GlJPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M10

 

Signalment (JPC #2133043): A 6-month-old West Highland white terrier

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord, thoracic and lumbar sections: Multifocally and frequently within white matter funiculi and occasionally extending into spinal nerve roots are small aggregates of plump macrophages that often aggregate around vessels or infiltrate myelin sheaths. Macrophages are up to 25 µm in diameter and contain moderate to abundant amounts of amphophilic, granular to flocculent cytoplasm that occasionally peripheralizes and compresses the nucleus (globoid cells). These cells are occasionally multinucleated. Diffusely within the white matter, there is moderate spongiosis as well as dilation of myelin sheaths that occasionally contain fragmented axonal debris. 

 

MORPHOLOGIC DIAGNOSIS: Spinal cord, white matter: Histiocytosis (globoid cells), perivascular and multifocal, moderate, with demyelination, West Highland white terrier, canine.

 

CONDITION: Globoid cell leukodystrophy (GLD)

 

SYNONYMS: Galactocerebrosidosis; galactosylceramide lipidosis; Krabbe’s disease

 

GENERAL DISCUSSION: 

• 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 

• In dogs, has been well documented the West Highland white terrier, Cairn terrier, miniature poodle, bluetick coonhound, basset hound, beagle, Irish setter, and Australian kelpie 

 

PATHOGENESIS:

• Oligodendrocytes and Schwann cells produce galactosylceramide (galactocerebroside) and psychosine (galactosylsphingosine) which are normally catabolized by GALC to ceramide and galactose and are recycled in the re-myelinization pathway 
  • Galactosylceramide is highly concentrated in myelin; while absent in systemic organs (except kidney) > oligodendroglia and Schwann cells are principally affected
• A decrease in lysosomal GALC enzymatic activity causes insufficient breakdown/catabolism of galactosylceramide and psychosine 

• Galactosylceramide is released into the extracellular space -> taken up by macrophages, but not degraded
• Psychosine accumulates within oligodendroglia, is cytotoxic to oligodendrocytes -> 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 of white matter and firmness
• Ventricles may be dilated due to white matter loss (hydrocephalus ex vacuo)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Globoid cells: Distinctive feature; macrophages with single or multiple, eccentric nuclei and 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  
• Globoid cells are also seen in the leptomeninges and in the endoneurium of peripheral nerves

 

ULTRASTRUCTURAL FINDINGS:

• 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); PAS-positive globoid cells in endoneurium 

 

DIFFERENTIAL DIAGNOSIS:

• Histologically distinct from other lysosomal storage diseases where material typically accumulates within neurons
• Histologic differentials for accumulations of swollen macrophages (or morphologically similar cells) in the CNS:

• Granulomatous meningoencephalitis (N-M26): Disseminated form and focal form; lesions nearly completely restricted to white matter; perivascular cuffs of lymphocytes and macrophages (often epithelioid); spinal cord involvement is common
• Necrotizing meningoencephalitis:  Cerebral hemispheres with bilateral foci of malacia and discoloration; robust nonsuppurative meningoencephalitis with marked gliosis; spinal cord involvement is uncommon; affects small breed dogs
• Granular cell tumor (N-N10):  Mass effect expected; not reported in the CNS in dogs (reported in CNS in rats)

• Necrotizing leukoencephalitis: Cerebral white matter cavitation and necrosis with gliosis and gitter cells; affects Yorkshire terriers and occasionally other small breed dogs

 

COMPARATIVE PATHOLOGY:

GLD reported in several other species: 

• Cat: described in domestic shorthaired and longhaired cats
• Sheep: described in polled Dorset sheep and one Merino sheep (Lee et.al., J Vet Diagn Invest 2019)
• Rhesus macaques: Rhesus monkey (Macaca mulatta):  Nearly identical mutation to human GLD
• Mice: Twitcher mouse is the 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 
• Humans  

 

References:

1. Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012: 750, 753-754.
2. Cantile C, Youssef S.  Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th ed. Philadelphia, PA: Elsevier Saunders; 2016: 339-342. 
3. Frosch MP, et al. The central nervous system. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9^th ed. Philadelphia, PA: Elsevier; 2015: 1302.
4. Lee E, Fuller M, Carr M, Manavis J, Finnie J. Globoid cell leukodystrophy (Krabbe disease) in a Merino sheep. Jour Vet Diagn Invest. 2019;31(1):118–121.
5. Miller AD, Zachary JF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO: Mosby Elsevier; 2022: 944-947, 987.
6. Snook ER, et. al. Innate immune activation in the pathogenesis of a murine model of globoid cell leukodystrophy. Am Jour Pathol. 2014;184(2):382-296.
7. Vandevelde M, Higgins RJ, Oevermann, A. Veterinary Neuropathology. Ames, IA: Wiley-Blackwell; 2012: 174-176, 179, 180.

 

 

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