NCL 2 Dachshund Type – Neuronal Ceroid Lipofuscinosis
Neuronal Ceroid Lipofuscinosis occurring in the Dachshund breed, the NCL 2 Dachshund Type, is a lysosomal storage disease, which is a part of a wider group of disorders. The neuronal ceroid lipofuscinoses (NCLs) are a group of hereditary neurological disorders known to affect humans, cats, sheep, goats, monkey, cattle etc. The neuronal ceroid lipofuscinoses (NCLs) are divided into genetically distinct forms, all causing accumulation of lipopigments in the body’s tissue. To date NCLs have been associated with 8 different genetic mutations. Another classification of NCLs includes age of onset, so they are divided into infantile (INCL), late-infantile, juvenile and adult onset forms. First time Neuronal Ceroid Lipofuscinosis Dachshund Type was described in a Wire-haired Dachshund in 1977. Since then, neuronal ceroid lipofuscinoses (NCLs) were reported several times in the Dachshund breed.
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
The first clinical signs of NCL 2 Dachshund Type in affected dog appear around 9 months of age and they include vomiting, mental dullness, weakness, loss of housebreaking, and unresponsiveness to previously learned commands. After observing the first signs, the disorder progresses and ataxia and visual deficits develop. Visual disorders often advance to complete blindness. The dog shows episodes of hyperactivity and howling. Behavioral changes are noticed, such as aggression and constant circling. As the disorder progresses, vomiting becomes more frequent and diarrhea develops as well. In an affected dog, diarrhea progression to hematochezia was reported, from which the dog died.
Examination of the central nervous system reveals present autofluorescent storage bodies. In some cells in the cerebral cortex, the accumulation of these storage bodies is massive. In the cerebellum, the accumulation is present in all cell layers, while in the spinal cord most of accumulation is localized in the large motor neurons. The measured tripeptidyl-peptidase 1 enzyme activity in the cerebral cortex is less than 1% of the average activity from the unaffected, healthy dog.
NCL 2 Dachshund Type is associated to a mutation of the TPP1 gene, which is encoding lysosomal tripeptidyl-peptidase 1 enzyme. This enzyme catalyzes cleavage of the N-terminal tripeptides from substrates within the lysosomes.
Neuronal Ceroid Lipofuscinosis Dachshund Type (NCL 2)is inherited as an autosomal recessive disorder. Dog can be clear, carrier or affected. Dog carrying one copy of the mutated gene is heterozygous and will not show the NCL2 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 NCL2.
Awano T, Katz ML, O’Brien DP, Sohar I, Lobel P, Coates JR, Khan S, Johnson GC, Giger U, Johnson GS. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab. 2006 Nov; 89(3):254-60.