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Cristina Dallabona1, Truus E. M. Abbink2, Rosalba Carrozzo3, Alessandra Torraco3, Andrea Legati4, Carola G. M. van Berkel2, Marcello Niceta5, Tiziana Langella4, Daniela Verrigni3, Teresa Rizza3, Daria Diodato3, Fiorella Piemonte3, Eleonora Lamantea4, Mingyan Fang6,7, Jianguo Zhang6,7, Diego Martinelli8, Elsa Bevivino8, Carlo Dionisi-Vici8, Adeline Vanderver9, Sunny G. Philip10, Manju A. Kurian11, 12, Ishwar C. Verma13, Sunita Bijarnia-Mahay13, Sandra Jacinto14, Fatima Furtado15, Patrizia Accorsi16, Anna Ardissone17, Isabella Moroni17, Ileana Ferrero1, Marco Tartaglia5, Paola Goffrini1, Daniele Ghezzi4, Marjo S. van der Knaap2, Enrico Bertini3

1- Department of Life Sciences, University of Parma, Parma, Italy
2- Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
3- Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, ‘Bambino Gesu` ’ Children’s Hospital, IRCCS, Rome, Italy
4- Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy
5- Molecular Genetics and Genomics Unit, Division of Genetics and Rare Diseases, ‘Bambino Gesu` ’ Children’s Hospital, IRCCS, Rome, Italy
6- BGI-Shenzhen, Shenzhen 518083, China
7- Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen 518083, China
8- Division of Metabolism, ‘Bambino Gesu` ’ Children’s Hospital, Rome, Italy
9- Department of Neurology, Children’s National Medical Center, Washington, USA
10- Department of Pediatric Neurology, Birmingham Children’s Hospital, Birmingham, UK
11- Department of Neurology, Great Ormond Street Hospital, London, UK
12- Developmental Neurosciences, UCL-Institute of Child Health, London, UK
13- Department of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi, India
14- Paediatric Neurology Department, Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
15- Paediatric Department, Unidade Local de Saúde do Baixo Alentejo, Beja, Portugal
16- Child Neuropsychiatry Unit, Spedali Civili, Brescia, Italy
17- Child Neurology Unit, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy

Brain 2016: 139; 782-794 (publicação)

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.

Palavras Chave: LYRM7, leukoencephalopathy, mitochondrial diseases, MRI