JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2020

N-M14

 

Signalment: (JPC #1641269):  Angus calf

 

HISTORY:  This calf developed hindlimb incoordination and fine intention tremors of the head at 2 months of age.

 

HISTOPATHOLOGIC DESCRIPTION: 

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, often replaced by large, irregularly round, clear areas (empty baskets) and a fenestrated ground layer. 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 often have enlarged, pale germinal centers (lymphoid hyperplasia).

 

MORPHOLOGIC DIAGNOSIS: 

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

 

GENERAL DISCUSSION: 

·      Glycoproteinoses are a group of diseases with defective degradation of the carbohydrate component of N-linked glycoproteins:

·      Glycoproteinoses include 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 Angus, Galloway, and Murray Grey cattle breeds; Angus cattle are an animal model of this human disease

·      Storage vacuoles are commonly found in nervous tissue, pancreas, kidney, endothelia, macrophages, and fibrocytes

 

PATHOGENESIS: 

Congenital form:

·      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 mannose/N-acetylglucosamine oligosaccharides

 

Induced/acquired form (N-T01):

·      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 II, 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:

·      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: 

·      CNS:  Mild to moderately dilated ventricles

·      Other organs:  Enlarged liver and kidney; maxillary brachygnathia

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Neuronal vacuolation is prominent and widespread

·      Secondary axonal degeneration (spheroids or meganeurites) present in both grey and white matter; most prominent in cerebellar roof nuclei, caudal brainstem proprioceptive nuclei and proximal parts of Purkinje cell axons (i.e. torpedoes)

·      Storage vacuoles appear granular or empty (material extracted during tissue processing)

·      Cytoplasmic vacuolation also occurs in other tissues, becoming more pronounced with age

·      Fixed macrophages (including Kupffer cells); fibroblasts; vascular endothelium; renal and pancreatic secretory epithelial cells

·      Lipofuscin accumulates in the glial cells, and there is slow, progressive neuronal loss and demyelination

 

ULTRASTRUCTURAL FINDINGS:

·      Vacuoles contain membranous fragments of fibrillar material

 

ADDITIONAL DIAGNOSTIC TESTS: 

·      Electron microscopy

·      Partial identification using special stains and lectin binding patterns; both the congenital and acquired forms of the disease exhibit positive staining with lectin histochemistry

·      Diagnosis made by plasma alpha‑mannosidase levels

 

DIFFERENTIAL DIAGNOSIS

·      Beta-mannosidosis:  Salers cattle  

·      Hydrolysis of the final mannose residue usually follows that of the alpha-linkages; autosomal recessive deficiency of β-mannosidase > storage of di- or trisaccharides containing one molecule of mannose

·      Vacuolated neurons and numerous axonal spheroids (especially in internal capsule, cerebellar white matter and basal ganglia)

·      There is also intense storage in other tissues (renal, thyroid, lymphoid)

·      GM₁ gangliosidosis:  Friesian calves with defective beta-galactosidase> accumulation of GM1 ganglioside (PAS-positive material); characteristic concentric membranous whorls in the cytoplasm on EM

 

COMPARATIVE PATHOLOGY: 

Glycoproteinoses reported in other species:

Canine:

·      Fucosidosis:

·      results from a deficiency of lysosomal a-L-fucosidase resulting in accumulation of glycolipids and oligosaccharides containing the sugar fucose

·      Reported in English Springer Spaniels

·      Severe disease with delayed onset (usually starts at 6 months old); autosomal recessive

·      Gross lesion: marked swelling of cervical portion of vagus nerves, cervical nerves and dorsal root ganglia

·      Microscopically: vacuolation in most tissues (appears empty as with mannosidosis); CNS vacuolation is in neurons, macrophages, astrocytes and microglial cells

·      Beta-mannosidosis: Recently reported in German Shepherd dogs (Jolly et. al., Vet Pathol. 2019; first report in dogs); see discussion in Differential Diagnosis section

Feline:

·       Alpha-mannosidosis reported in Persian, domestic shorthair, and domestic longhair cats

·       Persians and domestic shorthair: facial dysmorphism, 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: milder nervous signs, more slowly progressive but there is often loss of Purkinje cells; no pancreatic acinar cell involvement, ocular abnormalities, hepatomegaly or myelin deficiency

Caprine:

·      Beta-mannosidosis: Reported in Nubian goats; see discussion in Differential Diagnosis section

 

References: 

1.    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.

2.    Jolly RD, Dittmer KW, Garrick DJ., et al. β-Mannosidosis in German Shepherd Dogs. Vet Pathol. 2019; 56(5):743-748.

3.    Miller AD, Zachary JF.  Nervous system. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:858-861.

4.    Reis MO, Cruz RA, Oliveira LGS, et al. Hydrallantois in cows naturally poisoned by Sida carpinifolia in Brazil. Jour Vet Diagn Invest. 2019; 31(4):581-584.

5.    Vandevelde M, Higgins R, Oevermann A. Veterinary Neuropathology: Essentials of Theory and Practice. St. Louis, MO: Wiley-Blackwell; 2012:178-181.