LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance
| العنوان: | LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance |
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| المؤلفون: | Paola Goffrini, Fiorella Piemonte, Daniele Ghezzi, Teresa Rizza, Diego Martinelli, Rosalba Carrozzo, Adeline Vanderver, Sandra Jacinto, Anna Ardissone, Alessandra Torraco, Ishwar C. Verma, Carola G.M. van Berkel, Andrea Legati, Manju A. Kurian, Sunny Philip, Ileana Ferrero, Marco Tartaglia, Carlo Dionisi-Vici, Isabella Moroni, Marjo S. van der Knaap, Fatima Furtado, Truus E.M. Abbink, Mingyan Fang, Jianguo Zhang, Tiziana Langella, Patrizia Accorsi, Enrico Bertini, Elsa Bevivino, Cristina Dallabona, Daria Diodato, Marcello Niceta, Sunita Bijarnia-Mahay, Eleonora Lamantea, Daniela Verrigni |
| المساهمون: | Pediatric surgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Dallabona, C, Abbink, T, Carrozzo, R, Torraco, A, Legati, A, Van Berkel, C, 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, S, Kurian, M, Verma, I, Bijarnia-Mahay, S, Jacinto, S, Furtado, F, Accorsi, P, Ardissone, A, Moroni, I, Ferrero, I, Tartaglia, M, Goffrini, P, Ghezzi, D, Van Der Knaap, M, Bertini, E |
| المصدر: | Brain, 139, 782-794. Oxford University Press Dallabona, C, Abbink, T E M, Carrozzo, R, Torraco, A, Legati, A, van Berkel, C G M, 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, S G, Kurian, M A, Verma, I C, Bijarnia-Mahay, S, Jacinto, S, Furtado, F, Accorsi, P, Ardissone, A, Moroni, I, Ferrero, I, Tartaglia, M, Goffrini, P, Ghezzi, D, van der Knaap, M S & Bertini, E 2016, ' LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance ', Brain, vol. 139, pp. 782-794 . https://doi.org/10.1093/brain/awv392Test |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | LYRM7, 0301 basic medicine, Male, Molecular Chaperone, Pathology, medicine.medical_specialty, Adolescent, Complex III, Encephalopathy, Molecular Sequence Data, Respiratory chain, Saccharomyces cerevisiae, Biology, medicine.disease_cause, Leukoencephalopathy, Mitochondrial Proteins, 03 medical and health sciences, symbols.namesake, medicine, Mitochondrial Protein, Missense mutation, Humans, Amino Acid Sequence, Child, Sanger sequencing, Cavitation, Mutation, medicine.diagnostic_test, Leukoencephalopathy, Progressive Multifocal, Infant, Magnetic resonance imaging, medicine.disease, Mitochondrial respiratory chain complex III, Magnetic Resonance Imaging, Mitochondria, 030104 developmental biology, Child, Preschool, symbols, Female, Neurology (clinical), Human, Molecular Chaperones |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a546e9b00dd26f960d455e469f2ea927Test https://doi.org/10.1093/brain/awv392Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a546e9b00dd26f960d455e469f2ea927 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00068950 |
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