title: Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Whole-exome sequencing and follow up-screening by Sanger sequencing.
  
  
  METHODS
  Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France.
  
  
  METHODS
  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.
  
  
  METHODS
  Whole-exome sequencing in a family and Sanger sequencing of CSF1R.
  
  
  METHODS
  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
  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.
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: Rita
authors: R
authors: Guerreiro
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: Eleanna
authors: E
authors: Kara
authors: Inserm, UMR_S975, CRICM, UPMC Univ Paris 06, UMR_S975, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.|Centre de reference des Démences Rares, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Isabelle
authors: I
authors: Le Ber
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: Jose
authors: J
authors: Bras
authors: Dementia Research Centre, Institute of Neurology, University College London, London, England.
authors: Jonathan D
authors: JD
authors: Rohrer
authors: Queen Square Brain Bank, Institute of Neurology, University College London, London, England.|Neuropathology Unit, Hospital Santo Antonio, Centro Hospitalar do Porto, Oporto, Portugal.
authors: Ricardo
authors: R
authors: Taipa
authors: Queen Square Brain Bank, Institute of Neurology, University College London, London, England.
authors: Tammaryn
authors: T
authors: Lashley
authors: Département de Génétique et Cytogénétique, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Céline
authors: C
authors: Dupuits
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: Nicole
authors: N
authors: Gurunlian
authors: Inserm, UMR_S975, CRICM, UPMC Univ Paris 06, UMR_S975, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.|Département de Génétique et Cytogénétique, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Fanny
authors: F
authors: Mochel
authors: Dementia Research Centre, Institute of Neurology, University College London, London, England.
authors: Jason D
authors: JD
authors: Warren
authors: Département de Neurologie, Hôpital Charles Nicolle, CHU Rouen, Rouen, France.
authors: Didier
authors: D
authors: Hannequin
authors: Département de Neurologie, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Frédéric
authors: F
authors: Sedel
authors: Inserm, UMR_S975, CRICM, UPMC Univ Paris 06, UMR_S975, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.|Département de Génétique et Cytogénétique, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Christel
authors: C
authors: Depienne
authors: Inserm, UMR_S975, CRICM, UPMC Univ Paris 06, UMR_S975, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Agnès
authors: A
authors: Camuzat
authors: Service de Neurologie, CH Yves Le Foll, Saint Brieuc, France.
authors: Véronique
authors: V
authors: Golfier
authors: Département de Neurologie, Centre de mémoire de ressource et de recherche, CHU de Poitiers, Poitiers, France.
authors: Foucaud
authors: F
authors: Du Boisguéheneuc
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: Lucia
authors: L
authors: Schottlaender
authors: Dementia Research Centre, Institute of Neurology, University College London, London, England.
authors: Nick C
authors: NC
authors: Fox
authors: MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, England.
authors: Jonathan
authors: J
authors: Beck
authors: MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, England.
authors: Simon
authors: S
authors: Mead
authors: Dementia Research Centre, Institute of Neurology, University College London, London, England.
authors: Martin N
authors: MN
authors: Rossor
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: John
authors: J
authors: Hardy
authors: Queen Square Brain Bank, Institute of Neurology, University College London, London, England.
authors: Tamas
authors: T
authors: Revesz
authors: Inserm, UMR_S975, CRICM, UPMC Univ Paris 06, UMR_S975, CNRS UMR 7225, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.|Département de Génétique et Cytogénétique, Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Paris, France.
authors: Alexis
authors: A
authors: Brice
authors: Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, England.
authors: Henry
authors: H
authors: Houlden
mesh_terms: D000328:Adult; D017668:Age of Onset; D005060:Europe; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor
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