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

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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.

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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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Acknowledgments

The authors are indebted to the members of this kindred for their interest and willingness to cooperate in this study. The study was partially supported by the Morris K. Udall Center for Excellence in Parkinson’s Disease Research (P50 NS40256), VA Research Funds, the Indiana Alzheimer Disease Center (P30 AG10133) and the National Cell Repository for Alzheimer’s Disease (U24 AG21886). YB is a recipient of Robert and Clarice Smith fellowship.

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Authors and Affiliations

  1. Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    Yasuhiko Baba, Ryan J. Uitti & Zbigniew K. Wszolek

  2. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    Matthew C. Baker & Michael L. Hutton

  3. Department of Pathology (Neuroscience), Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Wenlang Lin, Michael W. DeLucia & Dennis W. Dickson

  4. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Bernardino Ghetti & Keiji Yamaguchi

  5. Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

    Thomas Bird

  6. Geriatric Research Service, Veterans Affairs Medical Center, Seattle, WA, USA

    Thomas Bird

Authors
  1. Yasuhiko Baba
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  2. Bernardino Ghetti
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  3. Matthew C. Baker
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  4. Ryan J. Uitti
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  5. Michael L. Hutton
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  6. Keiji Yamaguchi
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  7. Thomas Bird
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  8. Wenlang Lin
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  10. Dennis W. Dickson
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  11. Zbigniew K. Wszolek
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Correspondence to Dennis W. Dickson.

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Baba, Y., Ghetti, B., Baker, M.C. et al. Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropathol 111, 300–311 (2006). https://doi.org/10.1007/s00401-006-0046-z

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  • DOI: https://doi.org/10.1007/s00401-006-0046-z

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