Lysosomal storage disease

Lysosomal storage disease is a neurodegenerative disorder affecting the Lagotto Romagnolo breed of dog and is characterized by the presence of neuronal lesions and severe cytoplasmic vacuolization. A mutation in the ATG4D gene has been identified that appears to be related to the disease, affecting the autophagy process.

Symptoms

Progressive ataxia is the most common symptom in dogs affected by lysosomal storage disease. Prior to experiencing this clinical sign, breeders may observe some clumsiness in the dog. In addition, episodes of nystagmus and behavioral changes such as depression, aggression toward people or dogs, and restlessness have been reported. The rate of progression and onset of symptoms varies among the dogs studied, but it is estimated that symptoms may begin anywhere from 4 months to 4 years of age.

Disease Management

To date, there is no cure for lysosomal storage disease, however, symptomatic treatment and management of behavioral changes may help to improve the quality of life of the affected dog.

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

Lysosomal storage disease is a neurodegenerative disorder related to impairment of the autophagy process. The ATG4D gene encodes an endopeptidase that appears to play an important role in autophagy, which is an essential process for maintaining neuronal homeostasis. In a study by Kyöstilä K. et al. in 2015, a nonsense mutation (c.1288G>A) was identified that is likely the cause of the disease in Lagotto Romagnolo dogs. This mutation is expected to cause a partial loss of functionality of the protein, which would explain the variability in the age of disease onset and progression. Furthermore, if the canine protease were to completely lose its function, it is likely that the disease phenotype would be of greater severity than that observed in this study.

Most affected breeds

Lagotto Romagnolo

Bibliography

Kyöstilä K, Syrjä P, Jagannathan V,et al. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease. PLoS Genet. 2015 Apr 15;11(4):e1005169.