JPC SYSTEMIC PATHOLOGY
Signalment: (JPC #1641269): Angus calf
HISTORY: This calf developed hindlimb incoordination and fine intention tremors of the head at 2 months of age.
Slide A: Cerebellum and brainstem: Multifocally, neuronal cell bodies within the gray matter of the brainstem and cerebellar Purkinje cells are rounded and swollen up to twice normal with abundant microvacuolated eosinophilic cytoplasm that peripherally displaces nuclei and Nissl substance. Purkinje cells are multifocally lost. There are few swollen axons with hypereosinophilic, finely granular axoplasm (spheroids). Spheroids within the cerebellum are occasionally present within the granular cell layer (torpedoes).
Slide B: Exocrine pancreas: Diffusely, acinar cells are mildly swollen by numerous intracytoplasmic, 2 to 3um clear vacuoles, often with loss of zymogen granules. Focally, within a ganglion in the interlobular septa, neuronal cell bodes are rounded, swollen up to twice normal, and filled with abundant microvacuolated eosinophilic cytoplasm that frequently peripherally displaces nuclei and Nissl substance.
Lymph node: Diffusely, medullary sinuses are moderately expanded by increased numbers of macrophages with abundant microvacuolated cytoplasm. Within the cortex lymphoid follicles are enlarged, and coalescing, often with enlarged, pale, germinal centers (lymphoid hyperplasia).
1. Brainstem and cerebellum: Neuronal vacuolation and loss, multifocal, moderate, with spheroids and torpedoes, Angus, bovine.
2. Pancreas, acinar cells; ganglion neurons: Vacuolation, diffuse, moderate.
3. Lymph node, site unspecified: Sinus histiocytosis, diffuse, moderate, with marked vacuolation of histiocytes.
CAUSE: Autosomal recessive lysosomal alpha‑mannosidase deficiency
· Glycoproteinoses are a group of diseases with defective degradation of the carbohydrate component of N-linked glycoproteins:
o Alpha-mannosidosis, beta-mannosidosis and fucosidosis
· Alpha-mannosidosis is a lysosomal storage disease due to a deficiency of lysosomal alpha-mannosidase in all cells except hepatocytes
· Primarily seen in Aberdeen Angus, Galloway, Murray Grey breeds.
· Storage vacuoles are commonly found in pancreas, kidney, endothelia, macrophages, and fibrocytes
· Autosomal recessive
· Synthesis of a defective enzyme protein> deficient lysosomal alpha-mannosidase activity> defective degradation of the carbohydrate component of N-linked glycoproteins> lysosomal buildup of variety of water‑soluble mannose-containing oligosaccharides derived from high-mannose, complex, and hybrid oligosaccharides
· Occurs (typically in ruminants) following ingestion of the toxic plants: Swainsona sp. (Australia) and Astragalus and Oxytropis sp. (North American locoweeds), Sida carpinifolia (South America), Ipomoea sp. (Africa and Brazil)
· The active principle, swainsonine, is an indolizidine alkaloid and is a potent inhibitor of lysosomal alpha-mannosidase
· Biochemically distinct from the congenital form because the alkaloid also inhibits Golgi alpha-mannosidase, the enzyme associated with oligosaccharide processing during protein glycosylation
· Microscopically and ultrastructurally identical to the genetic disease
· Clinical findings: Effects appear weeks after ingestion of toxic plants:
o Depression, dull appearing eyes, incoordination progressing to aberrant behavior, including: aggression, staggering, and solitary behavior; emaciation, and death
· Associated problems include: Reproductive failure, abortion, birth defects (if ingested by pregnant animals), weight loss and enhanced susceptibility to brisket disease (at high elevations)
· Recovery: Possible if animals are removed from pasture early; in late stages, neuronal changes may be permanent
TYPICAL CLINICAL FINDINGS:
· Calves exhibit retarded growth, progressive ataxia, and behavioral changes
· Death usually occurs by 18 months
TYPICAL GROSS FINDINGS:
· Mild to moderately dilated ventricles
· Enlarged liver and kidney; maxillary brachygnathia
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Neuronal vacuolation is prominent and widespread; common sites include: Purkinje cells, parasympathetic nucleus of the vagus, hypoglossal nucleus, and spinal somatic motor neurons
· Secondary axonal swelling (spheroids or meganeurites)
· Lipofuscin accumulates in the glial cells, and there is slow, progressive neuronal loss and demyelination
· Storage vacuoles appear empty (material extracted during tissue processing)
· Cytoplasmic vacuolation also occurs in other tissues, becoming more pronounced with age
· Macrophages (including Kupffer cells); fibroblasts; vascular endothelium; epithelial cells of exocrine glands, especially in the pancreas, and renal epithelium
· Deficient myelination and axonal degeneration within white matter
· Vacuoles surrounded by a single, tripartite membrane approximately 9nm thick
· Most vesicles are electron lucent but can contain amorphous electron‑dense material and occasional membranous fragments of fibrillar material
ADDITIONAL DIAGNOSTIC TESTS:
· Tentative diagnosis can be made based on the breed of the animal, age, and clinical signs
· Electron microscopy
· Partial identification using special stains and lectin binding patterns
· Diagnosis made by plasma alpha‑mannosidase levels
o Absence of plasma alpha‑mannosidase activity is diagnostic in homozygotes
o Activity less than 50% of normal is diagnostic for heterozygotes
· Both the congenital and acquired forms of the disease exhibit positive staining
with lectin histochemistry
· Beta-mannosidosis: Salers cattle and Nubian goats; does not affect the lung, heart, skeletal muscle, liver, jejunal epithelium, pancreas, adrenal gland, or eyes; renal enlargement common
· Hydrolysis of the final mannose residue usually follows that of the alpha-linkages; autosomal recessive deficiency of beta-mannosidase> storage of di- or trisaccharides containing one molecule of mannose
· Vacuolated neurons and macrophages (especially in internal capsule, cerebellar white matter and basal ganglia), numerous axonal spheroids
· There is also intense storage in most other tissues (as for alpha-mannosidosis)
· GM1 gangliosidosis: Friesian calves with defective beta-galactosidase> accumulation of GM1 ganglioside (PAS-positive material); characteristic concentric membranous whorls in the cytoplasm on EM
· Angus cattle are an animal model of this human disease
· Fucosidosis results from a deficiency of lysosomal a-L-fucosidase resulting in accumulation of glycolipids and oligosaccharides containing the sugar fucose
· Severe disease with delayed onset (usually starts at 6 months old); autosomal recessive
· Gross lesion: swelling of cervical portion of vagus nerves, cervical nerves and dorsal root ganglia
· Microscopically: vacuolation in most tissues (appears empty as with mannosidosis); in CNS is in neurons, macrophages, astrocytes and microglial cells
· Alpha-mannosidosis reported in Persian, domestic shorthair and longhair cats
· Persians and domestic shorthair: retarded growth, tremors, hepatomegaly; intense neuronal storage and hypomyelination in cerebrum; widespread axonal degeneration; as with bovine disease, extensive storage in other tissues
· Domestic longhair: Reported as milder and more slowly progressive but there is often loss of Purkinje cells; no pancreatic acinar cell involvement, ocular abnormalities, hepatomegaly or myelin deficiency
· Skeletal deformities frequent
1. Cheville NF. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed. Ames, IA: Wiley-Blackwell; 2009:863-864.
2. Driemeier D, Colodel EM, Gimen EJ, Barros SS. Lysosomal storage disease caused by Sida carpinifolia poisoning in goats. Vet Pathol. 2000;37(2):153-159.
3. Laurent S, Sabot AS, Colle MA, Nicolier A. Lysosomal storage disease in two presumed-related springboks (Antidorcas marsupialis). J Zoo Wildl Med. 2010;41(1):104-110.
4. Cantile C, Youssef S. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Ltd; 2015:284-293.
5. Mendonça FS, Albuquerque RF, Evêncio-Neto J, et al. Alpha-mannosidosis in goats caused by the swainsonine-containing plant Ipomoea verbascoidea. J Vet Diagn Invest. 2012;24(1):90-95.
6. Panter KE, Welch KD, Gardner DR, et al. Poisonous plants of the United States. In: Gupta RC, ed. Veterinary Toxicology. New York, NY: Elsevier Ltd; 2012:1034-1035.
7. Summers BA, Cummings JF, de Lahunta A. Veterinary Neuropathology. St. Louis, MO: Mosby; 1995:226-227.
8. Vandevelde M, Higgins R, Oevermann A. Veterinary Neuropathology: Essentials of Theory and Practice. St. Louis, MO: Wiley-Blackwell; 2012:178-181.
9. Warren CD, Alroy J. Morphological, biochemical and molecular biology approaches for the diagnosis of lysosomal storage diseases. J Vet Diagn Invest. 2000;12(6):483-496.
10. Miller AD, Zachary JF. Nervous system. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:858-861.