Cerebellar Ataxia (NCL-A) in American Staffordshire Terrier and American Pit Bull Terrier

Neuronal ceroid-lipofuscinosis (NCL) is a neurodegenerative disease that affects humans, dogs and other animals (e.g. cattle, sheep, horses). In some animals, no causal mutation leading to NCL has been described yet. In connection with NCL in animals and humans, mutations in six different genes CLN 1,2,3,4,5,6,8 (Daly et al. 1998, Gupta et al. 2001) have been described so far. Each mutation in the given gene causes a unique form of NCL.
Neuronal ceroid-lipofuscinosis belongs to the group of lysosomal storage disorder characterized by accumulation of lipopigments (ceroid and lipofuscin) in the central nervous system and peripheral tissue. (Jalanko et al., 2009)
In connection with the NCL-disease in American Staffordshire Terriers, American Pit Bull Terriers and dogs of Pit Bull type (NCL-A) a causal mutation c.296G>A in the gene of arylsulphatase G (ARSG gene) on the chromosome 9 (Abitol et al., 2010) has been described. This mutation leads to the change p.R99H in protein, which results in fatal decrease in activity of this enzyme. Neurons lacking ARSG activity might accumulate undegraded substrates in their lysosomes. Storage of this undegraded material causes, after exceeding the limits, a number of characteristic symptoms of NCL-disease.
NCL-A affects the part of the brain called cerebellum. The cerebellum is closely related to the vestibular system of the brain and together with other brain parts controls the coordination of body movements. The first symptoms of disease occur in adult age, between the second and fifth year of age. At the beginning, the symptoms are slight; the dogs are clumsy, stumble during quick movement. With the disease progress, the clumsiness becomes more distinctive - the dogs often fall when moving the head from one side to other side, the males often loss stability when lifting the hind leg to urinate. When running, playing and moving fast in bends the dogs loose their coordination and fall. When observing the eyes of dogs after shaking the head, it is possible to observe a special movement of yeas from side to side or turning in circles that lasts up to one minute after the head movement. Other symptoms with early onset might be collapse, sudden stiffness of limbs, neck and body for several seconds.
With the disease progress, the difficulties of the dogs with the walking continuously increase and the dogs have problems to keep on their feet when eating and therefore lose their weight. In the final phase, the dogs are not able to stand up and the owners are often forced to euthanize the animal at the age of seven to eight years.

NCL-A is inherited autosomally recessively which means that the disease develops only in those dogs who inherit mutated allele from both parents. Carriers of mutated allele (heterozygotes) are clinically healthy but transmit the mutation on their descendants. In case of mating two heterozygous dogs there is a theoretical chance that 25% of descendants will be absolutely healthy, 50% will be carriers a 25% will inherit from both parents mutated allele and therefore will be NCL-A affected.

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References:

M. Abitol at al., A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis, National Academy of Sciences (2010)

M.J. Daly, et al., GENEHUNTER 2.0-A complete linkage analysis system, Am. J. Hum. Genet. Suppl. 63 (1998) A286.

P. Gupta, et al., Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice, Proc. Natl. Acad. Sci. USA 98 (2001)13566-13571

A.Jalanko et al., Neuronal ceroid lipofuscinoses. Biochim Biophys Acta (2009) 1793:697-709