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NCL 8 Setter Type
| Acronym: | NCL 8 |
| Gene: | CLN8 |
| Mutation: | c.491T>C |
| Inheritance: | Autosomal recessive |
| Sample type: | CHS (Cheek Swab), WBE (Whole Blood EDTA) |
Genetics and characteristics
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 the accumulation of lipopigments in the body’s tissue, but they can be divided into different forms, based on the age of symptoms’ onset and the 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 at high levels causes membrane damage and damage to mitochondria and lysosomes. Its balance within the cell is realized via formation and disposal mechanisms. When this balance is disrupted, the accumulation of lipofuscin occurs. In humans, this condition is related to several diseases, such as degenerative disease of the eye, macular degeneration, inherited juvenile form of macular degeneration, Stargardt disease, as well Alzheimer’s, Parkinson’s disease, etc. Abnormal accumulation of lipofuscin is the cause of neuronal ceroid lipofuscinosis, causing progressive and permanent loss of motor and psychological ability.
Neuronal Ceroid Lipofuscinosis 8 is a juvenile NCL, with the 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 the 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 cerebral atrophy, as a result of a massive neuronal degeneration. In progressed stages of the disorder, the affected dog’s brain weighs about 60% of that of a healthy, unaffected dog. The brain’s grey matter areas are reduced and display a yellow-brown discoloration. Degenerative changes are also present in the cerebellum. Microscopy shows the 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 autofluorescent material is found in a 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 the severity and progressive nature of NCL 8, affected dogs are usually euthanized by their owners due to humane reasons. Most affected dogs die by the age of 2 years.
NCL 8 Setter Type is caused by a mutation in the CLN8 gene. This mutation results in a lack of an enzyme needed for normal metabolism in dogs. Neuronal Ceroid Lipofuscinosis 10 (NCL 8 Setter Type) is inherited as an autosomal recessive disorder. A 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.
Results Reported As
Test Result |
Interpretation of test result |
CLEAR |
Tested mutation was not detected in animal with „clear“ result. Animal tested as clear has wild-type allele in homozygous state (i.e. two pairs of healthy alleles). It will not develop disease caused by tested mutation.* It will pass only wild-type allele to its offspring. |
CARRIER |
Tested mutation was detected in animal with „carrier“ result. Animal tested as carrier has one wild-type and one mutation allele, it is in heterozygous state. It will not develop disease caused by tested mutation.* It can pass wild-type or mutation allele to its offspring. |
AFFECTED |
Tested mutation was detected in animal with „affected“ result. Animal tested as affected has two copies of mutation alleles affecting the gene. It is likely the animal will experience a genetic disorder due to this mutation.** It will pass only mutation allele to its offspring. |
*Test excludes only tested mutation but not possible unknown mutations or factors that can lead to similar condition/symptoms.
** Potential unknown mutations or multiple other factors can possibly affect the likelihood of experiencing a genetic disorder.
References:
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.
Koppang N. (1992): English setter model and juvenile ceroid-lipofuscinosis I n man. Am J Med Genet. 42(4):599-604.
Koppang N. (1988): The English setter with ceroid-lipofuscinosis: a suitable model for the juvenile type of ceroid-lipofuscinosis in humans. Am J Med Genet Suppl. 5:117-25.