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. Mutat...
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| Published in | Brain (London, England : 1878) Vol. 140; no. 5; pp. 1204 - 1211 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Oxford University Press
01.05.2017
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0006-8950 1460-2156 1460-2156 |
| DOI | 10.1093/brain/awx045 |
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| 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. |
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| AbstractList | 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.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. 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. 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. 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. |
| Author | Mummery, Catherine J Morrison, Patrick J. Warren, Jason D Macedo-Souza, Lucia Inês Laurà, Matilde Hughes, Deborah Reilly, Mary M Fox, Nick C. Rodrigues Brandão de Paiva, Anderson Zhang, Wei Jia McMonagle, Paul Bajaj, Nin Herron, Brian Pittman, Alan Chataway, Jeremy Rossor, Alexander M. Davagnanam, Indran Freua, Fernando Lynch, David S. Lakshmanan, Rahul Kinsella, Justin A. Schott, Jonathan M. Houlden, Henry Tavares Lucato, Leandro Merwick, Aine Kok, Fernando Bugiardini, Enrico Murphy, Elaine Adams, Matthew |
| AuthorAffiliation | 16 Dementia Research Centre, UCL Institute of Neurology, London, UK 13 Department of Neuropathology, Royal Victoria Hospital, Belfast, Northern Ireland, UK 3 Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil 11 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK 15 Centre for Cancer Research and Cell Biology, Queens University of Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK 17 Department of Neuroinflammation, UCL Institute of Neurology, London, UK 12 Department of Neurology, Queens Medical Centre, Nottingham, UK 5 Instituto de Radiologia, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil 2 Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, London, UK 8 Neurology Department, St. Vincent’s University Hospital and University College Dublin, Ireland 18 Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, Queen Square, Lon |
| AuthorAffiliation_xml | – name: 16 Dementia Research Centre, UCL Institute of Neurology, London, UK – name: 11 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK – name: 3 Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil – name: 4 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK – name: 8 Neurology Department, St. Vincent’s University Hospital and University College Dublin, Ireland – name: 14 Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland, UK – name: 9 Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – name: 12 Department of Neurology, Queens Medical Centre, Nottingham, UK – name: 18 Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – name: 15 Centre for Cancer Research and Cell Biology, Queens University of Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK – name: 17 Department of Neuroinflammation, UCL Institute of Neurology, London, UK – name: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK – name: 5 Instituto de Radiologia, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil – name: 6 Centro de Estudos do Genoma Humano, Universidade de São Paulo, São Paulo, Brazil – name: 2 Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, London, UK – name: 7 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – name: 13 Department of Neuropathology, Royal Victoria Hospital, Belfast, Northern Ireland, UK – name: 10 Chelsea and Westminster NHS Foundation Trust, London, UK |
| Author_xml | – sequence: 1 givenname: David S. surname: Lynch fullname: Lynch, David S. organization: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, 2 Leonard Wolfson Experimental Neurology Centre, UCL Institute of Neurology, London, UK – sequence: 2 givenname: Anderson surname: Rodrigues Brandão de Paiva fullname: Rodrigues Brandão de Paiva, Anderson organization: 3 Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil – sequence: 3 givenname: Wei Jia surname: Zhang fullname: Zhang, Wei Jia organization: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK – sequence: 4 givenname: Enrico surname: Bugiardini fullname: Bugiardini, Enrico organization: 4 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK – sequence: 5 givenname: Fernando surname: Freua fullname: Freua, Fernando organization: 3 Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil – sequence: 6 givenname: Leandro surname: Tavares Lucato fullname: Tavares Lucato, Leandro organization: 5 Instituto de Radiologia, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil – sequence: 7 givenname: Lucia Inês surname: Macedo-Souza fullname: Macedo-Souza, Lucia Inês organization: 6 Centro de Estudos do Genoma Humano, Universidade de São Paulo, São Paulo, Brazil – sequence: 8 givenname: Rahul surname: Lakshmanan fullname: Lakshmanan, Rahul organization: 7 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – sequence: 9 givenname: Justin A. surname: Kinsella fullname: Kinsella, Justin A. organization: 8 Neurology Department, St. Vincent’s University Hospital and University College Dublin, Ireland – sequence: 10 givenname: Aine surname: Merwick fullname: Merwick, Aine organization: 9 Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK, 10 Chelsea and Westminster NHS Foundation Trust, London, UK – sequence: 11 givenname: Alexander M. surname: Rossor fullname: Rossor, Alexander M. organization: 4 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK, 11 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK – sequence: 12 givenname: Nin surname: Bajaj fullname: Bajaj, Nin organization: 12 Department of Neurology, Queens Medical Centre, Nottingham, UK – sequence: 13 givenname: Brian surname: Herron fullname: Herron, Brian organization: 13 Department of Neuropathology, Royal Victoria Hospital, Belfast, Northern Ireland, UK – sequence: 14 givenname: Paul surname: McMonagle fullname: McMonagle, Paul organization: 14 Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland, UK – sequence: 15 givenname: Patrick J. surname: Morrison fullname: Morrison, Patrick J. organization: 15 Centre for Cancer Research and Cell Biology, Queens University of Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK – sequence: 16 givenname: Deborah surname: Hughes fullname: Hughes, Deborah organization: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK – sequence: 17 givenname: Alan surname: Pittman fullname: Pittman, Alan organization: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK – sequence: 18 givenname: Matilde surname: Laurà fullname: Laurà, Matilde organization: 4 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK – sequence: 19 givenname: Mary M surname: Reilly fullname: Reilly, Mary M organization: 4 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK – sequence: 20 givenname: Jason D surname: Warren fullname: Warren, Jason D organization: 16 Dementia Research Centre, UCL Institute of Neurology, London, UK – sequence: 21 givenname: Catherine J surname: Mummery fullname: Mummery, Catherine J organization: 16 Dementia Research Centre, UCL Institute of Neurology, London, UK – sequence: 22 givenname: Jonathan M. surname: Schott fullname: Schott, Jonathan M. organization: 16 Dementia Research Centre, UCL Institute of Neurology, London, UK – sequence: 23 givenname: Matthew surname: Adams fullname: Adams, Matthew organization: 7 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – sequence: 24 givenname: Nick C. surname: Fox fullname: Fox, Nick C. organization: 16 Dementia Research Centre, UCL Institute of Neurology, London, UK – sequence: 25 givenname: Elaine surname: Murphy fullname: Murphy, Elaine organization: 9 Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – sequence: 26 givenname: Indran surname: Davagnanam fullname: Davagnanam, Indran organization: 7 Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK – sequence: 27 givenname: Fernando surname: Kok fullname: Kok, Fernando organization: 3 Neurogenetics Unit, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil – sequence: 28 givenname: Jeremy surname: Chataway fullname: Chataway, Jeremy organization: 17 Department of Neuroinflammation, UCL Institute of Neurology, London, UK – sequence: 29 givenname: Henry surname: Houlden fullname: Houlden, Henry organization: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, 18 Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28334938$$D View this record in MEDLINE/PubMed |
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| Keywords | neurodegeneration leukodystrophy white matter lesion imaging |
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| References | Lynch ( key 20180226040502_awx045-B4) 2016; 114 Dallabona ( key 20180226040502_awx045-B13) 2014; 82 Richards ( key 20180226040502_awx045-B7) 2015; 167A Wang ( key 20180226040502_awx045-B12) 2010; 38 Parikh ( key 20180226040502_awx045-B5) 2015; 114 Ahmed ( key 20180226040502_awx045-B1) 2014; 85 Bugiani ( key 20180226040502_awx045-B2) 2016; 87 Rademakers ( key 20180226040502_awx045-B6) 2011; 44 Vanderver ( key 20180226040502_awx045-B10) 2015; 114 Vanderver ( key 20180226040502_awx045-B11) 2016; 79 Scheper ( key 20180226040502_awx045-B9) 2007; 39 Richards ( key 20180226040502_awx045-B8) 2015; 17 Hurst ( key 20180226040502_awx045-B3) 2006; 8 |
| References_xml | – volume: 114 start-page: 494 year: 2015 ident: key 20180226040502_awx045-B10 article-title: Case definition and classification of leukodystrophies and leukoencephalopathies publication-title: Mol Genet Metab doi: 10.1016/j.ymgme.2015.01.006 – volume: 39 start-page: 534 year: 2007 ident: key 20180226040502_awx045-B9 article-title: Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation publication-title: Nat Genet doi: 10.1038/ng2013 – volume: 79 start-page: 1031 year: 2016 ident: key 20180226040502_awx045-B11 article-title: Whole exome sequencing in patients with white matter abnormalities publication-title: Ann Neurol doi: 10.1002/ana.24650 – volume: 87 start-page: 1777 year: 2016 ident: key 20180226040502_awx045-B2 article-title: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) publication-title: Neurology doi: 10.1212/WNL.0000000000003251 – volume: 114 start-page: 494 year: 2016 ident: key 20180226040502_awx045-B4 article-title: Analysis of mutations in AARS2 in a series of CSF1R -negative patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia publication-title: JAMA Neurol – volume: 38 start-page: e164 year: 2010 ident: key 20180226040502_awx045-B12 article-title: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data publication-title: Nucleic Acids Res doi: 10.1093/nar/gkq603 – volume: 85 start-page: 770 year: 2014 ident: key 20180226040502_awx045-B1 article-title: A practical approach to diagnosing adult onset leukodystrophies publication-title: J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2013-305888 – volume: 114 start-page: 501 year: 2015 ident: key 20180226040502_awx045-B5 article-title: A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies publication-title: Mol Genet Metab doi: 10.1016/j.ymgme.2014.12.434 – volume: 82 start-page: 2063 year: 2014 ident: key 20180226040502_awx045-B13 article-title: Novel (ovario) leukodystrophy related to AARS2 mutations publication-title: Neurology doi: 10.1212/WNL.0000000000000497 – volume: 167A start-page: 2541 year: 2015 ident: key 20180226040502_awx045-B7 article-title: Targeted leukodystrophy diagnosis based on charges and yields for testing publication-title: Am J Med Genet A doi: 10.1002/ajmg.a.37215 – volume: 44 start-page: 200 year: 2011 ident: key 20180226040502_awx045-B6 article-title: Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids publication-title: Nat Genet doi: 10.1038/ng.1027 – volume: 17 start-page: 405 year: 2015 ident: key 20180226040502_awx045-B8 article-title: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology publication-title: Genet Med doi: 10.1038/gim.2015.30 – volume: 8 start-page: 371 year: 2006 ident: key 20180226040502_awx045-B3 article-title: Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease publication-title: Genet Med doi: 10.1097/01.gim.0000223551.95862.c3 |
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| Snippet | Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are... Leukoencephalopathies are a diverse group of white matter disorders that can be difficult to diagnose. Using focused and whole-exome sequencing, Lynch et al .... |
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| SubjectTerms | Adolescent Adult Editor's Choice Exome - genetics Female Genetic Predisposition to Disease - genetics Humans Leukoencephalopathies - diagnosis Leukoencephalopathies - genetics Male Mutation Sequence Analysis, DNA Young Adult |
| Title | Clinical and genetic characterization of leukoencephalopathies in adults |
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