Glucocerebrosidosis

From Dog
Gaucher disease in the cerebellum of an Australian Silky Terrier, showing Gaucher cells present (arrow) in granular layer and loss of granule cells[1]

Neurovisceral glucocerebroside storage disease (Gaucher’s Disease) is a rare autosomal-recessive genetic lysosomal storage disease of dogs characterized by dysfunctional metabolism of sphingolipids and accumulation of glucocerebroside within lysosomes.

Also known as glucocerebrosidosis, acid beta-glucosidase deficiency and GBA deficiency, Gaucher disease is the most common lysosomal storage disorder and is caused by the defective activity of glucosylceramidase (also known as glucocerebrosidase), the lysosomal hydrolase that is responsible for the degradation of glucosylceramide[2]. As a result of the autosomal recessive genetic defect, these enzymes accumulate intracellularly. Tissue macrophages engorged with glycolipid-laden lysosomes (known as ‘Gaucher cells’) are the hallmark of the disease[3].

In humans, there is a wide spectrum of clinical manifestations from asymptomatic to severe neurological deficits[4], however a paucity of veterinary cases limits such classifications. Human classifications of types I to III are currently changing due to the continuum of clinical presentations[5].

The condition has been reported in the Australian Silky Terrier[1] and involved accumulation of glucocerebroside in most regions of the brain, liver and peripheral lymph nodes[6]. Because the canine case involved the brain as well as peripheral neuropathy and rapid clinical deterioration, canine glucocerebrosidosis closely resembles human juvenile glucocerebrosidosis.

Clinically affected dogs present at 6 - 8 months of age with poor weight gain, lymphadenopathy and progressive neurological signs. There is usually marked incoordination with general ataxia, a wide-based stiff gait, generalised trembling, hyperkinesis, hypermetria, exaggerated limb reflexes but normal sensory reflexes[7].

Diagnosis is based on presenting neurological signs, MRI imaging of the brain to exclude other differential neurological diseases, and histology of brain samples.

Histological analysis is usually diagnostic, with characteristic storage bodies in Gaucher cells containing tubular structures, characterized by mild to moderate spongy vacuolation of white matter. DNA testing is currently unavailable for this disease in dogs.

The condition usually progresses for four to six months after the onset of clinical signs, and is fatal. The younger the dog is when it begins to be affected, the more rapidly the signs progress. Due to the severity and lethal nature of the disease, affected dogs are often euthanased.

Experimental gene therapy is currently being investigated in human medicine and shows considerable promise as an effective palliative modality[8].

References

  1. 1.0 1.1 Hartley WJ & Blakemore WF (1973) Neurovisceral glucocerebroside storage (Gaucher's disease) in a dog. Vet Pathol 10(3):191-201
  2. Vitner EB et al (2010) Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem 285:20423–20427
  3. Farfel-Becker T et al (2011) Animal models for Gaucher disease research. Dis Model Mech 4(6):746-752
  4. Goker-Alpan O et al (2003) Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3. The Journal of pediatrics 143:273–276
  5. Sidransky E (2004) Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab 83:6–15
  6. Van De Water NS et al (1979) Canine Gaucher disease - the enzymic defect. Aust J Exp Biol Med Sci 57(5):551-554
  7. Dr Alexandra Brueckner, LIDA
  8. Blech-Hermoni YN et al (2010) In silico and functional studies of the regulation of the glucocerebrosidase gene. Mol Genet Metab 99(3):275-282