,Brian Herron,Indran Davagnanam,Rahul Lakshmanan,Elaine Murphy,Paul Mcmonagle,Jeremy Chataway,Nin Bajaj,Jonathan M Schott,Alan Pittman,Leandro Tavares Lucato,Fernando Kok,Anderson Rodrigues Brandão De Paiva,Henry Houlden,Patrick J Morrison,Fernando Freua,Wei Jia Zhang,Áine Merwick ,Catherine J Mummery ,Matilde Laurá ,Jason D Warren ,Lúcia Inês Macedo‐Souza ,Alexander M Rossor ,Justin Kinsella

doi:10.1093/brain/awx045

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 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.

Highlights

Leukodystrophies and genetic leukoencephalopathies represent a diverse group of disorders in which there is progressive degeneration of CNS white matter
The primary inclusion criteria included the presence of a progressive neurological syndrome with prominent T2weighted hyperintensity of the cerebral/spinal cord white matter, which was confluent and not consistent with an acquired inflammatory cause such as multiple sclerosis
We did not make any further diagnoses from this approach, confirming that in adult leukoencephalopathies, whole exome sequencing (WES) offers no benefit over focused exome sequencing

Summary

Introduction

Leukodystrophies and genetic leukoencephalopathies represent a diverse group of disorders in which there is progressive degeneration of CNS white matter They can present in children or adults, often with a constellation of clinical features including dementia, movement disorders, ataxia and upper motor neuron signs, accompanied by hyperintense signal abnormalities in the brain/spinal cord on T2weighted MRI (Vanderver et al, 2015). There are at least 60 genes implicated in the development of these disorders, involved in diverse cellular pathways including myelin formation, mitochondrial health and protein translation (Parikh et al, 2015). This heterogeneity, in combination with often overlapping clinical and radiological phenotypes, make definitive diagnosis challenging. Little is known about the genetic spectrum of these disorders in adults, where in many cases a definitive diagnosis is not reached

Methods

Results

Conclusion