title: Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred.
abstract: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Baba
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Baker
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Thomas
authors.initials: T
authors.lastname: Bird
authors.forename: Wenlang
authors.initials: W
authors.lastname: Lin
authors.forename: Michael W
authors.initials: MW
authors.lastname: DeLucia
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001369:Axons; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003704:Dementia / Q000209:etiology; D003863:Depression / Q000209:etiology; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D038203:alpha-Crystallin B Chain / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D020717:Eukaryotic Initiation Factor-2B; D038203:alpha-Crystallin B Chain