title: Enlarging the nosological spectrum of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
abstract: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.
authors.affiliation: Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany; Neurocure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Jill
authors.initials: J
authors.lastname: Murrell
authors.forename: Lutz
authors.initials: L
authors.lastname: Harms
authors.forename: Kelly
authors.initials: K
authors.lastname: Miller
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.forename: Thomas
authors.initials: T
authors.lastname: Brosch
authors.forename: Michael
authors.initials: M
authors.lastname: Scheel
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Hans-Hilmar
authors.initials: HH
authors.lastname: Goebel
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
mesh_terms: D000328:Adult; D001369:Axons / Q000648:ultrastructure; D054022:Cerebrum / Q000648:ultrastructure*; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D055815:Young Adult
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: ALSP; CSF1R; HDLS; POLD