title: A family with hereditary diffuse leukoencephalopathy with spheroids caused by a novel c.2442+2T>C mutation in the CSF1R gene.
abstract: Clinical phenotypes of hereditary diffuse leukoencephalopathy with spheroids (HDLS), a familial progressive neurodegenerative disorder affecting the white matter of the brain, are heterogenous and may include behavioral and personality changes, memory impairment, parkinsonism, seizure, and spasticity. Thus, HDLS is frequently unrecognized and misdiagnosed. Heterozygous mutations located within the kinase domain of the gene encoding the colony-stimulating factor 1 receptor (CSF1R), a cell surface receptor with key roles in development and innate immunity, have been shown in HDLS. These different gene mutations may be related to the various clinical phenotypes. We report here a newly identified family with HDLS harboring a mutation in the CSF1R gene. We examined clinical and neuropathological features in three members of this family. These patients presented with affective incontinence, memory impairment, and executive dysfunction at onset, and revealed nonfluent aphasia, parkinsonism, and seizure as the disease progressed. We identified a novel CSF1R splice site mutation (c.2442+2T>C) in intron 18 for two of the patients. MRI of these patients revealed progressive, frontotemporal-predominant, confluent leukoencephalopathy. We also observed severe myelin loss, axonal degeneration, and abundant axonal spheroids, astrocytes, and microglia in the cerebral white matter, consistent with HDLS neuropathological features. Additionally, we identified atypical neuropathological findings for HDLS, including neuronal loss and gliosis with ballooned neurons and central chromatolysis in the frontal cortex and hippocampus. This report provides further evidence for the clinical and neuropathological heterogeneity of HDLS.
authors.affiliation: PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan; Yokohama Hoyu Hospital, Psychiatry, Yokohama 241-0812, Japan; Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan. Electronic address: kawakami-it@igakuken.or.jp.
authors.forename: Ito
authors.initials: I
authors.lastname: Kawakami
authors.affiliation: PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan; Department of Psychiatry, Juntendo University School of Medicine, Tokyo 113-8421, Japan. Electronic address: iseki@juntendo.gmc.ac.jp.
authors.forename: Eizo
authors.initials: E
authors.lastname: Iseki
authors.affiliation: PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan; Department of Psychiatry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kasanuki
authors.affiliation: PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Minegishi
authors.affiliation: PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Yokohama Hoyu Hospital, Psychiatry, Yokohama 241-0812, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hino
authors.affiliation: Yokohama Hoyu Hospital, Psychiatry, Yokohama 241-0812, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: Yokohama Hoyu Hospital, Psychiatry, Yokohama 241-0812, Japan.
authors.forename: Kohshiro
authors.initials: K
authors.lastname: Fujisawa
authors.affiliation: Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Higashi
authors.affiliation: Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Psychiatry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Furuta
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8431, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takanashi
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8431, Japan.
authors.forename: Yuanzhe
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8431, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Daigo Hospital, Psychogeriatric Center, Miyazaki 889-1911, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Mitsuyama
authors.affiliation: Department of Psychiatry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Heii
authors.initials: H
authors.lastname: Arai
mesh_terms: D000328:Adult; D005190:Family; D017809:Fatal Outcome; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000473:pathology; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007438:Introns; D056784:Leukoencephalopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Axonal spheroid; CSF1R; HDLS; Leukoencephalopathy