Hereditary diffuse leukoencephalopathy with spheroids: Clinical, pathologic and genetic studies of a new kindred

Yasuhiko Baba, Bernardino Ghetti, Matthew C. Baker, Ryan J. Uitti, Michael L. Hutton, Keiji Yamaguchi, Thomas Bird, Wenlang Lin, Michael W. DeLucia, Dennis W. Dickson, Zbigniew K. Wszolek

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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 αB-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 αB-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 αB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Original languageEnglish (US)
Pages (from-to)300-311
Number of pages12
JournalActa neuropathologica
Issue number4
StatePublished - Apr 2006


  • Amyloid precursor protein
  • Corticobasal degeneration
  • Hereditary diffuse leukoencephalopathy with spheroids (HDLS)
  • Neurofilament
  • Parkinsonism

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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