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Neuronal ceroid lipofuscinosis 12 (ATP13A2 gene, Tibetan Terrier)

Neuronal ceroid lipofuscinosis 12 (ATP13A2 gene, Tibetan Terrier)

Neuronal ceroid lipofuscinosis type 12 (NCL12) is a late-onset neurodegenerative disease that has been identified in the Tibetan Terrier breed, and is associated with a genetic variant in the ATP13A2 gene. This lysosomal storage disorder is characterized by the intracellular accumulation of toxic fluorescent substances, mainly affecting neurons and other cells.

Symptoms

Neuronal ceroid lipofuscinosis type 12 is characterized by a number of clinical signs, ranging from brain atrophy and cognitive impairment to behavioral changes. Symptoms include dementia, aggressiveness, cerebellar ataxia, nervousness, tremors, loss of coordination, retinal degeneration and some photoreceptor impairment. It is important to note that in this specific type of lipofuscinosis, the neurodegenerative symptoms are milder and manifest later in life, usually between 5 and 7 years of age, compared to other variants of the disease.

Disease Management

There are no specific preventive measures or cure for NCL12. The treatment approach focuses on supportive care, such as physical therapy to improve mobility and maintaining a balanced diet. Possible therapeutic interventions, such as enzyme replacement and gene therapies, are currently under investigation.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Neuronal ceroid lipofuscinosis type 12 is a lysosomal storage disease associated with a pathological variant in the ATP13A2 gene, which encodes a P-type ATPase, a member of the superfamily of genes responsible for the transport of inorganic cations and other substrates. The specific variant identified in the Tibetan Terrier dog breed involves a single base deletion (c.1623del) in exon 16 of the ATP13A2 gene. This mutation induces an alternative splicing process in exon 16, resulting in a protein shortened by 69 amino acids. This canine variant may be a model for investigating the pathobiology of Kufor-Rakeb syndrome (KRS) in humans, a disease caused by truncating mutations in the ATP13A2 gene.

Most affected breeds

Tibetan Terrier

Bibliography

Farias FH, Zeng R, Johnson GS, et al. A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers. Neurobiol Dis. 2011 Jun;42(3):468-74.

Katz ML, Rustad E, Robinson GO, et al. Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. Neurobiol Dis. 2017 Dec;108:277-287.

Wöhlke A, Philipp U, Bock P, et al. A one base pair deletion in the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrier. PLoS Genet. 2011 Oct;7(10):e1002304.