NCL 8 Setter Type – Neuronal Ceroid Lipofuscinosis
NCL 8 Setter Type is a hereditary lysosomal storage disorder, which is a form of a bigger group of neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The NCLs cause accumulation of lipopigments in the body’s tissue, but they can be divided into different forms, based on the age on symptoms’ onset and genetic cause of the disorder. Based on the age of onset, NCLs can be classified as infantile (INCL), late-infantile, juvenile and adult onset forms. Until now, 8 distinct mutations have been associated with different forms of NCL. The disorder has been identified in humans, cats, sheep, goats, monkeys, cattle etc. NCL 8, neuronal ceroid lipofuscinosis Setter type, is affecting Irish Setter and Gordon Setter. A rare case of similar mutation as in NCL 8 has been identified in the Australian Shepherd.
Lipofuscin is a yellow to brown lipopigment composed of residues of lysosomal digestion. It is considered to be one of the aging pigments localized in the liver, kidney, heart muscle, retina, nerve cells and ganglion cells. Lipofuscin in high levels causes membrane damage, damage to mitochondria and lysosomes. Its balance within the cell is realized via formation and disposal mechanisms. When this balance is disrupted, accumulation of lipofuscin occurs. In humans, this condition is related to several diseases, such as degenerative disease of the eye, the macular degeneration and inherited juvenile form of macular degeneration, the Stargardt disease, as well the Alzheimer’s, Parkinson’s disease etc. Abnormal accumulation of lipofuscin is cause of the neuronal ceroid lipofuscinosis, causing progressive and permanent loss of motor and psychological ability.
Characteristics and Symptoms
Neuronal Ceroid Lipofuscinosis 8 is a juvenile NCL, with age of clinical onset between 14 to 18 months of age. The symptoms include stiffness of gaint, progressive vision loss, lack of muscle coordination and difficulties in balancing and jumping. They progress during following months and uncontrolled rhythmic head movements, ataxia and general weakness will develop. Affected dogs also show behavioral changes in form of mental dullness. From 18 months of age on, some dogs may show also muscular spasms.
Autopsy reveals a cerebral atrophy, as result of a massive neuronal degeneration. In progressed stages of the disorder, affected dog’s brain weights about 60% of that of a healthy, unaffected dog. Brain’s grey matter areas are reduced and display a yellow-brown discoloration. Degenerative changes are also present in the cerebellum. Microscopy shows heavy accumulation of autofluorescent storage material, lipofuscin, in neurons of the retina, cerebellum and cerebral cortex, which can be detected already around 2-3 months of age in about 30% of the neurons. By the age of 12 months, the autoflourescent material is found in high percentage in most of the cytoplasm of the large neurons. Around this age is when clinical signs appear in form of degenerative changes. By age of 15 to 24 months, there is a complete loss of neurons in grey matter areas, especially in the cerebellar cortex.
Due to severity and progressive nature of NCL 8, affected dogs are usually euthanized by their owners due to humane reasons. Most of affected dogs die by the age of 2 years.
NCL 8 Setter Type is caused by mutation in the CLN8 gene. This mutation results in lack of enzyme needed for normal metabolism in dogs.
Neuronal Ceroid Lipofuscinosis 10 (NCL 8 Setter Type) is inherited as an autosomal recessive disorder. Dog carrying one copy of the mutated gene is heterozygous and will not show the NCL 8 symptoms. When mating two carriers (heterozygotes) at conception each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Currently there is no cure for NCL 8.
Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS. (2005): A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun. 11; 327(2):541-7.