JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M13

 

Signalment (JPC #1590567): German shorthair pointer, age unspecified.   

 

HISTORY: Clinical signs of increased nervousness and a decreased ability for training were first observed at approximately six months of age. By one year of age, clinical signs had progressed to ataxia which became the most distinct sign of the general progressive neurologic impairment. Vision became reduced, but the dog never became completely blind.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum, cortical grey matter; brainstem, grey matter nuclei: Diffusely, neurons are swollen up to 55 µm in diameter, have rounded borders, and contain abundant pale, finely granular to foamy, amphophilic to pale eosinophilic cytoplasm and a peripheralized nucleus. Low numbers of glial cells with similar pale, foamy cytoplasm and peripheralized nuclei surround swollen neurons and cortical vessels. Predominantly within the cerebrum, moderate numbers of macrophages with previously described cytoplasm and peripheralized nuclei multifocally expand Virchow-Robin space.  

 

MORPHOLOGIC DIAGNOSIS: Cerebrum and brainstem: Neuronal vacuolation, cytoplasmic, diffuse, moderate, with multifocal intraglial and intrahistiocytic cytoplasmic vacuolation, German shorthair pointer, canine.

 

ETIOLOGY: Autosomal recessive lysosomal β-hexosaminidase deficiency

 

ETIOLOGIC DIAGNOSIS: Hereditary lysosomal neuropathy

 

CONDITION: GM2 gangliosidosis

 

SYNONYMS: Tay-Sachs disease, Sandhoff disease 

 

GENERAL DISCUSSION: 

Lysosomal storage diseases:

• Categorized according to the dominant storage material: sphingolipidoses, glycoproteinoses, mucopolysaccharidoses, glycogenosis, mucolipidoses, ceroid-lipofuscinoses
• Progressive, lethal, and multisystemic
• In general, lysosomal digestion is impaired by deficient activity of various lysosomal acid hydrolases because of a genetic defect
• Most are autosomal recessive
• Often gene-dose dependent: heterozygotes are phenotypically normal but enzyme activity is reduced by approximately 50%
• Most types affect juveniles (if enzyme activity is reduced, but not absent, age at onset of clinical signs is later and signs are milder)

 

Sphingolipidoses: caused by genetic defect in catabolism of sphingolipids (sphingomyelin and gangliosides/glycosphingolipids); include:

• GM1 and GM2 (Tay-Sachs) gangliosidosis
• Glucocerebrosidosis (Gaucher disease)
• Spnigomyelinosis (Niemann-Pick disease)

 

PATHOGENESIS: 

• Gangliosides are normal membrane constituents active in cell recognition and adhesion; neuronal signal transduction, outgrowth, and differentiation
• Ganglioside-containing vesicles fuse with lysosomes à phagolysosomes à decreased enzymatic breakdown or decreased egress à retention of ganglioside and globoside in lysosomes àcell distention and dysfunction à apoptosis
• Neurons primarily affected: long-lived, accumulate significant amounts of product
• Macrophages are often affected due to phagocytosis of material
• GM1 gangliosidosis: deficiency in β-galactosidase à buildup of GM1 ganglioside
• GM2 gangliosidosis: deficiency in hexosaminidase (or activator protein GM2A) à buildup of GM2 ganglioside and globoside
  1. Hexosaminidase has two forms: Hex A (α-β) and Hex B (β-β)

 

TYPICAL CLINICAL FINDINGS: 

• Early age onset of discrete head and limb tremors, dysmetria
• Progressive neurological signs +/- neurogenic muscle atrophy
• Behavioral changes (aggression, apprehension) 
• Blindness, quadriplegia, somnolence, and seizures

 

TYPICAL GROSS FINDINGS:

• Brain may be rubbery and firm
• +/- Hepatomegaly, splenomegaly

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Foamy, faintly eosinophilic cytoplasm in neurons, glial cells and macrophages with nucleus and Nissl substance displaced peripherally (storage material lost in paraffin processing)
• +/- Axonal spheroids in white matter and peripheral nerves due defects in retrograde axonal transport and degenerating organelles

• Meganeurites: swollen compartments in the beginning of the axon; form of focal hypertrophy to increase storage space; occur in pyramidal system, thalamic relay nuclei
• Torpedo-like axonal swellings in granular cell layer of cerebellum
• End stage: Degenerate, apoptotic, or necrotic neurons; gliosis; demyelination

• Less pronounced vacuolation in hepatocytes, leukocytes, renal tubular epithelium, pancreatic acinar cells, retinal neurons, and corneal stromal cells

 

ULTRASTRUCTURAL FINDINGS:

• Membrane-bound vacuoles distended with membranous cytoplasmic bodies arranged in concentric whorls, often with an electron-dense amorphous core
• Tangential sections through membranous cytoplasmic bodies may appear as stacked, parallel membranes referred to as zebra bodies
• Axonal spheroids contain degenerate mitochondria, membrane-bound dense bodies, and tubulovesicular profiles

 

ADDITIONAL DIAGNOSTIC TESTS:

• Cytoplasmic inclusions in circulating leukocytes suggestive of gangliosidoses
  • In frozen sections, storage material is PAS positive; +/- Toludine blue, Luxol fast blue, Sudan black positive
  • Golgi silver impregnation allows visualization of aberrant dendritic spines on swollen cells in the cerebral cortex, thalamus
  • Thin-layer chromatography/enzyme immunostaining on frozen brain sections and cerebrospinal fluid
  • Recent development of quantitative PCR to screen for disease and carrier state in cats; rapid, accurate and inexpensive; also used to screen for carriers in Shiba dogs

 

DIFFERENTIAL DIAGNOSIS:

 

COMPARATIVE PATHOLOGY: Spingolipidoses

 

GM1 Gangliosidosis:

• Cats: DSH, Korat, Siamese
• Dogs: Alaskan husky, beagle, English springer spaniel, Portuguese water dog, Shiba inu
• Reported in free-ranging black bears in northeastern United States; cytoplasmic vacuolization present in brain, retina, renal proximal tubules, hepatocytes, chondrocytes
• Other species: Friesian cattle; Coopworth-Romney sheep; emu; an adult pet rabbit
• Suffolk sheep have a dual enzyme deficiency involving β1-galactosidase and α-neuraminidase which phenotypically resembles GM1 gangliosidosis 
  1. In mice, schipperke dogs: deficiency in these two enzymes causes galactosialidosis with accumulation of gangliosides and oligosaccharides

 

GM2 Gangliosidosis:

• Tay Sachs disease (humans) may be caused by α subunit defect (B variant) or inactivity (B1 variant) resulting in deficient activity of Hex A; similar defect documented in Jacob sheep and Japanese chin dogs

• Sandhoff disease (humans) caused by deficiency in β subunit and deficient activity of both Hex A and B; similar defect documented in Yorkshire pig; Korat & DSH cats; Japanese spaniel, German shorthair pointers, golden retrievers, toy poodles 
• GM2A mutation has been documented in cats
• Rarely occurs in juvenile flamingos

 

Glucocerebrosidosis (Gaucher disease):

• Glucocerebrosidase leads to accumulation of glucocerebrosides (derived from the catabolism of ganlgiosides and in homeostasis is broken down to ceramide)
• Most common LSD in humans
• Storage material accumulates in macrophages (liver, lymph nodes), some neurons (not Purkinje cells or spinal cord)
• Ultrastructure: twisted, branching tubular material in lysosomes of macrophages (Gaucher cells); in neurons the material resembles membranous cytoplasmic bodies/zebra bodies
• Documented in Sydney silky terrier

 

Sphingomyelinosis (Niemann-Pick types A and C disease):

• Documented in Siamese, DSH, Balinese cats; miniature poodles, Hereford cattle
• Type A: Deficient sphingomyelinase encoded by SMPD1; most animal cases resemble Type A; recent article described Niemann-Pick disease type A in a kitten with a novel SMPD1 mutation (Vet Pathol 2020)
• Type C: Deficient NPC1 (cholesterol transport) or NPC2 (lysosomal cholesterol binding) protein; cats and boxer dogs 
• Types A and C cause buildup of sphingomyelin, cholesterol, and gangliosides in neurons, macrophages in multiple organs
• Type B does not affect the central nervous system

 

REFERENCES:

1. Buckles EL. Phoenicopteriformes. In: Terio KA, McAloose D, St. Leger J, Eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:690.
2. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1, 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:287-288.
3. Jolly RD, Walkley SU. Lysosomal storage diseases of animals: An essay in comparative pathology. Vet Pathol. 1997; 34: 527-548. 
4. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio KA, McAloose D, St. Leger J, Eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:233-234.
5. Kumar V, Abbas AK, Fausto N, Aster JC. Genetic disorders. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier Saunders; 2021:154-160.
6. Miller AD, Porter BF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:943-945.
7. Takaichi Y, Chambers JK, Kok MK, et al. Feline Niemann-Pick Disease with a Novel Mutation of SMPDI Gene. Vet Pathol. 2020; 57(4): 559-564.

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