Clinical and genetic characterization of leukoencephalopathies in adults.
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.
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, London, UK.
David S
DS
Lynch
Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil.
Anderson
A
Rodrigues Brandão de Paiva
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Wei Jia
WJ
Zhang
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
Enrico
E
Bugiardini
Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil.
Fernando
F
Freua
Instituto de Radiologia, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil.
Leandro
L
Tavares Lucato
Centro de Estudos do Genoma Humano, Universidade de São Paulo, São Paulo, Brazil.
Lucia Inês
LI
Macedo-Souza
Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Rahul
R
Lakshmanan
Neurology Department, St. Vincent's University Hospital and University College Dublin, Ireland.
Justin A
JA
Kinsella
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.|Chelsea and Westminster NHS Foundation Trust, London, UK.
Aine
A
Merwick
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.|Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
Alexander M
AM
Rossor
Department of Neurology, Queens Medical Centre, Nottingham, UK.
Nin
N
Bajaj
Department of Neuropathology, Royal Victoria Hospital, Belfast, Northern Ireland, UK.
Brian
B
Herron
Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland, UK.
Paul
P
McMonagle
Centre for Cancer Research and Cell Biology, Queens University of Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
Patrick J
PJ
Morrison
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Deborah
D
Hughes
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Alan
A
Pittman
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
Matilde
M
Laurà
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
Mary M
MM
Reilly
Dementia Research Centre, UCL Institute of Neurology, London, UK.
Jason D
JD
Warren
Dementia Research Centre, UCL Institute of Neurology, London, UK.
Catherine J
CJ
Mummery
Dementia Research Centre, UCL Institute of Neurology, London, UK.
Jonathan M
JM
Schott
Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Matthew
M
Adams
Dementia Research Centre, UCL Institute of Neurology, London, UK.
Nick C
NC
Fox
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Elaine
E
Murphy
Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Indran
I
Davagnanam
Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil.
Fernando
F
Kok
Department of Neuroinflammation, UCL Institute of Neurology, London, UK.
Jeremy
J
Chataway
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Henry
H
Houlden
D000293:Adolescent; D000328:Adult; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D056784:Leukoencephalopathies / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D055815:Young Adult
imaging; leukodystrophy; neurodegeneration; white matter lesion