Neuroaxonal dystrophy (NAD) in Miniature American Shepherds

Neuroaxonal dystrophy belongs to a group of rare heterogeneous inherited neurodegenerative disorders. It has been described in various mammalian species, including humans, dogs, sheep, cattle, horses or cats and occurs sporadically worldwide. The disease is primarily characterized by the presence of spheroids (swollen axons) throughout the central nervous system.

Clinical manifestations and onset of disease vary between mammalian species and between individuals of the same species. In Miniature American Shepherds, it is a slowly progressive neurodegenerative syndrome. Affected dogs are typically young adults and show characteristic gait abnormalities, pelvic limb weakness and ataxia. However, despite these disabilities, the dogs have a relatively long lifespan. Histopathology reveals the presence of the spheroids, neuronal degeneration and secondary gliosis.

The underlying genetic cause was identified as a 1bp deletion (c.367delG) in the RNF170 gene. The mutation leads to a frameshift, a premature inclusion of the stop codon and truncation of the resulting protein.

The mode of inheritance of the mutation is autosomal recessive. This means that only individuals who inherit the mutated gene from both parents will develop the disease. Carriers of the mutated gene are clinically healthy but pass the mutation on to their offspring. In the case of a mating between two heterozygous individuals, theoretically 25% of the offspring will be completely healthy, 50% of the offspring will be carriers and 25% of the offspring will inherit the mutated gene from both parents and will therefore be affected by the disease.

The genetic test can clearly reveal the genotype of the animal and is a useful tool for breeders to prevent unintentional breeding of affected puppies.

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References:

Shawna R. Cook, Cleo Schwarz, Julien Guevar, Charles-Antoine Assenmacher et. al: RNF170 frameshift deletion in Miniature American Shepherd dogs with neuroaxonal dystrophy provides a naturally occurring model for human RNF170 phenotypic spectrum; posted 01 Feb, 2024