Vacuolar neurodegenerative disease of the Lagotto Romagnolo, caused by a missense mutation in the ATG4D gene, which encodes a cysteine protease involved in macroautophagy. It causes progressive cerebellar ataxia, sometimes with episodic nystagmus and behavioural changes, and is characterised histologically by neuronal and extraneuronal cytoplasmic vacuolation with altered basal autophagy. It is inherited in an autosomal recessive manner.

Affected breed: Lagotto Romagnolo. In the published cohort of more than 2,300 Lagotto, 1 % (25/2,352) were mutant homozygotes and 11 % (266/2,352) were heterozygotes. The variant was not detected in 642 dogs from 40 additional breeds, including closely related breeds such as the Barbet or the Spanish and Portuguese water dogs.

- Progressive cerebellar ataxia
- Episodic nystagmus
- Behavioural changes
- Progressive neurological deficit
- Slowly progressive course with long-term deterioration
- Some elderly homozygotes without manifest signs at the time of the study

Lagotto Romagnolo LSD was characterised as a new neurodegenerative disease with a unique histological pattern of cytoplasmic vacuolation. In 2015, Kyöstilä and colleagues combined linkage analysis, homozygosity mapping and whole-genome sequencing in one case and, comparing with 118 control genomes, identified the missense variant c.1288G>A (p.Ala430Thr) in ATG4D, on canine chromosome 20. In a cohort of more than 2,300 Lagotto the association was highly significant. Later studies confirmed altered basal autophagy in fibroblasts from affected dogs and enabled the genetic test to be developed.

- Test breeding animals with the ATG4D test before mating.
- Do not mate two carriers: 25 % risk of affected homozygotes.
- A carrier can be mated to a clear animal; offspring intended for breeding must be tested.
- Exclude affected homozygotes and their known carrier parents from breeding.
- Given the moderate carrier frequency, prioritise progressive replacement with clear offspring without narrowing the breed's gene pool.

Differential diagnosis with other storage diseases (gangliosidosis, mucopolysaccharidosis) and with other hereditary cerebellar ataxias. Skin biopsy showing vacuolation of the sweat glands and other epithelia is a useful extraneuronal marker. Histology shows marked neuronal cytoplasmic vacuolation and spheroids; biochemical studies excluded the main known lysosomal storage diseases. The disease is considered more a disorder of basal autophagy than a classic lysosomal storage disease.

1. Kyöstilä K et al. 2015. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease. PLoS Genetics. PMID: 25875846
2. Syrjä P et al. 2020. Altered Basal Autophagy Affects Extracellular Vesicle Release in Cells of Lagotto Romagnolo Dogs With a Variant ATG4D. Veterinary Pathology. PMID: 33016245