JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

January 2023

N-M01

 

Signalment (JPC #4099182): An 11 week old male Labradoodle dog

 

HISTORY: Since 4 weeks of age this dog displayed progressive ataxia, incoordination, staggering gait, and head bobbing. None of its 8 littermates and neither parent displayed similar signs. At autopsy, there were no gross lesions found. CSF analysis was normal.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebellum: Diffusely, the cerebellar folia are mildly flattened. There is a diffuse, marked loss of Purkinje cells. The few scattered remaining Purkinje cells are often either shrunken and angular with hypereosinophilic cytoplasm and pyknotic nuclei (necrotic) or rarely swollen with central chromatolysis (degeneration), and there are rare, swollen proximal Purkinje cell axons within the granular cell layer (torpedoes). Lost Purkinje cells are often replaced by large, irregularly round, clear areas (empty baskets) and a fenestrated ground layer and/or increased numbers of astrocytes (Bergman’s astrocytosis). There is multifocal thinning and hypocellularity of the granular cell layer. There are rare dilated myelin sheaths within the cerebellar white matter. There is mild gliosis of the deep cerebellar nuclei.  

 

MORPHOLOGIC DIAGNOSIS: Cerebellum: Purkinje cell loss, necrosis, and degeneration, diffuse, severe, Labradoodle, canine.

 

CAUSE: Autosomal recessive disorder 

 

CONDITION: Cerebellar cortical abiotrophy (CCA)

 

CONDITION SYNONYMS: Cerebellar atrophy, cerebellar cortical degeneration

 

GENERAL DISCUSSION: 

• Nervous system abiotrophies are rare and include:  Motor-neuronal, multi-systemic, cerebellar degenerations, miscellaneous; the cerebellum is the most common site affected
• Most cerebellar defects in morphogenesis are subdivided into hypoplasia or atrophy
• Cerebellar abiotrophy: premature or accelerated degeneration of fully formed neurons
• Progressive cerebellar cortical degeneration is common in dogs

 

PATHOGENESIS:

• Degeneration and loss of Purkinje cells usually occurs at or near the time of birth; presumably caused by some intrinsic metabolic defect
• Purkinje cells are particularly susceptible to spontaneous degeneration; secondary depletion of granule cells occurs (the viability of the granule cell neuron is dependent on a synaptic relationship with the Purkinje dendrite), but other cortical layers are normal
• Studies suggest/establish an autosomal recessive mode of inheritance, but the defect remains mostly unknown; known defects:

• Finnish Harriers (Finnish hounds): missense mutation in SEL1L; thought to lead to endoplasmic reticulum stress (progressive cerebellar cortical degeneration)
• Chinese Crested dogs: mutation of a gene homologous to the human PARK2 gene (hereditary striatonigral and cerebello-olivary degeneration) 

• Mutations in human PARK2 cause autosomal recessive juvenile parkinsonism, which has similarities to this canine disease

• Coton de Tuléar: mutation in GRM1 gene that encodes metabotropic glutamate receptor (nonprogressive cerebellar ataxia, AKA Bandera’s neonatal ataxia)

• Differential diagnosis in Coton de Tuléar puppies:  a later-onset cerebellar ataxia with granule cell degeneration has been described, presumably immune-mediated

• Suspected pathogenesis of others:  may be similar to human spinocerebellar ataxias caused by triplet nucleotide repeats; the triplet (CAG) repeat à inserts in certain CNS genes à  altered function, neurotoxic effects 
• Arabian horses: Lowered expression of MUTYH, a DNA-repairing enzyme

 

TYPICAL CLINICAL FINDINGS:

• Early onset with rapid progression seen in Beagles, Samoyeds, Rhodesian Ridgebacks, Irish Setters
• Later onset with slow progression: Old English Sheepdogs, Gordon Setters, American Staffordshire Terriers, Pit Bull Terriers

• Cerebellar dysfunction: head tremor, intention tremor, truncal ataxia, symmetrical hypermetria, spasticity, broad-based stance and gait
• There is no evidence of general proprioceptive ataxia; normal muscle strength is retained; vision and facial motor function are normal

 

TYPICAL GROSS FINDINGS:

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Progressive loss of Purkinje cells often leaving empty baskets and a fenestrated ground layer, +/- replacement by proliferation of Bergmann astrocytes (Bergmann’s astrocytosis, confirm with GFAP immunohistochemistry)
• Remaining Purkinje cells are degenerate (pale, swollen, and vacuolated with chromatolysis) or necrotic (shrunken and hyperchromatic) 
• Changes secondary to Purkinje cell degeneration and loss may include:

• Transneuronal retrograde degeneration and loss of granule cells
• Shrinkage of the molecular layer
• Spheroids and/or axonal “torpedo” formation (swollen Purkinje cell axons) in the granule cell layer and/or cerebellar white matter 
• Wallerian-type degeneration of the white matter: dilated myelin sheaths with spheroids or digestion chambers oriented in chains

• Cerebellar nuclei are often gliotic, but obvious loss of nuclei is rare
• American Staffordshire terriers and Pit bull terriers: often intracytoplasmic accumulation of ceroid-lipofuscin
• Certain species have anatomic regional predilection; most severely affected areas:

• Gordon Setters: dorsal portions of median lobe and vermis
• Collies:  rostral folia of the vermis – macroscopic diminution of this area 
• Scottish Terriers: dorsal portion of the vermis; accumulation of polyglucosan bodies in the ventral half of the vermis

 

ULTRASTRUCTURAL FINDINGS:

 

DIFFERENTIAL DIAGNOSIS:

• Gross: Cerebellar hypoplasia (in utero viral, toxic, or unknown cause)
• Microscopic: Minamata disease (organomercurial poisoning):  shrunken, acidophilic neurons at all levels of brain and spinal cord, gliosis, and edema in white matter

 

COMPARATIVE PATHOLOGY:

• Other canine abiotrophies:

• Hereditary striatonigral and cerebello-olivary degeneration: Kerry Blue Terriers and Chinese Crested dogs, autosomal recessive mutation in a gene homologous to the human PARK2 gene; neuronal degeneration starts in the cerebellar cortex > caudal olivary nucleus, caudate nucleus, putamen > substantia nigra; proposed that the cerebellum and basal nuclei are the primary areas of involvement while the olivary nucleus and substantia nigra lesions are attributed to trans-synaptic neuronal degeneration along glutaminergic neurotransmission pathways
• Late-onset progressive spinocerebellar degeneration: Brittany Spaniels 7-14 years old; diffuse loss of Purkinje cells with massive neurofilament accumulation in degenerating neurons; bilateral neuronal degeneration in the dorsal horns of the spinal cord, the gracilis, and cuneate nuclei; secondary axonal degeneration in the spinal cord (“saluting disease” due to clinical signs)
• Rough coated collie, Border collie: Neuronal loss in cerebellar nuclei and brain stem with Wallerian degeneration
• Red haired cocker spaniel: Multisystemic neuronal degeneration; slowly progressive neurologic signs, onset around 6 months old; bilaterally symmetrical loss of neurons predominantly in the septal nuclei, globus pallidus, subthalamic nuclei, substantia nigra, tectum, medial geniculate nuclei, and cerebellar and vestibular nuclei; gliosis and axonal spheroids
• Cairn terrier: Multisystemic neuronal degeneration with widespread neuronal chromatolysis in the CNS and PNS
• Primary cerebellar degeneration (neonatal): beagle, Samoyed, Irish setter
• Primary cerebellar degeneration (postnatal): Airedale, German shepherd dog, Gordon setter, rough coated collie, Border collie, Finnish terrier, Bernese mountain dog (olivary nuclei may also be affected), Bern running dog, Labrador retriever, Golden retriever, cocker spaniel, Cairn terrier, great Dane
• Primary degeneration of the granule cell layer (cerebellar granuloprival degeneration), with sparing of other cerebellar cortex layers:   Brittany spaniel, Italian hound, Lagotto Romagnolo, Beagle, Border collie, Bavarian mountain dog, Australian kelpie, Labrador retriever
• Coton de Tuléar:  

• Nonprogressive cerebellar ataxia (Bandera’s neonatal ataxia) onset at 2 weeks of age, caused by mutation in GRM1 gene encoding metabotropic glutamate receptor 1; no histologic changes present
• Later-onset, presumed immune-mediated, cerebellar ataxia with granule cell degeneration

• Bernese mountain dogs: progressive cerebellar and hepatic disease (hepatocerebellar degeneration); hepatic lesions characterized by vacuolation, degeneration, and nodular regeneration

• Cats:

• Olivopontocerebellar atrophy (not associated with feline panleukopenia) has been reported in adult cats, characterized by loss of cerebellar cortical neurons, pontine nuclei, and olivary complex 
• Feline hereditary cerebellar cortical atrophy has been reported

• Horses:

• Arabian and part-Arabian horses: Decreased expression of MUTYH (a DNA-repairing enzyme); occurs at 0-6 months of age; widespread loss of Purkinje cell neurons and granular neurons, multifocal distribution
• Swedish Gotland ponies and American miniature horse: Similar syndrome to Arabian foals, inherited likely autosomal recessive; one American miniature horse also had degeneration of the dorsal accessory olivary and lateral (accessory) cuneate nuclei and focal necrosis of the putamen
• Gomen disease (N-M12): Cerebellar degeneration and ataxia of horses in New Caledonia with abundant deposition of lipofuscin-like pigment in remaining Purkinje cells and neurons of the brain and spinal cord

• Cattle: 

• Aberdeen angus (and crosses), Hereford crosses: Bovine familial convulsions and ataxia is a heritable disease with intermittent episodic seizures in newborn and young calves; distinctive features are Purkinje cell axonal swelling in the cerebellar granular layer and degeneration and loss of Purkinje cells
• Charolais, Angus (and crosses): Similar disease with later onset
• Holsteins: Cerebellar cortical degeneration almost exclusively affecting the Purkinje cells has been described in Holstein calves in Brazil

• Pigs: Reported in Yorkshire pigs, onset around 3-4 weeks of age, no head tremor
• Sheep: 

• Multiple breeds, including Corriedale and Drysdale lambs, in England and Canada: Daft lamb disease is present at birth; presumed inherited; lesions affect the Purkinje and Golgi cells especially in the median lobe; complete loss of Purkinje cells and thinning of the granular and molecular cell layers; cerebellum is grossly normal
• Wiltshire sheep in New Zealand: Onset at 4-7 weeks old, slowly progressive
• Australian Merino sheep: Onset at 3-6 years, called Yass ataxia; lesions are diffuse vacuolation, shrinkage, and loss of Purkinje cells with associated spinal Wallerian degeneration

• Laboratory animals:

• Nervous mice: autosomal recessive inheritance of cerebellar abiotrophy
• Weaver mutant mice

 

REFERENCES:

1. Cantile C, Youssef S. Nervous system. Maxie MG ed. In: Jubb Kennedy and Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:276, 318-320.
2. Miller AD, Zachary JF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease.  7th ed. Saint Louis, MO: Elsevier; 2022: 964.

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