TY - JOUR
T1 - LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance
AU - Dallabona, Cristina
AU - Abbink, Truus E M
AU - Carrozzo, Rosalba
AU - Torraco, Alessandra
AU - Legati, Andrea
AU - Van Berkel, Carola G M
AU - Niceta, Marcello
AU - Langella, Tiziana
AU - Verrigni, Daniela
AU - Rizza, Teresa
AU - Diodato, Daria
AU - Piemonte, Fiorella
AU - Lamantea, Eleonora
AU - Fang, Mingyan
AU - Zhang, Jianguo
AU - Martinelli, Diego
AU - Bevivino, Elsa
AU - Dionisi-Vici, Carlo
AU - Vanderver, Adeline
AU - Philip, Sunny G.
AU - Kurian, Manju A.
AU - Verma, Ishwar C.
AU - Bijarnia-Mahay, Sunita
AU - Jacinto, Sandra
AU - Furtado, Fatima
AU - Accorsi, Patrizia
AU - Ardissone, Anna
AU - Moroni, Isabella
AU - Ferrero, Ileana
AU - Tartaglia, Marco
AU - Goffrini, Paola
AU - Ghezzi, Daniele
AU - Van Der Knaap, Marjo S.
AU - Bertini, Enrico
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
KW - Cavitations
KW - Complex III
KW - Leukoencephalopathy
KW - LYRM7
KW - Mitochondria
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U2 - 10.1093/brain/awv392
DO - 10.1093/brain/awv392
M3 - Article
C2 - 26912632
AN - SCOPUS:84964649248
VL - 139
SP - 782
EP - 794
JO - Brain
JF - Brain
SN - 0006-8950
IS - 3
ER -