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LYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearance

2016Journal article Open access
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dc.contributor.authorDallabona, C
dc.contributor.authorAbbink, TEM
dc.contributor.authorCarrozzo, R
dc.contributor.authorTorraco, A
dc.contributor.authorLegati, A
dc.contributor.authorvan Berkel, CGM
dc.contributor.authorNiceta, M
dc.contributor.authorLangella, T
dc.contributor.authorVerrigni, D
dc.contributor.authorRizza, T
dc.contributor.authorDiodato, D
dc.contributor.authorPiemonte, F
dc.contributor.authorLamantea, E
dc.contributor.authorFang, M
dc.contributor.authorZhang, J
dc.contributor.authorMartinelli, D
dc.contributor.authorBevivino, E
dc.contributor.authorDionisi-Vici, C
dc.contributor.authorVanderver, A
dc.contributor.authorPhilip, SG
dc.contributor.authorKurian, MA
dc.contributor.authorVerma, IC
dc.contributor.authorBijarnia-Mahay, S
dc.contributor.authorJacinto, S
dc.contributor.authorFurtado, F
dc.contributor.authorAccorsi, P
dc.contributor.authorArdissone, A
dc.contributor.authorMoroni, I
dc.contributor.authorFerrero, I
dc.contributor.authorTartaglia, M
dc.contributor.authorGoffrini, P
dc.contributor.authorGhezzi, D
dc.contributor.authorvan der Knaap, MS
dc.contributor.authorBertini, E
dc.date.accessioned2023-10-27T14:29:31Z
dc.date.available2023-10-27T14:29:31Z
dc.date.issued2016
dc.description.abstractThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBrain . 2016 Mar;139(Pt 3):782-94pt_PT
dc.identifier.doi10.1093/brain/awv392pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/4720
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.subjectAdolescentpt_PT
dc.subjectAmino Acid Sequencept_PT
dc.subjectChildpt_PT
dc.subjectHumanspt_PT
dc.subjectLeukoencephalopathy, Progressive Multifocal / diagnosis*pt_PT
dc.subjectLeukoencephalopathy, Progressive Multifocal / genetics*pt_PT
dc.subjectLeukoencephalopathy, Progressive Multifocal / genetics*pt_PT
dc.subjectMitochondrial Proteins / genetics*pt_PT
dc.subjectMolecular Chaperones / genetics*pt_PT
dc.subjectMolecular Sequence Datapt_PT
dc.subjectMutation / genetics*pt_PT
dc.subjectSaccharomyces cerevisiaept_PT
dc.subjectHDE NEU PEDpt_PT
dc.titleLYRM7 Mutations Cause a Multifocal Cavitating Leukoencephalopathy with Distinct MRI Appearancept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage794pt_PT
oaire.citation.issue3pt_PT
oaire.citation.startPage782pt_PT
oaire.citation.titleBrainpt_PT
oaire.citation.volume139pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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