title: Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His.
abstract: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Robinson
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: EunRan
authors.initials: E
authors.lastname: Suh
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Wood
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H Branch
authors.initials: HB
authors.lastname: Coslett
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Raible
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA. vivianna@upenn.edu.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
mesh_terms: D001120:Arginine / Q000235:genetics*; D005260:Female; D006639:Histidine / Q000235:genetics*; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D035781:Siblings
chemical_list: D006639:Histidine; D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine