AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2018

U-M21 (NP)

 

 

Signalment (JPC # 1945143): Rat

 

HISTORY: Tissue from a rat fed a leguminous plant of the genus Swainsona.

 

MICROSCOPIC DESCRIPTION (U-M21a): Kidney: Diffusely within the cortex proximal tubular epithelial cells are swollen and contain abundant clear cytoplasmic vacuoles that are 2-50 um in diameter, often peripheralize the nucleus, and obscure or occlude tubular lumina. Tubules occasionally contain intraluminal eosinophilic amorphous material (protein cast). Within the medulla, epithelial cells of tubules and collecting ducts are mildly to moderately vacuolated. Occasional cells in glomerular tufts are distended by cytoplasmic vacuolation. Multifocally, there are low numbers of lymphocytes and plasma cells in the interstitium.

 

MORPHOLOGIC DIAGNOSIS (U-M21a): Kidney, tubular epithelium: Vacuolation, cytoplasmic, diffuse, severe, rat, rodent.

 

CAUSE: Swainsonine toxicity (toxic inhibition of alpha-mannosidase)

 

CONDITION: Acquired alpha-mannosidosis

 

Signalment (JPC # 1640-4): Calf

 

HISTORY (U-M21b): Tissue from a neonatal Salers calf.

 

HISTOPATHOLOGICAL DESCRIPTION (U-M21b): Kidney: Diffusely, tubular epithelial cells are swollen, severely vacuolated, and often obscure or occlude tubule lumina. Vacuoles are 2-40 um in diameter and peripheralize nuclei. Multifocally there are occasional lymphocytes and plasma cells in the interstitium.

 

Spinal cord: Multifocally, neurons have numerous intracytoplasmic vacuoles that are 1-10 um in diameter and often obscure or displace Nissl substance.

 

MORPHOLOGIC DIAGNOSIS (U-M21b): Kidney, tubular epithelium: Vacuolation, cytoplasmic, diffuse, severe, Salers, bovine.

 

Spinal cord, neurons: Vacuolation, cytoplasmic, multifocal, moderate.

 

CONDITION: Autosomal recessive hereditary beta-mannosidosis

 

GENERAL DISCUSSION:

·      Lysosomal storage diseases are inherited or induced defects of metabolism, characterized by an accumulation of storage material within lysosomes

·      May result from:

·      Genetic defect resulting in absence of enzyme, production of ineffective enzyme, or lack of specific activator protein

·      Exogenous toxin that specifically inhibits a lysosomal enzyme (i.e. swainsonine)

·      Substrate that is resistant to a normal enzymatic degradative pathway (i.e. chloroquine)

·      The storage material may be sphingolipids, glycolipids, oligosaccharides, or mucopolysaccharides

·      Glycoproteinoses are characterized by a deficiency of one of the enzymes in oligosaccharide catabolism, and accumulation of intermediate products.

·      Congenital alpha-mannosidosis:

·      Most common and economically important lysosomal storage disease of domestic animals

·      Autosomal recessive deficiency of lysosomal alpha-mannosidase

·      Described in Angus, Murray Grey and Galloway cattle, and Persian cats

·      Acquired alpha-mannosidosis:

·      Due to ingestion of plants of the genera Swainsona, Oxytropis, or Astragalus (“locoweed”) found in North America, broomweed (Sida carpinifolia) from Brazil, or shrubby morning glory (Ipomoea carnea) of Mozambique

·      Toxic principle is the indolizidine alkaloid, swainsonine

·      Histologically identical to congenital alpha-mannosidosis but biochemically distinct (considered an induced form of alpha-mannosidosis)

·      Congenital beta-mannosidosis:

·      Autosomal recessive deficiency of beta-mannosidase

·      Similar to, but more severe than, alpha-mannosidosis

·      Described in Anglo-Nubian goats and Salers cattle

·      Alpha-L-fucosidosis:

·      Autosomal recessive deficiency of lysosomal alpha-L-fucosidase

·      Described in Springer Spaniels

 

PATHOGENESIS:

Congenital alpha-mannosidosis:

·      Mutation in coding sequence for acid hydrolase in lysosome > dysfunction of alpha mannosidase > unable to break down oligosaccharides > accumulation of oligosaccharides and partially digested glycoproteins in vacuoles > lysosomes swell > increase in number and size > loss of cellular function > cell death

Acquired alpha-mannosidosis:

·      Swainsonine intoxication > inhibition of alpha-mannosidase > similar result as in congenital alpha-mannosidosis

·      Alkaloid also inhibits Golgi mannosidase II

·      Clinical signs may or may not resolve with removal of toxin

 

TYPICAL CLINICAL FINDINGS:

·      Inherited mannosidosis: Neurologic deficits, such as recumbency at birth, blindness, ataxia, incoordination, head tremors, intention tremors; poor body condition; renal dysfunction not reported, in spite of lesion

·      Swainsonine toxicosis: “locoism” (depression, incoordination, staggering), growth retardation, reproductive problems, depression, slow gait, dull eyes, muscular incoordination, nervousness

 

TYPICAL GROSS FINDINGS:

·      Dilation of lateral ventricles

·      Enlargement of kidneys (Salers calves with beta-mannosidosis)

·      Carpal contractures (goats with beta-mannosidosis)

·      Marked swelling, of cervical portion of vagus nerves, cervical nerves, and dorsal root ganglia (Springer Spaniel with alpha-L-fucosidosis)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Prominent intracytoplasmic vacuoles in various tissues:

·      Neurons, renal tubular epithelium, pancreas, thyroid follicular cells, reticuloendothelial cells (spleen, liver, lymph nodes)

·      Marked vacuolation of the cytoplasm of proximal tubular epithelial cells

·      Hypomyelination: Striking in the brains of calves with beta-mannosidosis

 

ULTRASTRUCTURAL FINDINGS:

·      Distended cells containing vacuoles bounded by a single membrane containing stored material (membranous fragments and some floccular material)

 

ADDITIONAL DIAGNOSTIC TESTS:

·      History, physical examination, pedigree analysis

·      Histopathology

·      Definitive diagnosis: Biochemical analysis of fresh tissues or blood for mannosidase activity

 

Comparative List of lysosomal storage Diseases

 

 

Disease

Storage Product

Deficient enzyme

Species

Breed

GM1 gangliosidosis

GM1 ganglioside

b-galactosidase

Bovine

Canine

 

 

Feline

Ovine

Holstein-Friesian

Beagle, English Springer spaniel, Portuguese water dog

Siamese, DSH

Suffolk, Coopworth-Romney

GM2 gangliosidosis

GM2 ganglioside

b-hexosaminidase

Canine

 

 

Feline

Porcine

German shorthair pointer, Japanese

Spaniel

DSH, Korat

Yorkshire

Globoid-cell

Leukodystrophy

(krabbe’s-like disease)

Galactosylceramide

(galactocerebroside)

Galactosylsphingosine

(psychosine)

Galactoslceramidase

(galactocerebroside

b-galactosidase)

Canine

 

 

 

Feline

Ovine

 

West Highland terrier, Cairn terrier, Miniature poodle, blue tick hound, beagle, Pomeranian

DSH

Polled Dorset

a-mannosidosis

Mannose-containing

oligosaccharide

a-mannosidase

Bovine

 

Feline

Angus, Murray Gray, Galloway

Persian, DSH

b-mannosidosis

Mannose-containing

oligosaccharide

b-mannosidase

Caprine

Bovine

Nubian

Salers

Mucopolysaccharidosis

Different glycosaminoglycans

Several different enzyme deficiencies

Canine

 

 

 

Feline

 

Caprine

Plott hound (type I, Hurler’s disease) miniature pinscher (type VI, Maroteaux-Lamy disease)

DSH(type I, Type VII sly disease)

Nubian (type III, sanfilippo’s disease)

Ceroid-lipofuscinosis

Subunit c of mitochondrial ATPase

Prelysosomal defect?

Canine

 

Ovine

Bovine

English setter, border collie, Tibetan terrier

South Hampshire

Devon

 

Sphingolipid

Activating proteins A & D

 

Palmitoyl protein thioesterase

Canine

Ovine

Miniature schnauzer

Swedish Landrace

 

 

REFERENCES:

1.    Armien AG, Tokarnia CH, Vargas Peixoto P, Frese K. Spontaneous and Experimental Glycoprotein Storage Disease of Goats Induced by Ipomoea carnea subsp fistulosa (Convolvulaceae). Vet Pathol 2007;44:170-184.

2.    Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed., vol. 1. St. Louis, MO: Elsevier Limited; 2016:288, 292.

3.    Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. 6th ed. Vol 2. Philadelphia, PA: Elsevier Saunders;2016:429.

4.    Haskins M, Giger U: Lysosomal storage diseases. In: Kaneko JJ, Harvey JW, Bruss ML, eds. Clinical Biochemistry of Domestic Animals., 5th ed. San Diego, CA: Academic Press; 1997: 741-760.

5.    Jolly RD, Walkley SU. Lysosomal storage diseases in animals: An essay in comparative pathology. Vet Pathol 1997;34:527-548.

6.    Laurent S, Sabot A, Colle M, Nicolier A. Lysosomal storage disease in two presumed-related springboks (Antidorcas marsupialis). Journal of Zoo and Wildlife Medicine. 2010;41(1):104-110.

7.    Mendonca FS, Albuquerque RF, Evencio-Neto J, et al. Alpha-mannosidosis in goats caused by the swainsonine-containing plant Ipomoea verbascoidea. JVDI. 2012;24(1):90-95.

8.    Skelly BJ, Franklin RJM. Recognition and diagnosis of lysosomal storage diseases in the cat and dog. J Vet Intern Med 2002;16:133-141.

9.    Stegelmeier BL, Molyneux RJ, Elbein AD, James LF. The lesions of locoweed (Astragalus mollissimus), swainsonine, and castanospermine in rats. Vet Pathol 1995;32:289-98.

10. Warren CD, Alroy J. Morphological, biochemical and molecular biology approaches for the diagnosis of lysosomal storage diseases. J Vet Diagn Invest 2000;12:482-496.


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