AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2017

N-M12

 

Slide A: Signalment (JPC #1663312): 22‑month‑old English setter

 

HISTORY: This dog had a history of progressive dullness, intermittent convulsions, and slight ataxia for 6 months.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: Diffusely in the cerebral cortical gray matter, approximately 50% of the neurons contain abundant, lightly eosinophilic to amphophilic, granular to globular, cytoplasmic pigment that often displaces the nuclei peripherally and markedly distends the perikarya (degeneration). Rarely, neurons are shrunken, angular, and hypereosinophilic, with hyperchromatic or pyknotic nuclei (neuronal necrosis). There is mild gliosis. Sulci are widened up to 2 mm (cerebral cortical atrophy).

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Neuronal degeneration, multifocal, moderate, with abundant neuronal intracytoplasmic granular pigment, cerebral cortical atrophy, and rare neuronal necrosis, English setter, canine.

 

ETIOLOGIC DIAGNOSIS: Hereditary neuronal ceroid‑lipofuscinosis

 

CAUSE: A defect in the CLN8 gene resulting in a missense mutation

 

Slide B: Signalment (JPC #1902490): A horse

 

HISTORY: This horse from New Caledonia exhibited progressive neurologic signs before euthanasia.

 

HISTOPATHOLOGIC DESCRIPTION: Spinal cord: Multifocally within the gray matter, approximately 50% of neurons contain moderate to abundant intracytoplasmic, yellow-brown to red, granular pigment. Multifocally, neurons exhibit variable loss of Nissl substance (chromatolysis). Rarely within the white matter, axon sheaths are mildly swollen and contain finely granular, pale eosinophilic spheroids. There is minimal scattered hemorrhage within the gray matter.

 

MORPHOLOGIC DIAGNOSIS: Spinal cord, neurons: Degeneration, neuronal, multifocal, mild, with abundant neuronal intracytoplasmic pigment, breed unspecified, equine.

 

ETIOLOGIC DIAGNOSIS: Idiopathic neuronal lipofuscinosis (Gomen disease)

 

GENERAL DISCUSSION:

·       Lipofuscin is a yellow-brown lipoprotein that accumulates in residual bodies in secondary lysosomes within long-lived postmitotic cells such as neurons, fixed phagocytes, macrophages, and myocytes and is a normal “wear and tear” pigment; ultrastructurally, lipofuscin has a granular appearance

·       Ceroid is a lipofuscin-like (same morphologic appearance) pigment that accumulates in disease states, cachexia, vitamin E deficiency, or other oxidative stress; ultrastructurally, ceroid is more likely to form membranous stacks or whorls (“myelin figures”)

·       Neuronal ceroid-lipofuscinosis (NCL) includes a group of inherited neurodegenerative storage diseases characterized by autofluorescent lipopigment deposition (lipofuscin-like, but NOT ceroid or lipofuscin) within lysosomes in several organs, but it is most damaging in neurons of the cerebral cortex, retina, and cerebellar Purkinje system, resulting in progressive mental and motor deterioration, blindness, seizures, ataxia, and premature death

·       Gomen disease is an idiopathic cerebellar degenerative disease described in horses from New Caledonia with characteristic neuronal pigment resembling lipofuscin within remaining Purkinje cells as well as neurons of the brain and spinal cord, and within macrophages in areas where Purkinje cells are missing

 

PATHOGENESIS:

NCL:

·       The underlying pathogenesis of NCL has not been entirely clarified, although it is inherited, and is due to a defect in mitochondria and/or in lysosomal catabolism with an autosomal recessive inheritance

·       Two forms of NCL can be differentiated by the major accumulating protein:

       Subunit C of mitochondrial ATP synthase is the major storage component in the majority of NCL cases; deficient ATP production has been proposed as a cause for neuronal loss; the likely mechanism of accumulation is a catabolism defect due to abnormal protein configuration or formation of a complex with lipids

       Sphingolipid activator protein (A and D) is the second major accumulating protein; this causes more severe disease; ultrastructurally there is an accumulation of granular osmophilic deposits (GRODs); the primary defect is a deficiency of palmitoyl protein thioesterase, a lysosomal enzyme

·       The following genetic mutations have been characterized in the following breeds:

·       CLN5 gene in border collies

·       CLN6 gene in Australian shepherds

·       CLN8 gene in English Setter dogs, with a T-to-C (thymine to cytosine) nucleotide transition resulting in a missense mutation

·       Cathepsin D gene in American bulldogs

·       ATP13A2 gene in Tibetan terriers

·       TPP1 gene (ortholog of human CLN2) in miniature dachshunds

·       PPT1 gene in dachshunds

·       Arylsulfatase G gene in American Staffordshire terriers

Gomen Disease:

·       The cause of Gomen disease is unknown but thought to be an environmental toxin

TYPICAL CLINICAL FINDINGS:

·       NCL:

·       Progressive psychomotor dysfunction, blindness, seizures, ataxia, premature death

·       Vision defects may be due to degeneration of the retina or CNS

·       Gomen disease:

·       Horses with Gomen disease have been reported to have progressive cerebellar signs for years

 

TYPICAL GROSS FINDINGS:

·       NCL: There may be cerebral and/or cerebellar atrophy with expansion of lateral ventricles and yellow to brownish discoloration

·       Gomen disease: horses have slightly smaller cerebellum with atrophy of the dorsal folia of the vermis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·       NCL:

·       The location and severity of neuronal changes depend on the breed of animal affected

·       Atrophied areas may have a distinctly brown tinge

·       Gray to yellow/brown granular pigment in neurons that may extend into the axon hillock and in some cases displaces the nucleus and Nissl bodies peripherally

·       Neuronal necrosis may be extensive with depletion of neurons most prominent in the Purkinje cells, cerebral cortex, and/or retina

·       Gomen Disease: Horses with Gomen disease have thinning of the cerebellar molecular layer and loss of Purkinje and granule cells, as well as considerable deposition of a pigment resembling lipofuscin in many of the surviving Purkinje cells and in neurons of the brain and spinal cord, as well as within macrophages in areas where Purkinje cells are missing

 

ULTRASTRUCTURAL FINDINGS:

·       Granules appear as membrane bound cytosomes up to 15nm in diameter with an irregular outline and a variety of forms:

·       Membranous material arranged as “curvilinear bodies” and “fingerprint bodies” are considered characteristic

·       Others may have laminated stacks of membranes (akin to zebra bodies), or membranous stacks or dense granular deposits

 

ADDITIONAL DIAGNOSTIC TESTS:

·       Granules stain magenta with PAS, intensely positive with luxol fast blue, +/- weakly acid fast

·       Granules autofluoresce under ultraviolet light, especially in unstained paraffin embedded sections

 

DIFFERENTIAL DIAGNOSIS:

·       Other lysosomal storage diseases: Glycoproteinoses, sphingolipidoses, mucopolysaccharidoses, glycogenoses (oligosaccharidoses)

·       Phalaris staggers: Tremorigenic syndrome due to chronic intoxication with tryptamine alkaloids of Phalaris spp. plants (canary grass); there may be a greenish-brown granular pigment within neurons of the brain stem nuclei, spinal gray matter, and dorsal root ganglia, macrophages in the CSF, and renal tubular epithelial cells; grossly, there may be greenish-gray discoloration of the kidney, brainstem, and spinal cord; this disease has been reported in cattle, sheep, and horses

·       Cerebellar abiotrophy

 

COMPARATIVE PATHOLOGY:

·       Neuronal ceroid-lipofuscinosis has been documented in many animal species: Dogs, cats, horse, cattle, sheep, goats, mice, one Vietnamese pot-bellied pig and one ferret

·       In Merino and South Hampshire sheep, there is a mutation in chromosomal region OAR7q13-15 that leads to accumulation of subunit C of mitochondrial ATP synthase

·       Congenital ovine NCL in white Swedish Landrace sheep is caused by a deficiency in the lysosomal aspartyl proteinase cathepsin D

·       Juvenile-onset neuronal ceroid-lipofuscinosis of Rambouillet sheep only affects the nervous system and thus could serve as model for the study of lipopigment deposition that affects the nervous system

·       In humans, classification is based on eight main genetic forms, with mutations in at least one of eight genes (CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8) resulting in at least four clinical forms (infantile NCL, late infantile NCL, juvenile NCL also known as Batten disease, adult NCL also known as Kuff’s disease)

 

Species

Age of Onset

Brain Atrophy

Retinal Atrophy

IHC

SCMAS

IHC

SAPs

EM

Animal model for Human NCL

Canine NCL

 

 

 

 

 

 

 

Min. Schnauzer

3-4 y

Yes

Yes

-

+++

GRODs

 

English Setter

12-15 m

Yes

No

+++

+

FP, CL

CLN 8

Border Collie

16-23 m

Yes

No

+++

+

dLP

 

Tibetan Terrier

4 y

Yes

Yes

+++

-

dLP

 

Dalmation

6 m

Yes

No

Nk

Nk

dLP

 

Ovine NCL

 

 

 

 

 

 

 

South Hampshire

9-12 m

Yes

Yes

+++

-

FP, RL

CLN 6 (LINCL)

Swedish Landrace

Congenital

No

Yes

-

+++

GRODs

Congenital NCL

Bovine NCL

 

 

 

 

 

 

 

Devon Cattle

14 m

Yes

Yes

+++

-

CL or dLP

 

Caprine NCL

 

 

 

 

 

 

 

Nubian Goat

10-18 m

Nk

Nk

Nk

Nk

FP, CL

 

Equine NCL

6 m

Yes

No

+++

+

dLP

 

Feline NCL

 

 

 

 

 

 

 

Domestic

9-11 m

Yes

Yes

+++

Nk

FP, CL

 

Siamese

1-2 y

Nk

Nk

Nk

Nk

dLP

 

Murine NCL

 

 

 

 

 

 

 

mnd/mnd

2 m

Yes

Yes

+++

Nk

RL or dLP

CLN 8

nclf

4 m

Yes

Yes

+++

Nk

RL or dLP

CLN 6

Human NCL

 

 

 

 

 

 

 

INCL

3 m-9 y

Yes

Yes

-

+++

GRODs

 

LINCL

2-8 y

Yes

Yes

+++

+++

CL or dLP

 

JNCL

4-10 y

Yes

Yes

+++

+++

FP or dLP

 

ANCL

10-55 y

Yes

No

+++

+++

dLP

 

Modified from Acta Neuropathol 101:410-414, 2001; INCL=infantile NCL, LINCL=late infantile NCL, JNCL=juvenile NCL, ANCL=adult NCL, SCMAS=subunit c of mitochondrial ATP synthase, SAPs=sphingolipid activator proteins, GROD=granular osmiophilic deposits, FP=fingerprint profiles, CL=curvilinear, dLP=different lamellar profiles, RL=rectilinear, Nk=not known

 

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. St. Louis, MO: Saunders Elsevier; 2016: 290-292, 319-320.

2.     Cesta MF, Mozzachio K, Little PB, Olby NJ, Sills RC, Brown TT. Neuronal ceroid lipofuscinosis in a Vietnamese pot-bellied pig (Sus scrofa). Vet Pathol. 2006;43(4):556-560.

3.     Chalkley MD, Armien AG, Gilliam DH, Johnson GS, Zeng R, Wünschmann A, Kovi RC, Katz ML. Characterization of neuronal ceroid-lipofuscinosis in 3 cats. Vet Pathol. 2014;51(4):796-804

4.     Hartley WJ, Kuberski T, LeGonidec G, Daynes P. The pathology of Gomen disease: A cerebellar disorder of horses in New Caledonia. Vet Pathol. 1982;19(4):399-405.

5.     Katz ML, Narstrom K, Johnson GS, O’Brien DP. Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan terriers with ceroid-lipofuscinosis. Am Jour Vet Research. 2005;66:67-76.

6.    Miller MA, Zachary JF. Mechanisms and morphology of cellular injury, adaptation, and death. In: Zachary JF, ed. Pathological Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby; 2017: 37.

7.     Nibe K, Miwa W, Matsunaga S, et al. Clinical and pathologic features of neuronal-ceroid lipofuscinosis in a ferret (Mustela putorius furo). Vet Pathol. 2011;48(6):1185-1189.

8.     Rooney JR, Robertson JL. Equine Pathology. Ames, IA: Iowa State Press; 1996.

9.     Summers BA, Cummings JF, De Lahunta A. Veterinary Neuropathology. St. Louis, MO: Mosby; 1995.

10.  Url A, Bauder B, Thalhammer J, Nowotyn N, Kolodziejek J, Herout N, Furst S, Weissenbock H. Equine neuronal ceroid lipfuscinosis. Acta Neuropathol. 2001;101:410-414.

11.  Vandevelde M, Higgins RJ, Oevermann, A. Veterinary neuropathology: essentials of theory and practice, 1st ed. Ames, IA: Wiley-Blackwell; 2012:50, 180-181.

 


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