title: De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
abstract: OBJECTIVE
  Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years.
  
  
  METHODS
  In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies.
  
  
  RESULTS
  HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing.
  
  
  CONCLUSIONS
  Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors.
authors.affiliation: From the Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Department of Neurology (K.N.K., S.B., R.S., K.J.S., R.K., L.S.), Institute of Medical Genetics and Applied Genomics (P.B.), and Department of Diagnostic and Interventional Neuroradiology (B.B., T.N.), Eberhard Karls-University Tübingen; German Research Center for Neurodegenerative Diseases (K.N.K., S.B., R.S., R.K., L.S.), Tübingen; and CeGaT GmbH (S.B.), Center for Genomics and Transcriptomics, Tübingen, Germany.
authors.forename: Kathrin N
authors.initials: KN
authors.lastname: Karle
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Schweitzer
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bender
authors.forename: Thomas
authors.initials: T
authors.lastname: Nägele
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D055815:Young Adult