Felipedia

©C. J. Sigurdson, R. J. Basaraba, E. M. Mazzaferro and D. H. Gould. Globoid Cell-like Leukodystrophy in a Domestic Longhaired Cat. Vet Pathol 39:494-496 (2002). http://www.vetpathology.org/cgi/content/full/39/4/494

Globoid cell leukodystrophy (GLD; Krabbe disease) is an autosomalrecessive neurologic disease of dogs, mutant twitcher mice,rhesus monkeys, and humans that results from a deficiency ingalactocerebrosidase (GALC) enzyme activity.⁶ In dogs, GLD hasbeen described most commonly in Cairn Terriers and West HighlandWhite Terriers, with clinical signs arising between 1 and 3months of age, typically beginning with limb weakness and tremorsand progressing to muscular atrophy and neurologic degeneration.Dogs are typically euthanased by 9 months of age because ofthe severity of the disease.^7,9 Humans with the infantile formof Krabbe disease usually present 3–6 months after birthwith irritability, spasticity, and mental regression that progressesto a severe decerebrate condition and death before 2 years ofage.^2,10. To date, only a single report has been made of felineGLD, which occurred in two genetically related shorthaired kittens.³Here we report a naturally occurring case of GLD in a domestic longhaired cat.

A 12-week-old intact female domestic longhaired kitten presentedto the Veterinary Teaching Hospital at Colorado State Universitywith a 4-week history of body tremors that progressed to tetraparesis,rear limb extensor rigidity, and a firm distended urinary bladderthat was difficult to express (upper motor neuron bladder).By 15 weeks of age, the cat had hind limb paralysis and at 21weeks of age, she developed acute respiratory distress and died.The early posterior dysmetria and incoordination in this kittenwere similar to the single previous report of GLD in the cat³and the clinical course described in the dog,⁷ and resembledsigns of cerebellar hypoplasia.

Significant gross lesions consisted of kyphosis of thoracicand lumbar vertebrae T10–L1 and hindlimb muscle atrophy.The vertebral bodies of T12 and T13 were slightly more narrow ventrally than dorsally, resulting in mildly deformed wedge-shaped vertebrae. Histopathologically, marked alterations were foundin all brain and spinal cord sections examined. These includedcerebral cortex, striatum, thalamus, hippocampus, cerebellum,cerebellar peduncle, medulla oblongata, and spinal cord. Allwhite matter areas had diminished stain intensity with Luxolfast blue (LFB) staining and white matter vacuolation occurredin areas of severe involvement. Vessels of the white matterhad abundant accumulations of large, pale mononuclear cellswith fine cytoplasmic vacuoles (globoid cells) located largelyin the perivascular space but in vascular walls as well (Fig. 1). Globoid cells were 20–30 µm and had large, eccentricoval nuclei with coarsely stippled chromatin. White matter parenchymahad increased numbers of glial cells, including hypertrophicastrocytes. Gray matter areas were unaffected. No evidence ofcerebellar hypoplasia was found in this kitten.

Fig. 1. Brain at subcerebellar white matter; 21-week-old kitten. Large vacuolated mononuclear cells (globoid cells) accumulate in vascular walls and perivascular spaces (arrow) and are characteristic of GLD. HE. Bar = 100 µm.
Fig. 2. Brain at subcerebellar white matter; 21-week-old kitten. Prominent vascular accumulations of globoid cells and gliosis are evident. HE. Bar = 1 mm.

Regional neuroanatomic differences were noted that includedextensive vacuolation at the junction between the grey and whitematter of the cerebral cortex; perivascular accumulations ofeosinophilic, homogenous material indicative of vasogenic oedemain the thalamus; especially prominent vascular accumulationsof globoid cells in the white matter of cerebellar peduncles(Fig. 2); marked rarification of white matter parenchyma; anda small number of spheroids in the ventral funiculus of thespinal cord. Lung histopathology revealed diffuse mild congestionand oedema. The cause of the respiratory distress is unknown.

In the spinal cord, LFB staining was characterized by extensive,diffuse pallor of white matter indicative of myelin loss; however,spinal nerve roots had the staining characteristics of normalmyelin. Myelin loss as assessed by LFB pallor was also significantin the subcortical white matter of the cerebral and cerebellarcortex, the pons, and the fimbria of the hippocampus. The thalamuswas relatively spared of extensive myelin loss. Globoid cellcytoplasmic contents were periodic acid–Schiff stain positiveand non-metachromatic. Bodian staining demonstrated the presenceof nerve fibres in all white matter areas, including those ofmarked pallor. By immunohistochemistry, globoid cells were CD68and ferritin positive, suggesting an origin of bone marrow–derivedmacrophages. This finding is consistent with previous findingsof GLD in humans.² Controls used included the substitution ofconcentration-matched irrelevant mouse and rabbit antibodies.

GLD is an autosomal recessive disorder resulting in a deficiencyof GALC enzyme activity (confirmed by enzyme analysis⁶). Unfortunately,enzyme analysis on this kitten was not possible because alltissues were formalin fixed. GALC is actolipids involved inmyelin production.⁹ Therefore, in the absence of functionalGALC, galactosphingolipids, including psychosine, accumulate.Psychosine is highly toxic to oligodendrocytes⁸ and myelin productionand maintenance cease with degeneration of these cells.⁴ InGALC-deficient dogs, psychosine has been shown to accumulateduring active myelination and is elevated by 4 months of age, resulting in toxicity and death of oligodendrocytes and a scarcityof myelin.^7,9 Neuropathologic lesions of affected humans andother animals are typified by extensive demyelination, globoidcell accumulation in the white matter, and severe gliosis.^2,8

In this kitten, the appearance of the globoid cells may raisethe question as to the possible differential diagnosis of idiopathicgranulomatous inflammation. However, the homogenous populationof large globoid cells accumulating perivascularly along withthe LFB stain demonstrating myelin loss characterize this diseaseas a myelin disorder. Moreover, the accumulation of globoidcells seen in this kitten is characteristic of GLD previouslydescribed in other species.⁹ In contrast to the previous reportof feline GLD involving domestic shorthaired kittens, the presentcase involves a longhaired kitten. Unfortunately, this kittenwas acquired from a pet store and we were unable to characterizethe familial history. The accumulation of globoid cells in GLDdiffers significantly from other lysosomal storage diseaseswhere storage of hydrophilic substrates in lysosomes occursin many cell types.⁹

Recently, Im et al.¹ showed the molecular target of psychosineto be a G protein–coupled receptor known as T cell death–associatedgene 8. Moreover, the in vitro binding of psychosine to cellsexpressing this receptor leads to the formation of globoid multinuclearcells.¹ Studies of humans with GLD treated early with bone marrowtransplants have shown slowing of disease progression, providinghope for possible therapeutic intervention strategies.⁵ In summary,GLD does occur in the cat and the progression and neuropathologyof the disease mirror those of the naturally occurring diseasedescribed in dogs, rhesus monkeys, mutant twitcher mice, andhumans.

Feline globoid cell leukodystrophy