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. Immunoh…
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HDLS is a progressive neurodegenerative disorder characterized by cerebral white matter degeneration with axonal spheroids, ballooned cortical neurons, reactive astrocytosis, and lipid- and pigment-laden macrophages.
“HDLS, also known as adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) [23], is a progressive neurodegenerative disorder characterized by cerebral white matter degeneration with axonal spheroids, ballooned cortical neurons, reactive astrocytosis, and lipid- and pigment-laden macrophages [2, 3, 28].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [3]
White matter near the cortical gray-white junction had many axonal spheroids, frequent lipid-laden macrophages, relatively intact oligodendroglia, and less myelin loss.
“We also noted that white matter near the cortical gray-white junction had many axonal spheroids, frequent lipid-laden macrophages, relatively intact oligodendroglia, and less myelin loss [3].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [3]
Despite little overt neocortical pathology in HDLS, with the exception of ballooned or chromatolytic neurons, the study also observed heterogeneous distribution of microglia in neocortex.
“Despite little overt neocortical pathology in HDLS, with the exception of ballooned or chromatolytic neurons [3], we also observed heterogeneous distribution of microglia in neocortex.”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [3]
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“Since the clinical presentation of ALSP has not been clearly elucidated, many patients have been clinically misdiagnosed as having Alzheimer’s disease [4], frontotemporal dementia [1], corticobasal degeneration [5], multiple sclerosis (MS) [1] or cerebral autosomal dominant arteriopathy with subcortical infarcts and l…”
BackgroundLynch, D. S., Zhang, W. J., Lakshmanan, R., Kinsella, J. A., Uzun, G. A., Karbay, M., Tüfekçioglu, Z., Hanagasi, H., Burke, G., Foulds, N., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.2229 · Cited by 90 · see citing works
Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy
Kempthorne, L., Yoon, H., Madore, C., Smith, S., Wszolek, Z. K., Rademakers, R., Kim, J., Butovsky, O., & Dickson, D. W. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00947-0 · Cited by 77 · see citing works
“cephalopathy with spheroids and pigmented glia (ALSP) [23], is a progressive neurodegenerative disorder characterized by cerebral white matter degeneration with axonal spheroids, ballooned cortical neurons, reactive astrocytosis, and lipid- and pigment-laden macrophages [2, 3, 28].”
BackgroundInfluentialSelf-citation
- Authors
- Baba, Y., Ghetti, B., Baker, M. C., Uitti, R. J., Hutton, M. L., Yamaguchi, K., Bird, T., Lin, W., DeLucia, M. W., Dickson, D. W., & Wszolek, Z. K.
- Affiliations
- Mayo Clinic (US)
- Indiana University School of Medicine (US)
- University of Washington (US)
- Corresponding author
- Dickson, Dennis W.
- Venue
- Acta Neuropathologica
- Published
- 2006-03-08
- Volume
- 111
- Issue
- 4
- Pages
- 300-311
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2045466260
- Cited by
- 106
- References
- 7
- Citations by year
- 2025: 3 · 2024: 1 · 2022: 4 · 2021: 11 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 6 · 2014: 11 · 2013: 9 · 2012: 7
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG010133, U24AG021886)
- National Institute of Neurological Disorders and Stroke (P50NS040256)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Keywords
- hereditary diffuse leukoencephalopathy with spheroids, axonal swellings, autosomal dominant neurodegeneration, corticobasal degeneration, white matter degeneration, amyloid precursor protein, alphaB-crystallin, phosphorylated neurofilament, intermediate filaments, ballooned neurons, lipid-laden macrophages, familial kindred
- MeSH terms
- Adult, Aged, Aged, 80 and over, Axons, Brain, Dementia, Depression, Female, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Pedigree, Polymerase Chain Reaction, Amyloid beta-Protein Precursor, Neurodegenerative Diseases, Eukaryotic Initiation Factor-2B, alpha-Crystallin B Chain, Microscopy, Electron, Transmission
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