Genetic Analysis of Inherited Leukodystrophies
Year: 2013
Type: article
Study design: Observational Study
Abstract: IMPORTANCE: The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE: To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN: Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING: Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS: A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS: Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES: Mutations in CSF1R. RESULTS: We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE: These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.
Source: JAMA Neurology
Authors: Rita Guerreiro, Eleanna Kara, Isabelle Le Ber, Jose Bras, Jonathan D. Rohrer, Ricardo Taipa, Tammaryn Lashley, Céline Dupuits, Nicole Gurunlian, Fanny Mochel, Jason D. Warren, Didier Hannequin, Frédéric Sedel, Christel Depienne, Agnès Camuzat, Véronique Golfier, Foucaud Du Boisguéheneuc, Lucia Schottlaender, Nick C. Fox, Jonathan Beck, Simon Mead, Martin N. Rossor, John Hardy, Tamas Revesz, Alexis Brice, Henry Houlden
Institutions: UCL Queen Square Institute of Neurology, University College London, Centre National de la Recherche Scientifique, Inserm, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Université Pierre-et-Marie-Curie, Hospital de Santo António, National Hospital for Neurology and Neurosurgery, Centro Hospitalar do Porto, Hôpital Charles-Nicolle, Centre Hospitalier de Saint-Brieuc, Centre Hospitalier Universitaire de Poitiers, MRC Prion Unit
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Comprehensive Sequencing and Analysis of Variation in NHLBI Cohorts, NIHR Senior Investigator Award, G1859083642, Northwest Genomics Center, ARRA - NHLBI Lung Cohorts Sequencing Project, G2845388095, WHI Sequencing Project (WHISP), G3550174423, G3942183342, Comprehensive Sequencing and Analysis of Variation in NHLBI Cohorts, ARRA - NHLBI Lung Cohorts Sequencing Project, Human Exome Sequencing in Six Well-Phenotyped NHLBI Cohorts, Human Exome Sequencing in Six Well-Phenotyped NHLBI Cohorts, WHI Sequencing Project (WHISP), Northwest Genomics Center, NIHR Senior Investigator Award, A systematic investigation into the pathogenesis and course of Parkinson's syndrome.
OpenAlex ID: W2018766159