JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2026

N-M14A

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 with abundant microvacuolated eosinophilic cytoplasm that peripherally displaces nuclei and Nissl substance. Purkinje cells are multifocally lost. In the white matter of the brainstem and cerebellum, there are few dilated myelin sheaths which contain swollen eosinophilic axons (spheroids). There is occasional proximal eosinophilic swelling of the axons in the granular cell layer (torpedoes).

Slide B:

Exocrine pancreas: Diffusely, acinar cells are mildly swollen by numerous intracytoplasmic clear vacuoles, often with loss of zymogen granules. Focally, within a ganglion in the interlobular septa, neuronal cell bodies are rounded and swollen 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 DIAGNOSES:

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, a subset of lysosomal storage disease, are a group of diseases with defective degradation of the carbohydrate component of N-linked glycoproteins; includes alpha-mannosidosis, beta-mannosidosis, and alpha-L-fucosidosis
• Mannosidosis is genetic (autosomal recessive) or acquired (N-T01) and results in accumulation of mannose-containing oligosaccharides
• Alpha-mannosidosis occurs primarily in cattle (Angus, Murray Gray, Galloway) and cats (Persian, domestic short or longhair) due to deficient alpha-mannosidase and affects virtually all cells except hepatocytes

PATHOGENESIS:

• Congenital form: autosomal recessive; synthesis of a defective enzyme protein --> deficient lysosomal alpha-mannosidase activity --> lysosomal buildup of mannose/N-acetylglucosamine oligosaccharides
• Induced/acquired form (N-T01, “locoism”): due to ingestion of Astragalus, Oxytropis, or Swainsona plants which have a fungal endophyte (Undifilum oxytropis) that produces swainsonin (an indolizidine alkaloid), which inhibits lysosomal and Golgi alpha-mannosidase, thus inducing acquired alpha-mannosidosis that mimics inherited storage disease

TYPICAL CLINICAL FINDINGS:

• Calves exhibit retarded growth, progressive ataxia, and behavioral changes
• Death usually occurs by 18 months

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Neuronal vacuolation is prominent and widespread; storage vacuoles appear granular or empty (material extracted during tissue processing)
• Axonal spheroids abundant in both gray and white matter, especially in the cerebellar roof nuclei, caudal brainstem proprioceptive nuclei, and proximal aspects of Purkinje cell axons
• Neuronal loss present at terminal stages of disease
• Cytoplasmic vacuolation in secretory epithelial cells (pancreas, kidney, etc), endothelial cells, fixed macrophages, and fibrocytes common

ULTRASTRUCTURAL FINDINGS:

• Vacuoles contain membranous fragments of fibrillar material

DIFFERENTIAL DIAGNOSIS

• Beta-mannosidosis: Salers cattle, Nubian goats, German shepherd dogs
  • Autosomal recessive deficiency of glucohydrolase β-mannosidase > accumulation of beta-mannose containing oligosaccharides in nervous, renal, thyroid, and lymphoid tissues
  • Clinical: neonates with domed heads, unable to rise, intention tremors, nystagmus, bilateral Horner’s syndrome, deafness (kids only), facial dysmorphisms
  • Gross: small palpebral fissures, dilation of ventricles, bilaterally kinked and folded auricles, narrowing of the cartilaginous external acoustic meatus, small tympanic bullae (calves only), polypoid mucosa in middle ear (kids only)
  • Histology: prominent neuronal vacuolation and spheroids, especially in the internal capsule, cerebellar white matter, basal ganglia, spinal motor neurons; mineralization of the cerebellum and cerebrum; vacuolization various cells of the ear (hair cells, spiral organ support cells, vestibular membrane cells, endothelium, fibroblasts, etc.)
• 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

Canine:

• Beta-mannosidosis: German Shepherd dogs
  • Alpha-L-fucosidosis: autosomal recessive in English springer spaniels; deficient activity of alpha-L-fucosidase results in storage of oligosaccharides containing fructose; delayed clinical onset with wasting, ataxia, and proprioceptive deficits around 6 months; grossly see marked swelling (up to 10mm) of the cervical vagus nerve, cervical nerves, and dorsal root ganglia; storage disease evident in most tissues (abundant empty intracytoplasmic vacuoles, axonal spheroids)

Feline: autosomal recessive alpha-mannosidosis reported in Persian, domestic shorthair, and domestic longhair kittens

• Persians and domestic shorthair: facial dysmorphism, retarded growth, tremors, ataxia, 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: autosomal recessive beta-mannosidosis reported in Anglo-Nubian goats; see above

Rodents:

• Rats – acquired alpha-mannosidosis resulting from Swainsonine toxicity; predominantly affects kidney (tubular epithelial cells)

References:

1. 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; 2015:257-258,286,288-289.
2. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:502.
3. Miller AD, Porter BF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:940,943-945.
4. Njaa BL. The Ear. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1372.

Click the slide to view.

---