Neuronal Ceroid Lipofuscinosis 12, NCL12

 

Gene: ATP13A2

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Tibetan Terrier mutation: Deletion, ATP13A2 gene; c.1623 del

Australien Cattle Dog mutation: Substitution, ATP13A2 gene; c.1118 C>T, p.(T373I)

Medical systems: Neurologic, lysosomal storage disease

Breeds: American Staffordshire Terrier/Amstaff, Australian Cattle Dog, Russell Terrier, Schnauzer - Miniature, Tibetan Terrier

Age of onset of symptoms: From 2 to 3 years

Neuronal Ceroid Lipofuscinosis describes a family of genetic diseases that affect the function of lysosomes within the cell.   NCL-A is a form of this disease seen in Tibetan Terriers. It is caused by dysfunction of the ATP synthase enzyme which leads to the accumulation of lipopigments within cells.  The nervous system is particularly affected, notably ganglia and Purkinje cells.  At first, the affected animal suffers from night blindness which eventually leads to complete blindness a few years later.  Other neurological signs also appear in adulthood and include epilepsy, dementia, motor disorders, aggression, behavioral disorders, cognitive decline and generalized brain atrophy.  The disease is progressive and no treatment currently exists.

 

References :

OMIA link: [1552-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Cerda-Gonzalez S, Packer RA, Garosi L, et al. (2021) International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification. J Vet Intern Med 35:1218-1230 [pubmed/33769611]

Story BD, Miller ME, Bradbury AM, et al. (2020) Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80. [pubmed/32219101]

Schmutz I, Jagannathan V, Bartenschlager F, et al. (2019) ATP13A2 missense variant in Australian Cattle Dogs with late onset neuronal ceroid lipofuscinosis. Mol Genet Metab 127:95-106.  [pubmed/30956123]

Katz ML, Rustad E, Robinson GO. (2017) Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. Neurobiol Dis. 108:277-287.  [pubmed/28860089]

Kluth S, Eckardt J, Distl O. (2014) Selection response to DNA testing for canine ceroid lipofuscinosis in Tibetan terriers. Vet J. 201(3):433-4. [pubmed/24929534]

Farias FHG, Zeng R, Johnson GS, Wininger FA, et al. (2011) A truncated mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers.  Neurobiology of Disease 42:468-474.  [pubmed/21362476]

Wohlke A, Philipp U, Bock P, et al. (2011) A one base pair deletion in the canine ATP13PA2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan Terrier.  PLoS Genet 7(10):e1002304.  [pubmed/22022275]

Kluth S, Eckardt J, Distl O. (2014) Selection response to DNA testing for canine ceroid lipofuscinosis in Tibetan terriers. Vet J. 201(3):433-4. [pubmed/24929534]

Alroy J, Schelling SH, Thalhammer JG, et al. (1992) Adult onset lysosomal storage disease in a Tibetan terrier: clinical, morphological and biochemical studies. Acta Neuropathol 84:658-63. [pubmed/1471473]