Cerebellar Ataxia – NCL-A American Staffordshire Terrier Type
NCL-A American Staffordshire Terrier Type is an inherited disorder, which is a form of a bigger group of neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The NCLs are disorder of lysosomal storage, characterized by accumulation of lipopigments in the body’s tissue. Different forms of NCLs cause similar symptoms, but they can be divided into different forma, 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. Neuronal Ceroid Lipofuscinosis American Staffordshire Terrier Type (NCL 4A) is a neurological disease and its equivalent the Kufs’ disease, affecting human patients.
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
NCL-A American Staffordshire Terrier Type is an adult onset form, with an age of onset between 3 to 5 years. 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 and dementia.
Histopathological examination reveals cerebellum atrophy, loss of Purkinje cells and heavy accumulation of lipopigments in Purkinje cells and thalamic neurons.
Due to severity and progressive nature of NCL-A, affected dogs are usually euthanized by their owners due to humane reasons.
Neuronal Ceroid Lipofuscinosis American Staffordshire Terrier Type (NCL-A) is associated to a mutation in the ARS G gene (Arylsulfatase G). The mutation in affected dogs causes a decrease in sulfatase activity of 75% which is needed for certain protein breakdown. Researchers estimated high carrier rate among American Staffordshire Terrier dogs of 30%.
NCL-A American Staffordshire Terrier Type is inherited as an autosomal recessive disorder. Dog carrying one copy of the mutated gene is heterozygous and will not show the 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 4A.
Abitbol M, Thibaud JL, Olby NJ, Hitte C, Puech JP, Maurer M, Pilot-Storck F, Hédan B, Dréano S, Brahimi S, Delattre D, André C, Gray F, Delisle F, Caillaud C, Bernex F, Panthier JJ, Aubin-Houzelstein G, Blot S, Tiret L. (2010): A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A.; 107(33):14775-80.