Neuroaxonal dystrophy (NAD) in Spanish water dogs and Lagotto Romagnolo

Neuroaxonal dystrophy belongs to the group of rare heterogenous hereditary neurodegenerative disorders. It has been described in various kinds of mammals including humans, dogs, sheep, cattle, horses, or cats and occurs sporadically all over the world.

Clinical signs and the disease onset vary between mammalian species and between individuals of the same species. In Spanish water dogs, the first signs of the slowly progressing disease can be observed between 6 and 11 months of age.  The signs include gait abnormalities, behavioural disturbances such as dullness, nervousness, vocalization, and incontinence alone or in combination with uncontrolled defecation. A characteristic pathological feature of NAD is severe swelling of axons, called spheroids, especially in the grey matter of the cerebral hemispheres, cerebellum, brainstem, and sensory spinal cord tracts.

In Spanish Water Dogs, the disease is caused by a mutation in the gene for the autophagy-related protein TECPR2, and impairment of autophagy has been discussed as a main pathomechanism in several neurodegenerative conditions.  This is the c.4009C>T missense mutation, which leads to the exchange of the amino acid arginine for tryptophan at the protein level.

NAD is a recessively inherited disease. The disease develops in dogs which inherit the mutated gene from each parent.  These dogs are designated as P/P (positive/positive). The carriers of the mutated gene are designated as N/P (negative/positive). The carriers inherited the mutated gene from one parent only and are without clinical signs. However, they pass the disease on to their offspring.  When mating two heterozygotes (N/P), there will be theoretically 25% of the offspring healthy, 50% of the offspring will be carriers and 25% of the offspring will inherit the mutated gene from both parents and will be affected by NAD.  Mating one healthy dog (N/N) with a carrier of this mutation (N/P) will theoretically produce 50% carriers and 50% healthy offspring.  If a carrier (N/P) is mated with an affected dog (P/P), there will be theoretically 50% affected dogs and 50% carriers.

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References:

Hahn, K., Rohdin, C., Jagannathan, V., Wohlsein, P., Baumgärtner, W., Seehusen, F., Spitzbarth, I., Grandon, R., Drögemüller, C., Jäderlund, K.H. : TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs. PLoS One 10:e0141824, 2015. Pubmed reference: 26555167.