Gangliosidosis

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Markedly swollen neurons filled with the storage materials, characteristic of gangliosidosis in dogs[1]

Gangliosidosis is an autosomal-recessive genetic lysosomal storage disease of dogs characterized by various neurological symptoms.

This disease, which mirrors that of human gangliosidosis[2], results from a enzyme deficiency that causes accumulation of various carbohydrates (ganglioside) within the CNS, peripheral nerves and liver[3].

It is caused by structural defects of the beta-galactosidase gene, resulting in severe phenotypical impairment in homozygous individuals, while most heterozygous carriers are clinically asymptomatic carriers[4]. Accumulation of ganglioside in neurones results in neuronal apoptosis, inflamamtion and abnormal axonal transport[5].

Two variants are recognized in dogs:

Clinical signs become apparent from 5 - 6 months of age and include ataxia, muscle tremors, dysphagia, dysbasia (stiff-stilted gait), reduced postural reflexes, megaesophagus, corneal opacity[10] (swelling and dysfunction of keratocytes), blindness and salivary gland cysts[11]. Symptoms progressively worsen by 12 - 18 months, with abasia, collapse and respiratory distress, often requiring euthanasia due to poor quality of life parameters.

Diagnosis cannot be performed on clinical symptoms alone and requires CSF analysis (determined using thin-layer chromatography (TLC)–enzyme immunostaining)[12], which often shows elevated levels (up to 40 times higher than normal) of GM1 (monosialotetrahexosyl ganglioside) due to leakage into the CSF from the central nervous system[13].

A number of enzyme assays using leukocyte or tissue specimens[14] and PCR assays[15][16] are now available for definitive diagnosis.

Neonatal screening can also be performed on amniotic tissue samples[17] using specialist referral centers.

There is no known treatment for this disease and dogs gradually deteriorate and require euthanasia when quality of life is poor.

References

  1. Hasegawa D et al (2012) Serial MRI features of canine GM1 gangliosidosis: a possible imaging biomarker for diagnosis and progression of the disease. Scientific World Journal 2012:250197
  2. Kreutzer R et al (2008) Insights into post-translational processing of beta-galactosidase in an animal model resembling late infantile human G-gangliosidosis. J Cell Mol Med 12(5A):1661-1671
  3. 3.0 3.1 Tamura S et al (2010) GM2 gangliosidosis variant 0 (Sandhoff-like disease) in a family of toy poodles. J Vet Intern Med 24(5):1013-1019
  4. Kreutzer R et al (2008) Rapid and accurate G M1-gangliosidosis diagnosis using a parentage testing microsatellite. Mol Cell Probes 22(4):252-254
  5. Satoh H et al (2007) Cerebrospinal fluid biomarkers showing neurodegeneration in dogs with GM1 gangliosidosis: possible use for assessment of a therapeutic regimen. Brain Res 1133(1):200-208
  6. Kreutzer R et al (2009) Impact of beta-galactosidase mutations on the expression of the canine lysosomal multienzyme complex. Biochim Biophys Acta 1792(10):982-987
  7. Wang, ZH et al (2000) Isolation and characterization of the normal canine GLB1 gene and its mutation in a dog model of GM1-gangliosidosis. J Inherit Metab Dis 23:593–606
  8. Kreutzer R et al (2005) A duplication in the canine beta-galactosidase gene GLB1 causes exon skipping and GM1-gangliosidosis in Alaskan huskies. Genetics 170(4):1857-1861
  9. Matsuki N et al (2005) Magnetic resonance imaging of GM2-gangliosidosis in a golden retriever. Can Vet J 46(3):275-278
  10. Nagayasu A et al (2008) Morphological analysis of corneal opacity in Shiba dog with GM1 gangliosidosis. J Vet Med Sci 70(9):881-886
  11. Rahman MM et al (2012) Pathological features of salivary gland cysts in a Shiba dog with GM1 gangliosidosis: a possible misdiagnosis as malignancy. J Vet Med Sci 74(4):485-489
  12. Izumi T et al (1993) Normal developmental profiles of CSF gangliotetraose-series gangliosides from neonatal period to adolescence. Pediatr Neurol 9:297–300
  13. Satoh H et al (2011) Rapid detection of GM1 ganglioside in cerebrospinal fluid in dogs with GM1 gangliosidosis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. J Vet Diagn Invest 23(6):1202-1207
  14. Yamato O et al (2004) Comparison of polymerase chain reaction-restriction fragment length polymorphism assay and enzyme assay for diagnosis of GM1-gangliosidosis in Shiba dogs. J Vet Diagn Invest 16:299–304
  15. Yamato O et al (2004) Rapid and simple mutation screening of G(M1) gangliosidosis in Shiba dogs by direct amplification of deoxyribonucleic acid from various forms of canine whole-blood specimens. J Vet Diagn Invest 16(5):469-472
  16. Chang HS et al (2010) Rapid and reliable genotyping technique for GM1 gangliosidosis in Shiba dogs by real-time polymerase chain reaction with TaqMan minor groove binder probes. J Vet Diagn Invest 22(2):234-237
  17. Yamato O et al (2006) Use of amnion and placenta in neonatal screening for canine GM1-gangliosidosis and the risk of diagnostic misclassifications. Vet Clin Pathol 35(1):91-94