CNS nontumor
Disorders of CNS myelin
Leukodystrophies

Author: Jesse Kresak, M.D. (see Authors page)
Editorial Board review: Maria Martinez-Lage, M.D.

Revised: 21 August 2017, last major update June 2015

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Leukodystrophies CNS
Cite this page: Kresak, J., Martinez-Lage, M. Leukodystrophies. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cnsleukodystrophies.html. Accessed December 17th, 2017.
Definition / general
  • Leukodystrophy generally refers to a genetic disorder that affects white matter
  • Most often present in children, can occur in adulthood
  • Demyelination often progresses in occipital to frontal manner and there is often sparing of the U fibers (short association fibers, Wikipedia: Association Fiber)
  • Can result from a wide range of genetic defects involving formation, maintenance and breakdown of myelin
  • Most often classified based on etiology: peroxisomal, lysosomal and other
    • Peroxisomal: adrenoleukodystrophy and neonatal adrenoleukodystrophy
    • Lysosomal: Krabbe disease and metachromatic leukodystrophy
    • Other: Alexander disease, Canavan disease, vanishing white matter disease, others
Pathophysiology
  • Peroxisomal:
    • Adrenoleukodystrophy: X linked, single enzyme defect in ATP binding transporter, leads to reduced capacity to form coenzyme A derivative of very long chain fatty acids
    • Neonatal adrenoleukodystrophy: autosomal recessive, defective peroxisome assembly leads to decreased numbers of peroxisomes
  • Lysosomal:
    • Krabbe disease: autosomal recessive, galactocerebroside β-galactosidase deficiency
    • Metachromatic leukodystrophy: autosomal recessive (rarely autosomal dominant), aryl sulfatase A deficiency, rarely SAP-1
  • Other:
    • Alexander disease: sporadic, gain of function mutation of GFAP leads to Rosenthal fiber accumulation
    • Canavan disease: autosomal recessive, defective aspartoacylase activity
    • Vanishing white matter disease: autosomal recessive, mutation of genes involved in translation of factor EIF-2B
Clinical features
  • Varies depending on type and age at presentation
  • In infancy: often includes motor disabilities, macrocephaly, seizures or spasticity and developmental failure
  • In childhood: ataxia, vision changes, behavioral / educational issues
  • In adulthood: behavioral changes, psychosis, spasticity
Radiology description
Radiology images

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Marked loss of posterior white matter

Case reports
Treatment
Gross description
  • Coronal autopsy specimens often show unaffected gray matter, spared subcortical U fibers and either firm (adrenoleukodystrophy), chalky white matter (Krabbe, metachromatic leukodystrophy) or markedly softened white matter (vanishing white matter disease, Canavan disease)
Gross images

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Krabbe disease

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Vanishing white matter disease

Microscopic (histologic) description
  • Peroxisomal:
    • Adrenoleukodystrophy: severe demyelination in cerebral white matter, optic nerves and internal capsule, yet sparing of U fibers
    • May see lesions of different ages: new lesions with large aggregates of macrophages with demyelination and perivascular lymphoid aggregates; older lesions with gliotic scar and no macrophage activity
    • Adrenal glands show enlarged "ballooned" eosinophilic cells with striated cytoplasm
  • Lysosomal:
    • Krabbe disease: pathognomonic PAS+ "globoid macrophages" (may be multinucleated giant cells), extensive myelin and oligodendrocyte loss, reactive astrocytic gliosis
    • Metachromatic leukodystrophy: accumulation of PAS and Luxol fast blue / LFB+ macrophages that show brown metachromasia with acidified cresyl violet, toluidine blue or thionine on frozen sections
    • Also extensive myelin and axonal loss in white matter and corticospinal tracts
    • Deposition of metachromatic sulfatides can also be seen in basal ganglia, numerous deep nuclei and peripheral nerves
  • Other:
    • Alexander disease: abundant Rosenthal fibers (especially perivascular, subpial and periventricular) with diffuse demyelination of white matter
      • Rosenthal-like fibers can be seen in cell bodies of astrocytes
    • Canavan disease: white matter vacuolation and demyelination predominantly at gray white junction; "spongiform leukodystrophy"
    • Vanishing white matter disease: significant cavitation of white matter with excessive oligodendrocytes in pericavity residual white matter
Microscopic (histologic) images

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Peroxisomal:
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X linked adreno-leukodystrophy: gliosis and inflammation



Lysosomal:
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Krabbe disease: globoid cells

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Metachromatic leukodystrophy: loss of myelin

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Metachromatic
leukodystrophy:
brown metachromasia
in peripheral nerve



Other:
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Pelizaeus-Merzbacher disease: loss
of myelin

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Pelizaeus-
Merzbacher
disease: cerebellar
degeneration

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Alexander disease, Rosenthal
fibers

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Canavan disease

Positive stains
  • Demyelination is highlighted by loss of Luxol fast blue (LFB), often (but not always) with spared axons demonstrated by neurofilament protein and accompanied by macrophages
  • Macrophages: CD68+, also positive for PAS in Krabbe and metachromatic leukodystrophy
  • Reactive gliosis highlighted by GFAP
Electron microscopy images

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Peroxisomal:
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X linked adreno-leukodystrophy: trilamellar lipid products



Lysosomal:
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Metachromatic leukodystrophy: storage of sulfatides

Differential diagnosis