JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2133043): A 6-month-old West Highland white terrier
HISTOPATHOLOGIC DESCRIPTION: Spinal cord (thoracic and lumbar sections): Multifocally, within white matter tracks and occasionally in spinal nerve roots are small aggregates of plump macrophages up to 25 um, that that often aggregate around vessels or infiltrate myelin sheaths. Macrophages contain moderate to abundant amounts of amphophilic, fibrillar to flocculent cytoplasm that occasionally peripheralizes and compresses the nucleus (globoid cells). These cells are occasionally multinucleated. Multifocally, similar globoid cells extend into the spinal nerve roots.
MORPHOLOGIC DIAGNOSIS: Spinal cord, white matter: Histiocytosis (globoid cells), perivascular and multifocal, moderate, with demyelination, West Highland white terrier, canine.
CONDITION: Globoid cell leukodystrophy
SYNONYMS: Galactocerebrosidosis; galactosylceramide lipidosis; Krabbe’s disease
· Autosomal recessive lysosomal storage disease affecting primarily the white matter of both the CNS and PNS with accumulation of large, globose macrophages that contain abundant, PAS-positive material
· Defect in lysosomal galactocerebrosidase (galactosylceroside β-galactosidase) [GALC]; a type of sphingolipidosis
· Principal lesion is primary demyelination
· CNS: Affecting oligodendrocytes
· PNS: Affecting Schwann cells
· Affects several species including cat, sheep (polled Dorset) rhesus macaques, mice, sheep, dogs, and humans
· Has been well documented the West Highland white terrier, Cairn terrier, miniature poodle, bluetick coonhound, basset hound, beagle, Irish setter, and Australian kelpie
· Oligodendrocytes and Schwann cells produce galactosylceramide (galactocerebroside) and psychosine (galactosylsphingosine) which is catabolized by GALC to ceramide and galactose
· A deficiency of GALC, causes insufficient breakdown of galactosylceramide (galactocerebroside) and psychosine (galactosylsphingosine)
· Galactosylceramide is highly concentrated in myelin; while absent in systemic organs (except kidney)
· In large quantities, psychosine (galactosylsphingosine) is cytotoxic to oligodendrocytes
· Defect in lysosomal galactocerebrosidase (GALC) > accumulation of toxic psychosine within oligodendroglia, with release of galactosylceramide into extracellular space > galactosylceramide accumulates within macrophages, psychosine results in oligodendroglial death and demyelination
· Both peripheral blood-derived monocytes/macrophages and resident parenchymal microglia give rise to globoid cells
TYPICAL CLINICAL FINDINGS:
· Neurological signs typically appear between 3 and 5 months of age
· Initial signs include ataxia, hypermetria, tremors, and proprioceptive deficits
· Progression leads to blindness, anorexia, muscular atrophy, and paraplegia
· Death usually occurs before one year of age
TYPICAL GROSS FINDINGS:
· CNS is usually grossly normal except for a slight gray discoloration and firmness
· Ventricles may be dilated due to white matter loss
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Globoid cells: Single or multinucleate, eccentric nuclei, abundant granular (PAS-positive) cytoplasm
· Early stage: Lesions are bilaterally symmetrical with pronounced loss of myelin and striking perivascular accumulation of globoid cells
· Late stage: Globoid cells are less numerous with diffuse demyelination, axonal loss, axonal spheroids, and dense astrogliosis in the brain and spinal cord
· Also seen in the leptomeninges and in the endoneurium of peripheral nerves
· Cytoplasmic contents include myelin membranes in various states of degeneration
· Aggregates of straight or arched tubules of galactosylceramide bound by a membrane
ADDITIONAL DIAGNOSTIC TESTS:
· Globoid cell cytoplasm is PAS‑positive
· Nerve biopsy (antemortem); endoneurium of peripheral nerves
· Histologically distinct from other lysosomal storage diseases where material typically accumulates within neurons
· Twitcher mouse: Murine model for human GLD; recent research indicates that TLR-2 up-regulation in the hindbrain and cerebellum as a response to dying oligodendrocytes may play a role in the pathogenesis
· Rhesus monkey (Macaca mulatta): Nearly identical mutation to human GLD
· Globoid cell leukodystrophies are described in domestic shorthaired and longhaired cats, polled Dorset sheep, and other canine breeds
· Canine: globoid cell leukodystrophy in four Australian kelpie puppies; axonal spheroids (ubiquitin stained) were most prominent in the cerebellum
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