title: LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.
abstract: 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.
authors.affiliation: 1 Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.affiliation: 2 Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Truus E M
authors.initials: TE
authors.lastname: Abbink
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.affiliation: 4 Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Legati
authors.affiliation: 2 Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Carola G M
authors.initials: CG
authors.lastname: van Berkel
authors.affiliation: 5 Molecular Genetics and Genomics Unit, Division of Genetics and Rare Diseases, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Niceta
authors.affiliation: 4 Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Langella
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.affiliation: 4 Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Lamantea
authors.affiliation: 6 BGI-Shenzhen, Shenzhen 518083, China 7 Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Fang
authors.affiliation: 6 BGI-Shenzhen, Shenzhen 518083, China 7 Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 8 Division of Metabolism, 'Bambino Gesù' Children's Hospital, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.affiliation: 8 Division of Metabolism, 'Bambino Gesù' Children's Hospital, Rome, Italy.
authors.forename: Elsa
authors.initials: E
authors.lastname: Bevivino
authors.affiliation: 8 Division of Metabolism, 'Bambino Gesù' Children's Hospital, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: 9 Department of Neurology, Children's National Medical Center, Washington, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.affiliation: 10 Department of Pediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Sunny G
authors.initials: SG
authors.lastname: Philip
authors.affiliation: 11 Department of Neurology, Great Ormond Street Hospital, London, UK 12 Developmental Neurosciences, UCL-Institute of Child Health, London, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: 13 Department of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi, India.
authors.forename: Ishwar C
authors.initials: IC
authors.lastname: Verma
authors.affiliation: 13 Department of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi, India.
authors.forename: Sunita
authors.initials: S
authors.lastname: Bijarnia-Mahay
authors.affiliation: 14 Paediatric Neurology Department, Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jacinto
authors.affiliation: 15 Paediatric Department, Unidade Local de Saúde do Baixo Alentejo, Beja, Portugal.
authors.forename: Fatima
authors.initials: F
authors.lastname: Furtado
authors.affiliation: 16 Child Neuropsychiatry Unit, Spedali Civili, Brescia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Accorsi
authors.affiliation: 17 Child Neurology Unit, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ardissone
authors.affiliation: 17 Child Neurology Unit, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: 1 Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.affiliation: 5 Molecular Genetics and Genomics Unit, Division of Genetics and Rare Diseases, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: 1 Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.affiliation: 4 Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy enricosilvio.bertini@opbg.net ms.vanderknaap@vumc.nl dghezzi@istituto-besta.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.affiliation: 2 Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands enricosilvio.bertini@opbg.net ms.vanderknaap@vumc.nl dghezzi@istituto-besta.it.
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.affiliation: 3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy enricosilvio.bertini@opbg.net ms.vanderknaap@vumc.nl dghezzi@istituto-besta.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007968:Leukoencephalopathy, Progressive Multifocal / Q000175:diagnosis* / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012441:Saccharomyces cerevisiae
chemical_list: C000588844:LYRM7 protein, human; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones
keywords: LYRM7; cavitations; complex III; leukoencephalopathy; mitochondria