CNS non tumor
Disorders of CNS myelin
Leukodystrophies

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

Revised: 19 November 2015, last major update June 2015

Copyright: (c) 2005-2015, PathologyOutlines.com, Inc.

PubMed Search: Leukodystrophies [title] CNS
Cite this page: Leukodystrophies. PathologyOutlines.com website. http://pathologyoutlines.com/topic/cnsleukodystrophies.html. Accessed February 22nd, 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)
  • 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

Micro 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 peri-cavity residual white matter
Micro Images
Peroxisomal:

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X-linked
adrenoleukodystrophy: gliosis and inflammation, trilamellar lipid products EM)



Lysosomal:

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Krabbe disease:
Globoid cells

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Metachromatic leukodystrophy: left-loss of myelin, center-brown metachromasia in peripheral nerve, right-storage of sulfatides (EM)



Other:

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Pelizaeus-Merzbacher disease: left-loss of myelin; right-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
Differential Diagnosis