JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2840045): 2.6-week-old Fvb/NCr mouse
HISTORY: Tissue from a mouse that was normal clinically and grossly.
HISTOPATHOLOGIC DESCRIPTION: Eyes: Diffusely the retina is 1/2 the normal thickness with loss of the outer plexiform, outer nuclear, and photoreceptor layers.
HISTOPATHOLOGIC DIAGNOSIS: Eye, retina: Degeneration and atrophy, diffuse, severe, characterized by 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)
- Inherited retinal degeneration in mice is an autosomal recessive trait linked to the rd 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 week of life
- 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”
- Sudden acquired retinal degeneration syndrome (SARDS) in dogs
- Toxic retinopathies
- Choroidal perfusion problems/vascular disease
- Nutritional retinopathies
- Diseases of retinal pigmented epithelium (like lipofuscinosis)
- In cats, diffuse phororeceptor 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
- 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; studies have shown that there is some ERG activity during the second week after birth, followed by rapid deterioration
TYPICAL GROSS FINDINGS:
- No visible lesions
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
- By 20 days, only the inner layers, bipolar cells 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
- 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
- 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
- RCS rats have hereditary retinal degeneration because of a defect in retinal pigmented epithelium; RPE is unable to phagocytose and degrade rod outer segment discs, which are produced at a constant rate; outer segment material accumulates between RPE and photoreceptors leading to degeneration from interference with nutrition or possibly accumulation of a toxin; lesions start centrally and progress to include the peripheral retina; retinal degeneration in albino rats subjected to light intensities that would be relatively harmless to animals with normal pigmented uveal tracts
- 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
- Leber congenital amaurosis is a genetic disease in humans with photoreceptor loss associated with a gene encoding Aipl1 protein; Aipl1 is necessary for cGMP phosphodiesterase stability and photoreceptor viability; there is a transgenic mouse model for this condition
- Recently described in mountain lion cub; found in red-tailed hawks with West Nile Virus infection
- DiSalvo AR, Reilly CM, Wiggans KT, Woods LW, Wack RF, Clifford DL. Photoreceptor degeneration in a mountain lion cub (Puma concolor). Journal of Zoo and Wildlife Medicine. 2016;47(4):1077-1080.
- Dubielzig RR, Ketring KL, McLellan GJ, Albert DM. Veterinary Ocular Pathology: A Comparative Review. Louis, MO: Saunders Elsevier; 2010:354-369.
- Fielden M, et al. Retinal toxicity induced by a novel b-secretase inhibitor in the Sprague-Dawley rat. Tox Path. 2014; XX: 1-12.
- Labelle P. The eye. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2016:1315-1316.
- Mudry MC, Kronenburg S, Komatsu S, Aguierre GD. Blinded by the light: retinal phototoxicity in the context of safety studies. Tox Path. 2013; 41: 813-825.
- Narfstrom K, Petersen-Jones M. Diseases of the canine ocular fundus. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary Ophthalmology. 5th Ames, IA: John Wiley & Sons, Inc.; 2013:1323-1351.
- Rajan I, Read R, Small DL, Perrard J, Vogel P. An alternative splicing variant in Clcn7–/– mice prevents osteopetrosis but not neural and retinal degenerate on. Vet Pathol. 2011;48(3)663-675.
- Vogel P, et al. Nephronophthisis and retinal degeneration in Tmem218–/– mice: a novel mouse model for Senior-Løken syndrome?. Vet Pathol On-line. 2014; 1-16.
- Wunschmann A, Armien AG, Khatri M, et al. Ocular lesions in red-tailed hawks (Buteo jamaicensis) with naturally acquired west nile disease. Veterinary Pathology. 2017;54(2):277-287.
- Yang L, et al. Nicotine alters morphology and function of retinal pigment epithelial cells in mice. Tox Path. 2010;38:560-567.
- Yoshizawa K, et al. Retinal degeneration induced in adult mice by a single intraperitoneal injection of N-Ethyl-N-Nitrosourea. Tox Path. 2011;39:606-613.
- Ziess ZJ. Review paper: animals as models of age-related macular degeneration: an imperfect measure of the truth. Vet Patho 2010;47(3)396-413.