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Neuronal Ceroid Lipofuscinosis 8 (CLN8 gene, English Setter)

Neuronal Ceroid Lipofuscinosis 8 (CLN8 gene, English Setter)

Neuronal ceroid lipofuscinosis 8 (NCL8) is a rare neurodegenerative disease that has been identified in some breeds of dogs, including the English Setter. This disease is caused by mutations in the CLN8 gene, which produces a protein involved in lipid transport and lysosomal function.

Symptoms

Dogs affected by LCN8 usually show progressive neurological symptoms starting at an early age, between 14 and 18 months. Progressive loss of vision, lack of muscle coordination and an abnormally stiff gait usually occur. Within a few months after the onset of the disease, seizures occur which can be lethal and most affected dogs do not live more than two years.

Disease Management

Currently, there is no cure for LCN8 and treatment focuses on symptom management. Due to the severity of the disease, euthanasia is often resorted to.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by the accumulation of fluorescent lipofuscin granules in the lysosomes of neurons, resulting in early neuronal death and progressive neurodegeneration of the central nervous system. These diseases are caused by mutations in various genes, the age of onset of symptoms and progression vary with the specific form of the disease and the underlying mutation. The variant causing this type of lipofuscinosis in English Setter dogs is c.491T>C of the CLN8 gene which codes for a transmembrane protein of the endoplasmic reticulum and possibly mediates transport with the Golgi apparatus. The function of this protein is not well understood, but it is thought to play a role in lipid synthesis and transport and it has been shown that mutations in CLN8 could affect the levels of certain lipids in the brain, such as sphingolipids and phospholipids.

Most affected breeds

Australian Shepherd
English Setter
German Shorthaired Pointer
Saluki

Bibliography

Katz ML, Khan S, Awano T,et al. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun. 2005 Feb 11;327(2):541-7.