Introduction

• Description of a pathologic change rather than specific disease or syndrome.
• May involve primarily white or gray matter, but typically spares neural elements (ie neuron cell bodies and axons), distinguishing these conditions from the transmissible spongiform encephalopathies, which involve spongiform change of the neurons.
• Numerous etiological processes may result in spongy degeneration, including hepatic disease (hepatic encephalopathy Hepatic encephalopathy), renal disease (uremic encephalopathy), intoxications (organic tin compounds, ammonium, hexachlorophene, isoniazid, cuprizone), viral infections and various familial conditions.
• Current text deals only with specific reports for which there were no obvious acquired etiologies (ie intoxication, hepatic or renal disease, infection); many are suspected to be inherited or familial conditions with some now having a genetic mutation identified.
• Also not included are some diseases or syndromes which may have vacuolation or spongiform pathologic changes within the central nervous system as part of a larger pathologic picture or process; includes leukodystrophies (cavitating leukodystrophy of Dalmatians) and the similar leukoencephalomalacia described in several mixed breed dogs, Afghan Hound myelopathy, demyelinating disease of miniature Poodles, leukoencephalomyelopathy of Rottweilers Leukoencephalomyelopathy and hypomyelination syndromes seen in Weimaraners and Chow Chows Brain: cerebellum - congenital disorders.

Pathogenesis

Etiology

• Unknown in many; likely due to deficiencies of enzymes important to maintenance of myelin or other CNS components.
• Several disorders compared to Canavan's disease (or spongy degeneration of the van Bogaert-Bertrand type) in man, which results from a deficiency of aspartoacylase.
• Most disorders are likely inherited, although sparse numbers of cases make proving this difficult; Bull Mastiffs with familial cerebellar ataxia thought to inherit the disease through an autosomal recessive mechanism.

Specific

• Unknown.
• For Canavan's disease in man - aspartoacylase deficiency (detected antemortem in cultured fibroblasts) → lack of hydrolysis of N-acetylaspartate to aspartate and acetate; specific role of these substances is unclear, but hydrolysis of N-acetylaspartate appears to be important for maintenance of myelin and white matter; result is intramyelinic edema and splitting of the myelin lamellae at the intraperiod line.
• Shetland Sheepdog/Australian Cattle dog leukodystrophy: 3-4 weeks: 
  • A missense mutation in cytochrome b appears to be causal for this disease. 
  • Cytochrome b is an integral membrane protein. The substitution is hypothesized to reduce electron transfer and limit ATP production. 
• Canine spongiform leukoencephalomyelopathy in Border terriers: 3 weeks: 
  • Recently, a genetic test has become available, but no information regarding the gene involved has been published. 
• Central nervous system status spongiosus of Saluki dogs: 2-3 months: 
  • Missense variant in ALDH5A1 associated with canine succinic semialdehyde dehydrogenase deficiency (SSADHD). 
  • Succinic semialdehyde dehydrogenase is an enzyme that catabolizes succinic semialdehyde (SSA) to succinic acid. Excess SSA is converted to 4-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Excess SSA also interacts with an intermediate in the pyruvate dehydrogenase complex to form 4,5-dihydroxyhexanoic acid (DHHA). 
  • Increased GHB in the brain seems to be predominantly responsible for the pathogenesis. 
  • Excess SSA, DHHA and GHB is often found in the body fluids, eg urine. 
• Neuronal vacuolation and spinocerebellar degeneration in Rottweiler dogs: 
  • Homozygous RAB3GAP1:c.743delC mutation appears to be causal. 
  • RAB3GAP1 codes for the catalytic subunit that combines with a noncatalytic subunit encoded by RAB3- GAP2 to form Rab3GAP (a GTPase activator protein that enhances the activity of Rab). 
  • Rab proteins function as molecular switches that regulate the formation, transport, tethering and fusion of a variety of membrane structures by cycling between inactive GDP-bound and active GTP-bound states. 
  • GTP binding to Rab proteins is mediated by a guanine exchange factor (GEF), and subsequently Rab3GAP was shown to also function as a GEF for another Rab protein, Rab18.

Timecourse

• Spongy degeneration of Labrador Retrievers: progressive over weeks - months.
• Shetland Sheepdog/Australian Cattle dog leukodystrophy: progressive leading to euthanasia. 
• Canine spongiform leukoencephalomyelopathy in Border terriers: non-progressive.
• Spongiform leucoencephalopathy with congenital myoclonia: non-progressive.
• Spongiform degeneration of the white matter: progression over few days to generalized tremor. Further details of timecourse unknown.
• Familial cerebellar ataxia with hydrocephalus in Bull Mastiffs: duration 2-4 months. Details of progression not reported.
• Central nervous system status spongiosus of Saluki dogs: not reported.
• Spongy degeneration with congenital tremor: non-progressive.
• Neuronal vacuolation and spinocerebellar degeneration in Rottweiler dogs: progressive leading to euthanasia. 
• Congenital tremor and cerebellar ataxia with spongy degeneration in Malinois dogs: progressive leading to euthanasia. 

Diagnosis

Treatment

Prevention

Outcomes