OMIA:001954-9615 : Neurodegenerative vacuolar storage disease in Canis lupus familiaris (dog)

Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611340 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Lagotto storage disease

Species-specific symbol: LSD

History: This disorder was first described by Kyöstilä et al. (2015).

Inheritance: LSD is inherited as a monogenic autosomal recessive trait. The age of onset varies and clinical symptoms appear at a mean age of 23 months with a range of approximately 4 months to 4 years. Kyöstilä et al. (2015) also noted incomplete penetrance as they encountered 3 out of 25 homozygous mutant dogs that did not show any clinical symptoms. These 3 dogs were 4, 7, and 12 years old at the time of the investigation.

Mapping: By conducting a linkage and homozygosity-mapping analysis, Kyöstilä et al. (2015) determined that the locus for this disorder is located in one of three regions on canine chromosomes 11, 13 and 20. Subsequent analysis of genome sequence in these three regions identified the causal mutation to be a C>T exchange on chromosome CFA20:50,618,958 (CanFam 3.1 assembly).

Molecular basis: Missense mutation: c.1288G>A; p.A430T; Chr20:50,618,958C>T (CanFam 3.1 assembly) (Kyöstilä et al., 2015)

Clinical features: As reported by Kyöstilä et al. (2015), "The typical clinical presentation in affected dogs was progressive ataxia". Neurological examination "revealed a mild to severe cerebellar ataxia . . . The majority of dogs had normal paw positioning responses when postural reactions were tested but showed delayed onset of correction in hopping reactions. Spinal reflexes were normal except for decreased or absent patellar reflexes in five dogs. Menace reaction was decreased in eight dogs, and exaggerated in one dog. Positional nystagmus was visible in four dogs during the eurological examination. Magnetic resonance imaging of the brain was performed in 11 affected dogs. The principal findings included signs of mild atrophy of the cerebellum in nine dogs and of the forebrain in six dogs. In five dogs, lateral ventricles were enlarged. A small corpus callosum was detected in three affected dogs when compared to age matched LRs. In two affected dogs, the brain imaging was unremarkable."

Pathology: As also reported by Kyöstilä et al. (2015), "Histological examination revealed widespread swelling and clear vacuolization of the neuronal cytoplasm, diffusely affecting the central and peripheral nervous system. The cytoplasmic vacuolization varied from fine vesiculation to large confluent vacuoles". Syrjä et al. (2017) investigated the cellular alterations in detail and found that basal, but not induced autophagy, is altered in homozygous mutant cells from affected dogs. In a study aimed "to clarify the origin of the limiting membrane of the accumulating vacuoles and determine whether altered basal autophagy affects the extracellular release of vesicles in cells from diseased dogs" Syrjä et al. (2020) concluded that "An increased release of extracellular vesicles may serve as a compensatory mechanism in disposal of intracellular proteins during dysfunctional basal autophagy in this spontaneous disease."

Breed: Lagotto Romagnolo (Dog) (VBO_0200804).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ATG4D autophagy related 4D, cysteine peptidase Canis lupus familiaris 20 NC_051824.1 (51146788..51141597) ATG4D Homologene, Ensembl , NCBI gene


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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
94 Lagotto Romagnolo (Dog) Neurodegenerative vacuolar storage disease ATG4D missense Naturally occurring variant CanFam3.1 20 g.50618958C>T c.1288G>A p.(A430T) 2015 25875846 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:001954-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2023 Stee, K., Van Poucke, M., Lowrie, M., Van Ham, L., Peelman, L., Olby, N., Bhatti, S.F.M. :
Phenotypic and genetic aspects of hereditary ataxia in dogs. J Vet Intern Med 37:1306-1322, 2023. Pubmed reference: 37341581. DOI: 10.1111/jvim.16742.
2020 Syrjä, P., Palviainen, M., Jokinen, T., Kyöstilä, K., Lohi, H., Roosje, P., Anderegg, L., Leeb, T., Sukura, A., Eskelinen, E.L. :
Altered basal autophagy affects extracellular vesicle release in cells of Lagotto Romagnolo dogs with a variant ATG4D. Vet Pathol 57:926-35, 2020. Pubmed reference: 33016245. DOI: 10.1177/0300985820959243.
2017 Syrjä, P., Anwar, T., Jokinen, T., Kyöstilä, K., Jäderlund, K.H., Cozzi, F., Rohdin, C., Hahn, K., Wohlsein, P., Baumgärtner, W., Henke, D., Oevermann, A., Sukura, A., Leeb, T., Lohi, H., Eskelinen, E.L. :
Basal autophagy is altered in Lagotto Romagnolo dogs with an ATG4D mutation. Vet Pathol 54:953-63, 2017. Pubmed reference: 28583040. DOI: 10.1177/0300985817712793.
2015 Kyöstilä, K., Syrjä, P., Jagannathan, V., Chandrasekar, G., Jokinen, T.S., Seppälä, E.H., Becker, D., Drögemüller, M., Dietschi, E., Drögemüller, C., Lang, J., Steffen, F., Rohdin, C., Jäderlund, K.H., Lappalainen, A.K., Hahn, K., Wohlsein, P., Baumgärtner, W., Henke, D., Oevermann, A., Kere, J., Lohi, H., Leeb, T. :
A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease. PLoS Genet 11:e1005169, 2015. Pubmed reference: 25875846. DOI: 10.1371/journal.pgen.1005169.

Edit History

  • Created by Frank Nicholas on 21 Apr 2015
  • Changed by Frank Nicholas on 21 Apr 2015
  • Changed by Tosso Leeb on 21 Apr 2015
  • Changed by Tosso Leeb on 16 Jun 2017
  • Changed by Frank Nicholas on 27 Oct 2020
  • Changed by Imke Tammen2 on 23 Jun 2023