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Ceroid neuronal lipofuscinosis 12 (NCL12) of the Tibetan terrier

Neurological · Dog

Ceroid neuronal lipofuscinosis 12 (NCL12) of the Tibetan terrier is an adult-onset neurodegenerative disease included in the group of neuronal ceroid lipofuscinoses (Batten disease), characterised by intraneuronal accumulation of autofluorescent material and neuronal death. In the Tibetan terrier behavioural and visual changes begin around 4-6 years of age. It is caused by variants of the ATP13A2 gene and is inherited in an autosomal recessive manner.

Inheritance pattern	Autosomal recessive.
Gene / Mutation	ATP13A2. One-base deletion in exon 16: c.1623delG according to Farias et al. (2011), termed c.1620delG by Wöhlke et al. (2011). Sources disagree on the consequence: Farias et al. predict frameshift and premature stop codon (p.P541fsX597), while Wöhlke et al. describe an in-frame skipping of exon 16 with loss of 69 amino acids. OMIA001552-9615. Another variant (c.1118C>T) has been described in the Australian Cattle Dog, not in the Tibetan terrier.
Penetrance	Apparently high penetrance in homozygosity for late onset: all affected dogs studied were homozygous. Limited data on penetrance over the whole lifespan and on carrier frequency in the breed.
Code	enmi
Turnaround time	7 days
Price	41,60 €

Incidence

Documented in the Tibetan terrier, a breed in which it is comparatively more frequent due to its small population size and its late onset. No reliable allele frequency figures are available for the breed: limited data.

Breeder management

- Test breeding animals with the ATP13A2 test before breeding.\n- Do not mate two carriers: 25% risk of affected homozygous offspring.\n- A carrier may be mated with a clear dog; test offspring intended for breeding.\n- Exclude affected homozygotes from breeding.\n- Given the late onset, an apparently healthy breeding animal may be a carrier: testing is the only reliable way to know.

Specialist notes

Differential diagnosis with other neuronal ceroid lipofuscinoses and with other adult-onset neurodegenerative diseases. Confirmation is molecular (ATP13A2). A distinct variant exists in the Australian Cattle Dog (c.1118C>T), so the test must be breed- and variant-specific. The discrepancy in nomenclature (c.1623delG versus c.1620delG) reflects differences in the reference transcript.

References

1. Farias FH et al. 2011. A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers. Neurobiology of Disease. PMID: 21362476
2. Wöhlke A et al. 2011. A one base pair deletion in the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrier. PLoS Genetics. PMID: 22022275
3. OMIA:001552-9615. Neuronal ceroid lipofuscinosis, 12 in Canis lupus familiaris. Online Mendelian Inheritance in Animals.

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