JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M11 (NP)

 

Signalment (JPC #2056945): 6-month-old heifer

 

HISTORY: The heifer could not rise but appeared to be alert and had been eating and drinking normally.

 

HISTOPATHOLOGIC DESCRIPTION: Slide A: Spinal cord: Diffusely, neurons are swollen up to 100 µm by abundant pale eosinophilic to amphophilic, lacy, granular to fibrillar, vacuolated material that peripheralizes the nucleus and Nissl substance. Multifocally within the white matter there are scattered spheroids (axonal degeneration) and there is diffuse, mild gliosis. Glial cells within the white matter rarely contain similar cytoplasmic vacuolated material. Within the tunica media of small leptomeningeal arteries and arterioles, scattered smooth muscle cells are mildly vacuolated. 

 

Slide B (PAS): Diffusely, neurons, vascular smooth muscle cells, and to a lesser extent astrocytes and ependymal cells contain moderate to abundant intracytoplasmic, granular, PAS-positive material.

 

MORPHOLOGIC DIAGNOSIS: Spinal cord, neurons and leptomeningeal arteriolar smooth muscle: Cytoplasmic vacuolation (PAS-positive), diffuse, moderate, with mild axonal degeneration and gliosis, breed unspecified, bovine.

 

CAUSE: Alpha‑1,4-glucosidase deficiency (Acid alpha-glucosidase)

 

CONDITION: Glycogenosis type II 

 

SYNONYMS: Acid maltase deficiency, Pompe's disease, glycogen storage disease, generalized glycogenosis

 

GENERAL DISCUSSION: 

• Glycogen storage diseases are systemic diseases; however, the cells largely affected are those of tissues with high rates of metabolism (neurons, skeletal muscle, cardiac muscle, hepatocytes, renal tubules cells, leukocytes)
• Storage diseases can be divided into two broad categories:
  • Inherited storage diseases: Subclassified by the class of macromolecule whose degradation is defective (sphingolipidoses, glycoproteinoses, mucopolysaccharidoses, glycogenoses, ceroid-lipofuscinoses)
  • Induced storage diseases: Due to ingestion of certain toxic plants that produce swainsonine such as locoweed (N-T01; Astragalus sp., Oxytropis sp.) and others (Swainsona spp., Trachyandra spp. [N-T09], Phalaris spp., Solanum spp., Sida carpinifolia, possibly Gomen disease [N-M12B])
• Glycogenosis type II: A type of lysosomal storage disease seen in Shorthorn and Brahman beef cattle due to an alpha-1,4-glucosidase deficiency resulting in widespread glycogen accumulation in multiple organs to include skeletal, cardiac, and smooth muscle, and in neurons of the cenral and autonomic nervous systems; autosomal recessive defect 

 

PATHOGENESIS:

• Normally, glycogen is mainly catabolized within the cytoplasm by cytosolic enzymes; occasionally, there is uptake of glycogen within autophagic vacuoles and enzymatic degradation via the lysosomal enzyme, alpha-1,4-glucosidase (acid maltase)  
• Lack of alpha-1,4-glucosidase leads to accumulation of glycogen within lysosomal vacuoles and the cytoplasm
• The most damaging effects are produced in the skeletal and cardiac muscle

 

TYPICAL CLINICAL FINDINGS: 

• Affected calves have severe clinical signs by 1 year of age
• Progressive muscle weakness, incoordination, difficulty in rising, and poor growth
• Congestive heart failure
• Clinical deterioration develops more rapidly after weaning; most calves die as result of respiratory and cardiac failure, or are killed before they reach a year old
• Clin Path: Elevated muscle enzymes (CK, AST, LDH)

 

TYPICAL GROSS FINDINGS:

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Nervous system:
  • Large neurons, especially in the brainstem and spinal cord ventral horns, are swollen with granular to vacuolated (lacy) cytoplasm and loss of Nissl substance
    • Neuronal storage is universal and severe
  • Similar changes in ganglia throughout the body, glial cells, ependymal and choroid plexus epithelium, and arterial smooth muscle
  • Scattered spheroids, particularly in vestibular and cuneate nuclei, terminal fasciculus gracilis, and throughout the spinal cord gray matter
  • +/- Mild Wallerian degeneration in ventral and lateral columns of spinal cord and some peripheral nerves
• Other tissues: Vacuolation of hepatocytes; Kupffer cells; renal tubular epithelial cells; vascular, urogenital, alimentary, and respiratory smooth muscle; and skeletal and cardiac myocytes 

 

ULTRASTRUCTURAL FINDINGS: 

• Accumulation of glycogen in large, membrane-bound secondary lysosomes (glycogenosomes) and free in the cytoplasm (10-30 nm dense granules) of cells in CNS (neurons, astrocytes, oligodendrocytes), PNS (Schwann cells, fibroblasts), and myocytes  
• Glycogen normally is stored free in the cytosol as individual, 10-30nm diameter dense beta-particles or clustered as 50-200nm diameter alpha-rosettes

 

ADDITIONAL DIAGNOSTIC TESTS:

• Histochemical staining of glycogen: PAS-positive and diastase-sensitive; carminophilic with Best's carmine; negative for lipid stains (Luxol fast blue, Sudan black, oil-red-O)
• Alpha‑ 1,4-glucosidase assays: enzymatic assay conducted on skin fibroblasts or blood leukocytes
• Muscle biopsy

 

DIFFERENTIAL DIAGNOSIS:

Other neuronal storage diseases in cattle:

• GM1-gangliosidosis: Occurs in Friesian cattle; due to beta-galactosidase deficiency; vacuolation of cells in CNS, liver, and kidney; PAS-positive granules in frozen sections, which are osmiophilic in plastic sections; and on EM, concentric membranous whorls with a 5nm periodicity 
• Alpha-mannosidosis (N-M14): Occurs in Angus, Murray grey, and belted Galloway cattle; due to alpha-mannosidase deficiency; vacuolation in virtually all cells except hepatocytes; on EM, floccular, vesicular, and membranous material to open vacuoles 
• Beta-mannosidosis: Occurs in Salers cattle and Anglo-Nubian goats; due to beta-mannosidase deficiency; severe vacuolation of nervous, renal, thyroid, and lymphoid tissue; similar EM findings to alpha-mannosidosis 
• Swainsonine toxicosis (N-T01):  Swainsona spp. (cause of "peastruck"), Astragalus spp., and Oxytropis spp. (causes of “locoism”) ingestion produces a form of alpha-mannosidosis by enzyme inhibition in cattle and other grazing stock; has similar lesions to the genetic disease 
• Phalaris spp. poisoning: Mainly affects sheep, rarely affects cattle; produces greenish-brown pigment granules typically with perinuclear distribution in neurons in brain stem nuclei, spinal gray matter, and dorsal root ganglia, CSF macrophages, and renal tubular epithelium  
• Bovine metabolic myopathy: Occurs in Charolais cattle; due to myophosphorylase deficiency; metabolic dysfunction confined to skeletal muscle; collapse can be seen in affected cattle as young as 7 weeks of age; increased serum activities of CK, AST, and subsarcolemmal vacuoles due to glycogen storage within myofibers are characteristic

 

COMPARATIVE PATHOLOGY:

• Glycogenosis type II reported in domestic cats, Lapland dog, Corriedale sheep (myophosphorylase deficiency), Japanese quail, and humans (Pompe’s disease)
• Lapland dogs:  Insidious onset of muscular (skeletal, myocardial, and smooth) weakness often with megaesophagus in pups between 6-18 months old; similar changes as in cattle
• Japanese quail:  Observed in quail over six months old; no enlargement of the heart or liver; vacuolar myopathy with formation of autophagic vacuoles followed by fiber loss and fatty replacement are

characteristic; animal model of acid maltase deficiency of people

Other glycogenoses:

Glycogenosis	Disease in Man	Enzyme deficiency	Organ Category	Animals Affected
Type I (a & b)	von Girke	Glucose-6-phosphatase	Hepatic or hepatorenal	Maltese, knockout mice
Type II (a & b)	Pompe	Alpha-1,4-glucosidase (acid maltase), lysosomal	Generalized, myopathic most prominent	Shorthorn & Brahman cattle, Corriedale sheep, cat, Lapland dog, & Japanese quail
		Myophosphorylase deficiency	Skeletal muscle	Sheep
Type III	Cori	Amylo-1,6-glucosidase (debranching)	Hepatic- (branched glycogen)	German shepherd dog, Akitas, curly coated retrievers
Type IV	Brancher or Andersen	Branching, 6-glycosyltrans-ferase	Generalized (unbranched glycogen)	Norwegian forest cats & quarter horses
Type V	McArdle	myophosphorylase muscle	Myopathic	Charolais cattle
Type VI	Hers	Phosphorylase liver	Hepatic
Type VII	Tauri	Phospho-fructokinase	Myopathic	English Springer Spaniel
Type VIII		Phosphorylase kinase liver	Alpha-rosettes in neurons
Type IX		Phosphorylase kinase
Type X		Phosphorylase kinase, cAMP-dependent

 

 

 

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; 2016:290.
2. Cheville NF. Ultrastructural Pathology. 2nd ed. Ames, IA. Wiley-Blackwell; 2009:161-162,866-869.
3. Cooper BJ, Valentine BA. Muscle and tendon. In: Maxie MG ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:204-205,208.
4. Kumar V, Abbas AK, Aster JC, eds.   Robbins and Cotran Pathologic Basis of Disease. 10th ed.   Philadelphia, PA: Elsevier; 2021:160-162.
5. Summers BA, Cummings JF, De Lehunta A. Veterinary Neuropathology. St. Louis, MO: Mosby; 1995:214-236.
6. Valentine, BA. Skeletal Muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1007.

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