LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.17/4720 |
Resumo: | This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years. |
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LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI AppearanceAdolescentAmino Acid SequenceChildHumansLeukoencephalopathy, Progressive Multifocal / diagnosis*Leukoencephalopathy, Progressive Multifocal / genetics*Leukoencephalopathy, Progressive Multifocal / genetics*Mitochondrial Proteins / genetics*Molecular Chaperones / genetics*Molecular Sequence DataMutation / genetics*Saccharomyces cerevisiaeHDE NEU PEDThis study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years.Oxford University PressRepositório do Centro Hospitalar Universitário de Lisboa Central, EPEDallabona, CAbbink, TEMCarrozzo, RTorraco, ALegati, Avan Berkel, CGMNiceta, MLangella, TVerrigni, DRizza, TDiodato, DPiemonte, FLamantea, EFang, MZhang, JMartinelli, DBevivino, EDionisi-Vici, CVanderver, APhilip, SGKurian, MAVerma, ICBijarnia-Mahay, SJacinto, SFurtado, FAccorsi, PArdissone, AMoroni, IFerrero, ITartaglia, MGoffrini, PGhezzi, Dvan der Knaap, MSBertini, E2023-10-27T14:29:31Z20162016-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.17/4720engBrain . 2016 Mar;139(Pt 3):782-9410.1093/brain/awv392info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-29T06:43:36Zoai:repositorio.chlc.min-saude.pt:10400.17/4720Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:26:06.586820Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
title |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
spellingShingle |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance Dallabona, C Adolescent Amino Acid Sequence Child Humans Leukoencephalopathy, Progressive Multifocal / diagnosis* Leukoencephalopathy, Progressive Multifocal / genetics* Leukoencephalopathy, Progressive Multifocal / genetics* Mitochondrial Proteins / genetics* Molecular Chaperones / genetics* Molecular Sequence Data Mutation / genetics* Saccharomyces cerevisiae HDE NEU PED |
title_short |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
title_full |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
title_fullStr |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
title_full_unstemmed |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
title_sort |
LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance |
author |
Dallabona, C |
author_facet |
Dallabona, C Abbink, TEM Carrozzo, R Torraco, A Legati, A van Berkel, CGM Niceta, M Langella, T Verrigni, D Rizza, T Diodato, D Piemonte, F Lamantea, E Fang, M Zhang, J Martinelli, D Bevivino, E Dionisi-Vici, C Vanderver, A Philip, SG Kurian, MA Verma, IC Bijarnia-Mahay, S Jacinto, S Furtado, F Accorsi, P Ardissone, A Moroni, I Ferrero, I Tartaglia, M Goffrini, P Ghezzi, D van der Knaap, MS Bertini, E |
author_role |
author |
author2 |
Abbink, TEM Carrozzo, R Torraco, A Legati, A van Berkel, CGM Niceta, M Langella, T Verrigni, D Rizza, T Diodato, D Piemonte, F Lamantea, E Fang, M Zhang, J Martinelli, D Bevivino, E Dionisi-Vici, C Vanderver, A Philip, SG Kurian, MA Verma, IC Bijarnia-Mahay, S Jacinto, S Furtado, F Accorsi, P Ardissone, A Moroni, I Ferrero, I Tartaglia, M Goffrini, P Ghezzi, D van der Knaap, MS Bertini, E |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório do Centro Hospitalar Universitário de Lisboa Central, EPE |
dc.contributor.author.fl_str_mv |
Dallabona, C Abbink, TEM Carrozzo, R Torraco, A Legati, A van Berkel, CGM Niceta, M Langella, T Verrigni, D Rizza, T Diodato, D Piemonte, F Lamantea, E Fang, M Zhang, J Martinelli, D Bevivino, E Dionisi-Vici, C Vanderver, A Philip, SG Kurian, MA Verma, IC Bijarnia-Mahay, S Jacinto, S Furtado, F Accorsi, P Ardissone, A Moroni, I Ferrero, I Tartaglia, M Goffrini, P Ghezzi, D van der Knaap, MS Bertini, E |
dc.subject.por.fl_str_mv |
Adolescent Amino Acid Sequence Child Humans Leukoencephalopathy, Progressive Multifocal / diagnosis* Leukoencephalopathy, Progressive Multifocal / genetics* Leukoencephalopathy, Progressive Multifocal / genetics* Mitochondrial Proteins / genetics* Molecular Chaperones / genetics* Molecular Sequence Data Mutation / genetics* Saccharomyces cerevisiae HDE NEU PED |
topic |
Adolescent Amino Acid Sequence Child Humans Leukoencephalopathy, Progressive Multifocal / diagnosis* Leukoencephalopathy, Progressive Multifocal / genetics* Leukoencephalopathy, Progressive Multifocal / genetics* Mitochondrial Proteins / genetics* Molecular Chaperones / genetics* Molecular Sequence Data Mutation / genetics* Saccharomyces cerevisiae HDE NEU PED |
description |
This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016 2016-01-01T00:00:00Z 2023-10-27T14:29:31Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.17/4720 |
url |
http://hdl.handle.net/10400.17/4720 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Brain . 2016 Mar;139(Pt 3):782-94 10.1093/brain/awv392 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799134142602936320 |