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Lagotto storage disease (LSD)

Neurological · Dog

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.

Inheritance pattern	Autosomal recessive.
Gene / Mutation	ATG4D c.1288G>A p.(Ala430Thr)
Penetrance	High but possibly incomplete penetrance: in the original cohort three homozygotes showed no clear signs at the time of the study, although on re-evaluation two had mild findings (video or biopsy). The disease is progressive and of late onset, so some homozygotes may remain without evident signs for years; this makes it difficult to estimate the true lifetime penetrance.
Code	hgnq
Turnaround time	10 days
Price	52,60 €

Incidence

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.

Breeder management

- 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.

Specialist notes

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.

References

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

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