February 2017

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 degenerate and swollen up to 100 um, have rounded irregular margins, eccentric nuclei, loss of Nissl substance, and pale eosinophilic to amphophilic, lacy, fibrillar, and vacuolated cytoplasm. Multifocally, within the white matter, there are scattered spheroids (axonal degeneration) and there is mild gliosis. Within the tunica media of small leptomeningeal arteries and arterioles, scattered smooth muscle cells are mildly vacuolated.


Slide B (PAS): Multifocally, neurons and vascular smooth muscle cells contain intracytoplasmic, granular, PAS-positive material.


MORPHOLOGIC DIAGNOSIS: Spinal cord, neurons and leptomeningeal arteriolar smooth muscle: Degeneration, vacuolar, multifocal, moderate, with PAS-positive intracytoplasmic glycogen, and axonal degeneration, breed unspecified, bovine.


CAUSE:  Alpha‑1, 4-glucosidase deficiency


CONDITION: Glycogenosis type II


SYNONYMS: Acid maltase deficiency, Pompe"s disease, and glycogen storage disease



·       A type of lysosomal storage disease seen in shorthorn and Brahman beef cattle due to an alpha-1, 4-glucosidase deficiency resulting in glycogen accumulation in multiple organs

o   Autosomal recessive defect

·       Storage diseases can be divided into two broad categories:

o   Inherited storage diseases:  Subclassified by the class of macromolecule whose degradation is defective (sphingolipidoses, glycoproteinoses, mucopolysaccharidoses, glycogenoses, ceroid-lipofuscinoses)

o   Induced storage diseases:  Due to ingestion of certain toxic plants that produce swainsonine such as locoweed (Astragalus sp., Oxytropis sp.) and others (Swainsona spp., Trachyandra spp., Phalaris spp., Solanum spp., Sida carpinifolia, possibly Gomen disease)



·       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

·       Affected Brahman cattle lack RNA for the alpha-1, 4 glucosidase gene and the enzyme is not formed; in shorthorns, there is a failure to process a larger precursor form to the functional form

·       Most damaging effects are produced in the skeletal and cardiac muscle



·       Progressive muscle weakness, incoordination, difficulty in rising, and poor growth

·       Regurgitation secondary to megaesophagus

·       Congestive heart failure

·       Clinical deterioration develops more rapidly after weaning; most calves die or are killed before they reach a year old

·       Clin Path:  Elevated muscle enzymes (CK, AST, LDH)



·       Usually no significant gross lesions

·       Muscle wasting and pale muscles

·       Hepatomegaly and cardiomegaly occasionally



·       Nervous system:

o   Large neurons, especially in the brainstem and spinal cord ventral horns, are swollen with granular to vacuolated (lacy) cytoplasm and loss of Nissl substance

o   Similar changes in ganglia throughout the body, glial cells, ependymal and choroid plexus epithelium, and arterial smooth muscle

o   Scattered spheroids

·       Other tissues:  Vacuolation of hepatocytes; Kupffer cells; renal tubular epithelial cells; vascular, urogenital, alimentary, and respiratory smooth muscle; and skeletal and cardiac myocytes



·       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



·       PAS-positive and diastase-sensitive; carminophilic with Best"s carmine

·       Negative for lipid stains (Luxol fast blue, Sudan black, oil-red-O)

·       Analysis of blood lymphocytes for alpha- 1, 4-glucosidase activity

·       Alpha‑ 1, 4-glucosidase assays (enzymatic assay in skin fibroblasts or blood leukocytes)

·       Muscle biopsies



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:Occurs in Angus, Murray grey, and belted Galloway cattle; due to alpha-mannosidase deficiency; has vacuolation in virtually all cells except hepatocytes; and 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; has severe vacuolation of nervous, renal, thyroid, and lymphoid tissue; and similar EM findings to alpha-mannosidosis

·       Swainsonine toxicosis: 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 but 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 



·       Reported in domestic cats, a Lapland dog, Corriedale sheep, Japanese quail, and humans (Pompe’s disease)

·       Lapland dogs:  Insidious onset of muscular weakness often with megaesophagus in pups between 6-18 months old; similar changes as in cattle

·       Japanese quail (Coturnix coturnix japonica):  Observed in quail over six months old; no enlargement of the heart or liver 

·       Humans:  At least 10 glycogen storage deficiencies designated type’s I-X 





Disease in Man

Enzyme deficiency

Organ Category

Animals Affected

Type I (a & b)

von Girke


Hepatic or hepatorenal

Maltese, knockout mice

Type II (a & b)


Alpha-1, 4-glucosidase (acid maltase), lysosomal

Generalized, myopathic most prominent

Shorthorn & Brahman cattle, Corriedale sheep, cat, Lapland dog, & Japanese quail

Type III


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


Phosphorylase muscle


Charolais cattle

Type VI


Phosphorylase liver



Type VII




English Springer Spaniel



Phosphorylase kinase


Alpha-rosettes in neurons


Type IX


Phosphorylase kinase



Type X


Phosphorylase kinase, cAMP-dependent






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