Hello test xxxxSELECT * FROM cases WHERE caseID = "88" Conference 22 - 2007    Case: 3       20080416


Signalment:  

An approximately 14-week-old, male, European Burmese kitten (Felis catus) presented for euthanasiaNervous signs including ataxia, dysmetria, head and limb tremors and constant loud purring


Gross Description:  

Necropsy was unremarkable with no gross lesions observed


Histopathologic Description:

Histologically neurons throughout the brain are diffusely swollen with abundant finely granular foamy cytoplasm which often displaces the nucleus to the periphery (Fig. 3-1). Small numbers of individual neurons are shrunken, with deeply basophilic clumped chromatin material and with variable degree of cytoplasmic hypereosinophilia. Many glial cells contain a single, large, clear discrete vacuole which displaces the nucleus to the periphery. Additional lesions include many hypereosinophilic and swollen axons with dilated myelin sheaths (Fig. 3-2). The fragmented myelin sheath of a few axons form ellipsoids arranged in a row which contain small amounts of eosinophilic granular necrotic debris and macrophages (digestion chambers) (Fig. 3-3). Electron microscopy revealed the presence of characteristic electron-dense concentric lamellar membranous whorls, separated by clear spaces (membranous cytoplasmic bodies) within the neuronal somata (Fig. 3-4).


Morphologic Diagnosis:  

Cerebrum: Neuronal vacuolation, cytoplasmic, diffuse, severe, with neuronal degeneration and necrosis and axonal degeneration, European Burmese, feline


Lab Results:  

Enzyme assays for total hexosaminidase, _-hexosaminidase and control lysosomal enzymes, _-galactosidase and mannosidase and molecular analysis was conducted under Dr. Henry J. Baker at Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University. The tests revealed a deficiency in total hexosaminidase activity, identifying the disease as a variant of GM2 gangliosidosis. Further molecular analysis identified a deletion in the subunit of the hexosaminidase gene as the cause of disease. Though virology was not conducted on samples from this kitten, no virus could be isolated from a previously submitted kitten from the same litter with similar clinical signs and lesions.


Condition:  

GM2 gangliosidosis


Contributor Comment:  

Lysosomal storage disorders are a diverse group of mainly autosomal recessive inherited diseases that can result from the lack of any protein that is necessary for the normal functioning of lysosomal degradation pathways.5 Lysosomal acid hydrolases are important for the catabolism of a variety of macromolecules. Faulty breakdown of these macromolecules results in their accumulation within the lysosomes, which progressively enlarge and lead to interference with normal cell functions. Although initially described as disorders that are caused by the deficiency of lysosomal enzymes, lysosomal storage disorders can also occur through defective posttranslational modification of lysosomal enzymes, lack of enzyme activator, lack of substrate activator, or the lack of transport proteins required for the removal of digested material from the lysosomes.5 The organs affected by particular lysosomal storage diseases are determined by the tissue in which the substrate to be degraded is found and where it is degraded.5

Biochemically, the inherited lysosomal storage diseases can be broadly divided into sphingolipidoses, cholesterol ester storage disease, glycoproteinoses, glycogenoses, mucopolysaccharidoses, mucolipidoses and ceroid-lipofuscinoses.3 Sphingolipidoses comprise diseases in which there is a failure to properly catabolize various complex lipids derived from ceramide.3 These include GM1 and GM2 gangliosidosis, galactocerebrosidosis, glucocerebrosidosis, sphingomyelin lipidosis and galactosialidosis.3 GM2 ganglioside is a cell membrane glycolipid which is catabolized by the action of N-acetylyhexosaminidase and GM2 activator (GM2A) protein.6,7 N-acetylyhexosaminidase exists as a dimer in two forms, __ (hexosaminidase A) and __ (hexosaminidase B). Improper functioning of either one of these subunits (_ or _) or GM2A results in accumulation of GM2 ganglioside in the lysosomes of neurons leading to a progressive deterioration of the central nervous system (GM2 gangliosidosis).6,7 Tay-Sachs disease of humans is a GM2 gangliosidosis caused by a mutation in the _ subunit resulting in the deficiency of hexosaminidase A, whereas Sandhoff disease is caused by mutation of _ subunit which affects both hexosaminidase A and B.3 GM2 gangliosidosis has been previously described in German shorthaired pointer and Japanese Spaniel dogs, domestic short haired and Korat cats, and Muntjak deer.1,3

GM1 gangliosidosis (generalized gangliosidosis) is caused by the deficiency of _ galactosidase which cleaves the terminal galactose from GM1 ganglioside. GM1 gangliosidosis has been described in dogs, cats, cattle and sheep.3 Galactocerebrosidosis (globoid cell leukodystrophy, Krabbe disease of humans) is primarily a leukodystrophy and has been described in dogs, cats and sheep. Galactocerebrosides are found in myelin sheaths and the deficiency of galactocerebrosidase causes accumulation of the lipids in the macrophage-like -�-�globoid cells and in oligodendrogial cells.3 Glucocerebrosidosis (Gaucher disease of humans) is caused by a deficiency in the lysosomal enzyme glucocerebrosidase, a _-glucosidase, which results in the accumulation of the lipid glucocerebroside in neurons and in macrophages. The disease has been described in Sydney Silky dogs.3 Sphingomyelin lipidosis (Niemann-Pick disease of humans) is caused by a deficiency of sphingomyelin phosphodiesterase (sphingomyelinase) which results in the accumulation of sphingomyelin in neurons and macrophages. The disease has been described in cats and a single case in miniature Poodle dog.3


JPC Diagnosis:  

Brain, cerebrum, neurons and glia: Cytoplasmic vacuoles, diffuse, moderate, European Burmese (Felis catus), feline.


Conference Comment:  

The contributor gives an excellent overview of the sphingolipidoses. GM2 gangliosidosis results from a defect in only one of three gene products, the _-subunit, the β-subunit or the GM2 activator. Three variant forms of GM2 gangliosidosis have been described and are based on the specific subunits that retain functionality: Variant B (_-subunit deficiency), variant 0 (β-subunit deficiency), and variant AB (GM2 activator deficiency).7

Neurons of the central and autonomic nervous system and retina are primarily affected.5 Typical histopathologic findings in GM2 gangliosidosis include swollen neurons with cytoplasmic vacuoles consisting of lysosomes distended with accumulated gangliosides. Oil red O and Sudan black B may stain storage material in astrocytes and macrophages.3,5 With electron microscopy (EM), the cytoplasmic inclusions are visualized and consist of membrane layers forming "onion-skin" whorls within the lysosomes.5

Lysosomal storage bodies visualized on EM are not considered characteristic of a particular storage disorder. In general, GM1 and GM2 may form similar concentric lamellations, whereas in mucopolysaccharide storage diseases, membranous stacks (zebra bodies) are more common.3 Abnormal twisted tubular structures are often seen in glucocerebrosidosis and galactocerebrosidosis, while glycogen particles may be seen in the glycogen storage diseases.3


References:

1. Fox J, Li YT, Dawson G, Alleman A, Johnsrude J, Schumacher J, Homer B. Naturally occurring GM2 gangliosidosis in two Muntjak deer with pathological and biochemical features of human classical Tay-Sachs disease (type B GM2 gangliosidosis). Acta Neuropathol 97: 57-62, 1999
2. Hasegawa D, Yamato O, Kobayashi M, Fujita M, Nakamura S, Takahashi K, Satoh H, Shoda T, Hayashi D, Yamasaki M, Maede Y, Arai T, Orima H: Clinical and molecular analysis of GM2 gangliosidosis in two apparent littermate kittens of the Japanese domestic cat. J Feline Med Surg 9:232-237, 2007
3. Jolly RD, Walkley SU. Lysosomal storage diseases of animals: An Essay in Comparative Pathology. Vet Pathol 34:527-548, 1997
4. Kroll RA, Pagel MA, Roman-Goldstein S, Barkovich J, D'Agostino AN, Neuwelt EA: White matter changes associated with feline GM2 gangliosidosis (Sandhoff disease): Correlation of MR findings with pathologic and ultrastructural abnormalities. Am J Neuroradiol 16:1219-1226, 1995
5. Kumar V, Abbas, AK, Fausto N: Genetic disorders. In: Robbins and Cotran Pathologic Basis of Disease, 7th ed., pp. 158-168. Elsevier Saunders, Philadelphia, PA, 2005
6. Martin DR, Krum BK, Varadarajan GS, Hathcock TL, Smith BF, Baker HJ. An inversion of 25 base pairs causes feline GM2 gangliosidosis variant. Exp Neurol. 187:30-37, 2004
7. Martin DR, Cox NR, Morrison NE, Kennamer DM, Peck SL, Dodson AN, Gentry AS, Griffin B, Rolsma MD, Baker HJ. Mutation of the GM2 activator protein in a feline model of GM2 gangliosidosis. Acta Neuropathol 110:443-50 2005
8. Yamato O, Satoh H, Matsuki N, Ono K, Yamasaki M, Maede Y: Laboratory diagnosis of canine GM2-gangliosidosis using blood and cerebrospinal fluid. J Vet Diagn Invest 16:39-44, 2004
9. Yamato O, Matsunaga S, Takata K, Uetsuka K, Satoh H, Shoda T, Baba Y, Yasoshima A, Kato K, Takahashi K, Yamasaki M, Nakayama H, Doi K, Maede Y, Ogawa H: GM2-gangliosidosis variant O (Sandhoff-like disease) in a family of Japanese domestic cats. Vet Rec 155:739-744, 2004

A virtual slide is not available for this case.



(Fig 3-1) . Cerebrum, cat


(Fig 3-2) Cerebrum, cat


(Fig 3-3) Cerebrum, cat


(Fig 3-4) TEM, cerebrum



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