Acta Neuropathologica

, Volume 111, Issue 4, pp 300–311

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
Original Paper

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 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.

Keywords

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

Abbreviations

HDLS

Hereditary diffuse leukoencephalopathy with spheroids

eIF2B

Eukaryotic translation initiation factor 2B

MMSE

Mini-Mental Status Examination

H&E

Hematoxylin and eosin

LFB–PAS

Luxol fast blue–periodic acid Schiff

APP

Amyloid precursor protein

GFAP

Glial fibrillary acidic protein

PCR

Polymerase chain reaction

MAPT

Microtubule associated protein tau

FTDP-17

Frontotemporal dementia and parkinsonism linked to chromosome

CBD

Corticobasal degeneration

MRI

Magnetic resonance imaging

EEG

Electroencephalogram

CT

Computed tomogram

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Yasuhiko Baba
    • 1
  • Bernardino Ghetti
    • 4
  • Matthew C. Baker
    • 2
  • Ryan J. Uitti
    • 1
  • Michael L. Hutton
    • 2
  • Keiji Yamaguchi
    • 4
  • Thomas Bird
    • 5
    • 6
  • Wenlang Lin
    • 3
  • Michael W. DeLucia
    • 3
  • Dennis W. Dickson
    • 3
  • Zbigniew K. Wszolek
    • 1
  1. 1.Department of NeurologyMayo Clinic College of MedicineJacksonvilleUSA
  2. 2.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  3. 3.Department of Pathology (Neuroscience)Mayo Clinic College of MedicineJacksonvilleUSA
  4. 4.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  5. 5.Department of NeurologyUniversity of Washington School of MedicineSeattleUSA
  6. 6.Geriatric Research ServiceVeterans Affairs Medical CenterSeattleUSA

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