NCL 12 in Tibetan Terriers

Neuronal Ceroid Lipofuscinosis (NCL 12) is 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, mutation in six different genes, for example CLN 1,2,3,4,5,6 ,8,10 have been described so far (Daly et al. 1998, Gupta et al. 2001, Awano et al. 2006). Each mutation in the given gene causes a unique form of NCL.

In Tibetan Terriers, a causal mutation in position 1623 encoding the sequences in exon 16 of ATP13A2 gene has been found in relation to NCL. It is a single-point deletion (c.1623delG, p.P541fsX597) that results in creation of premature termination codon (Farias et al. 2011).

Clinical symptoms

The Neuronal Ceroid Lipofuscinosis is characterized by accumulation of phospholipids in lysosomes of brain, retina and other tissues. Inclusions in retina occur with the age in the inner nuclear layer and the layer of ganglion cells. Ophthalmoscopic changes can be observed at the age of 3 to 4 years. The first signs of NCL in Tibetan Terriers can be nyctalopia or night blindness, which may occur as early as 7 weeks and will show up on an electroretiongram (ERG). The individual dies usually at the age of 7 to 10 years.

The clinical symptoms can be observed at 4 to 6 years of age. The start and clinical course of the disease are very variable and individual. As the disease progresses, problems with muscle coordination during walking with occasional tripping and change of posture may occur. The NCL affected dogs have often problems to jump up and to go upstairs. In the end stage, the dogs often fall and cannot stand up. The common sign of NCL in Tibetan Terriers is development of aggressiveness towards people and other dogs. Dogs with this defect are often nervous and anxious and lose their house training. Sometimes appetite changes (from poor to ravenous) are observed. Moderate attacks intensify with the age.

Impact of the NCL disease on the vision of Tibetan Terriers

The dogs have worsened vision under bed light conditions and sometimes as the disease progresses even under good light conditions. The eye examinations show slowly progression of retina degeneration that slightly differs among the individual dogs. Essential functional damage to retina is recognisable particularly in later stages of the disease. The function of rods is reduced by up to 90 % in dogs with NCL.

The statistics of CERF (Canine Eye Registration Foundation) for Tibetan Terriers have shown two separate peaks of occurrence of retina problems. The first peak occurs at the age of 2 to 3 years and the second peak begins approx. at 5 to 7 years. Former, some eye doctors and dog owners designated all these changes as progressive retinal atrophy (PRA). However, the studies proved that the later onset of retina changes is probably caused by Neuronal Ceroid Lipofuscinosis (NCL) that means completely different genetic disease (Lionel F. Rubin et al. 1995).

Inheritance

NCL is an autosomal recessive inherited disease i.e. the disease develops in dogs, who inherit the mutated allele from both parents. The carriers of the mutated allele (heterozygotes) are clinically healthy, but pass the mutation on to their offsprings. If two of those heterozygous individuals are mated, theoretically 25 % of the resultant generation will be completely healthy, 50 % will be carriers and 25 % will inherit the mutated allele from their parents and will suffer from NCL.

References:

Farias, F.H.G., et al., A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.02.009

Late-Onset PRA Diagnoses in Tibetan Terriers, Probably CCL, A Different Genetic Condition,

Liz Hansen, Stuart F. Eckmann, Linda W. Bell (= "Major Inherited Eye Problems in Tibetan Terriers," by Lionel F. Rubin, VMD, which appears in the Tibetan Terrier Breeder's Manual, 1995, Tibetan Terrier Club of America) info z: The Veterinary Medical DataBases-VMDB/CERF

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.