Introduction

• Hereditary ataxias are a heterogeneous group of neurodegenerative diseases characterized clinically by cerebellar ataxia.
• They are described in many breeds of dog as a progressive juvenile onset cerebellar dysfunction. It is uncommon and breed-specific. Occasionally, it can be neonatal or adult in onset (the latter is referred to as late onset ataxia; LOA). It is commonly considered to be an inherited condition.
• Various types of hereditary ataxia exist, classified according to neuropathology:
  • Cerebellar cortical degeneration (also cerebellar abiotrophy; cerebellar degeneration; cerebellar ataxia).
  • Spinocerebellar ataxia.
  • Canine multiple system degeneration.
  • Cerebellar ataxias without significant neurodegeneration.
  • Episodic ataxia.
• Two terms defining cerebellar pathology that are not included in the umbrella term of hereditary ataxia are:
  •  Cerebellar hypoplasia - reserved for cases in which the cerebellum has failed to fully develop affecting the animal from birth as a non-progressive condition Brain: cerebellum - congenital disorders.
  • Cerebellar atrophy - the result of a destructive process that destroys cerebellar tissue, eg an infarct.

Pathogenesis

Etiology

• Reduction in cell populations in the cerebellum, mainly the Purkinje cells due to inherited 'programed' cell degeneration and death.
• Cerebellar cortical degeneration:
  • Reduction in cell populations in the cerebellum, mainly the Purkinje cells (sometimes the granular neurons) due to inherited 'programed' cell degeneration and death.
  • Can be further divided into those diseases affecting Purkinje cells, and those affecting granular neurons (granuloprival degeneration).
• Spinocerebellar ataxia:
  • As well as reduction in cell populations in the cerebellum (this can be spared in some cases), the spinocerebellar tracts and medulla can have variable involvement.
• Canine multiple system degeneration:
  • In addition to cerebellar pathology, the olivary nuclei, putamen, substantia nigra and caudate nuclei are also affected.
• Cerebellar ataxias without significant neurodegeneration:
  • No histopathological changes are identified in the cerebellum, ultrastructural examination reveals synaptic abnormalities of the Purkinje cells.
• Episodic ataxia:
  • Episodes of severe cerebellar ataxia interspersed by periods of normality.
  • No histopathological changes identified.

Predisposing factors

General

• Only predispositions reported are related to specific breeds.
• Reduction in cell populations in the cerebellum reduces its overall size and function, causing incoordination of a progressive nature.

• No evidence of toxic, infectious, nutritional or metabolic insults responsible for this progressive condition.

Specific

• Purkinje cell degneration and death is most commonly documented as an autosomal recessive inherited condition.
• Purkinje cell degeneration can lead to other cell populations being involved in the degenerative process via transsynaptic degeneration.
• Excitotoxicity has been proposed to be involved in the degeneration of the various cell populations. Excessive glutamate concentrations can cause influx of calcium to the cell and ultimate cell death.

Pathophysiology

• A familial or autosomal recessive degenerative condition of the cerebellum accounts for the majority of cases. The degeneration or premature aging most commonly affects the Purkinje cells but it can also affect the granule cells, olivary neurons and pontine neurons. These latter cell populations may be affected due to the process of transynaptic degneration. Excitotoxicity may play a role in this condition. ( No pontine neuronal loss has been documented in animals - only in humans.)

• The precise pathophysiology has not been documented. Regression of various cerebellum cell populations may be due to an inherited and programed cell death and/or excitotoxic mechanisms. It has been suggested that such conditions could be based on a genetically defined immune defect leading to autoimmune destruction of granular cells. This has been based in one report on a marked diffuse T cell infiltration (CD3(+) cells). CD18 staining showed an upregulation of microglial cells at the lesion site. Histopathologically the lesions resembled paraneoplastic cerebellar degeneration which is caused by an autoimmune mediated T cell reaction.

Timecourse

• The condition is often slow and progressive; in the majority of dogs it has an onset between 2-4 months of age and has often resulted in euthanasia by 12 months. Some reports suggest individual cases will plateau clinically and therefore may have a protracted or indefinite clinical course.
• Some late-adult onset breeds may have dogs that live to old age without being so disabled that they need to be euthanized.

Diagnosis

Treatment

Prevention

Outcomes