JPC SYSTEMIC PATHOLOGY

SPECIAL SENSES SYSTEM

April 2024

S-M17

 

Signalment (JPC #2840045): 2.6-week-old Fvb/NCr mouse

 

HISTORY: Tissue from a mouse that was normal clinically and grossly.  

 

HISTOPATHOLOGIC DESCRIPTION: Eye: Diffusely the retina is half the normal thickness with complete loss of the outer plexiform, outer nuclear, and photoreceptor layers.  

 

HISTOPATHOLOGIC DIAGNOSIS: Eye, retina: Degeneration and atrophy, diffuse, severe, with loss of the outer plexiform, outer nuclear, and photoreceptor layers, Fvb/NCr mouse, rodent.

 

ETIOLOGIC DIAGNOSIS: Hereditary outer retinal atrophy.

 

CAUSE: Autosomal recessive gene (homozygous rd-1 allele)

 

GENERAL DISCUSSION: 

• Inherited retinal degeneration in mice is an autosomal recessive trait linked to the rd (rodless retina) gene localized on chromosome 5
• The gene is carried by over 60 strains of mice and is most prevalent in C3H and FVB strains
• Mice are normal at birth, but rods and cones undergo rapid apoptotic death beginning in the second to third week of life; affected mice become totally blind
• Progressive retinal atrophy (PRA): 

• Diverse group of inherited (or presumed to be inherited) photoreceptor disorders that have the following features in common:

• Bilaterally symmetrical involvement
• Progressive photoreceptor degeneration leading to blindness

• Important models for human inherited retinopathies
• Dogs affected more commonly (usually inherited); most are recessive but autosomal dominant and X-linked forms have been identified
  • Miniature and toy poodle, Labrador retriever, American and English Cocker spaniel, Miniature Schnauzer
• Broadly subdivided into:
  • Early onset (photoreceptor dysplasias and dystrophies) – Significant visual deficits early in life
  • Late onset (photoreceptor degenerations) – Photoreceptors morphologically normal in young animals; rod outer segments preferentially affected (shortened, disorganized, degenerating); blindness in middle-aged animals
• Early microscopic features: Shortening, disorganization, and distortion of outer photoreceptor segments progressing to loss of outer and inner segments; loss of photoreceptor nuclei with thinning of outer nuclear layer
• Chronic microscopic features: Severe retinal atrophy (profoundly affecting outer retina) and phagocytic cells within the neurosensory retina culminating in end-stage retinal atrophy with gliosis; may see retinal detachment, cataracts which can lead to lens-induced uveitis or lens luxation and glaucoma
• Cannot diagnose based on morphologic characteristics alone; can only conclude that changes are “consistent with PRA”
• Differential diagnoses: Sudden acquired retinal degeneration syndrome (SARDS) in dogs; toxic; nutritional; choroidal perfusion problems/vascular disease; diseases of retinal pigmented epithelium (like lipofuscinosis)
• In cats, diffuse photoreceptor degeneration is uncommon, unless secondary to vascular disease, nutritional, or toxic causes
  • Clinical and microscopic features similar to what is described above for dogs
  • Abyssinian cat has been studied, has 2 inherited forms:
    • Early-onset form (autosomal dominant inheritance)
    • Later-onset form (autosomal recessive inheritance, slowly progressive)
  • A colony of Persian cats are described as having an early onset recessively inherited retinal degeneration
  • Older Siamese cats are over-represented in some studies                 

 

PATHOGENESIS:

• In the normal eye, absorption of light by photoreceptor cells leads to hydrolysis of cGMP, the internal transmitter of phototransduction, by activated phosphodiesterase (PDE); cGMP levels are replenished in the dark phase by guanylate cyclase
• The rd gene encodes the beta subunit of cGMP phosphodiesterase (b-PDE)
• Xmv-28, a xenotropic murine leukemia virus is always associated with the retinal degeneration phenotype
• The provirus is integrated into the first intron of the b-PDE gene leading to aberrant transcription with introduction of a nonsense ochre mutation (C to A transversion in codon 347) producing a stop codon; the result is production of a truncated gene product and inactivation of PDE
• Loss of photoreceptor cGMP phosphodiesterase leads to high levels of cGMP followed by photoreceptor loss
• Photoreceptor death is from apoptosis by an unknown mechanism

 

TYPICAL CLINICAL FINDINGS:

• Blindness
• Failure to perform normally in behavioral studies

 

TYPICAL GROSS FINDINGS:

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• 7-11days: Normal retinal development (rods are partially developed at this time)
• 15 days: Marked degeneration of the photoreceptor cell processes and of the outer nuclear layer
• 20+ days: Absence or degeneration of the rods, outer nuclear layer, and outer plexiform layer; only the inner layers, bipolar cells (inner nuclear layer), and ganglion cells remain; cone cells degenerate at a slower rate and may survive up to 18 months of age  
• Degeneration can progress to involve the inner layers as well and may progress to complete loss of the entire retina with only a fibrous remnant

 

ADDITIONAL DIAGNOSTIC TESTS:

 

DIFFERENTIAL DIAGNOSIS:

• Photoreceptor degeneration and loss
  • Light-induced retinal degeneration produces fragmentation and loss of the photoreceptor and outer plexiform layers with no changes to the inner retinal layers
  • Chronic vitamin A deficiency leads to degeneration and loss of the photoreceptor outer and inner segments; other layers of the retina remain healthy
  • Urethan causes fragmentation and vacuolization of outer segments of photoreceptor cells and accumulation of debris and macrophages in the subretinal space

 

COMPARATIVE PATHOLOGY:

• Irish setter rod/cone dysplasia similarly results from a nonsense mutation in the rod cGMP phosphodiesterase beta subunit gene
• Sudden acquired retinal degeneration syndrome (SARDS) causes sudden  blindness in dogs, females may be predisposed; the pathogenesis is unknown; initially there is a loss of the rods and cones, which progresses to generalized retinal degeneration over time
• Taurine deficiency in cats – Concurrent dilated cardiomyopathy; progressive photoreceptor degeneration
• Retinal degeneration (rd) chickens are blind at birth and have progressive photoreceptor cell degeneration and loss; the mechanism involves a null mutation in the photoreceptor guanylate cyclase gene leading to loss of cGMP
• Central retinal degeneration of ferrets and mink is relatively common and is characterized by degeneration of rods, cones, and outer retinal layers; may accompany cataract formation in ferrets
• West Nile Virus infection in raptors may cause necrosis of the retina and retinal pigmented epithelium with associated lymphoplasmacytic inflammation, sometimes accompanied by pectinitis

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed., Ames, IA: John Wiley & Sons Inc; 2016:89, 99.
2. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1430-1433.
3. Schmidt R, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. John Wiley & Sons, Inc.; 2015:272-273.
4. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:468-470.
5. Williams BH, Burek-Huntington KA, Miller M. Mustelids. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:291. 

 

 

Click the slide to view.

---