OMIA:001503-9615 : Lysosomal storage disease, ARSG related in Canis lupus familiaris (dog)

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 610008 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2010

Cross-species summary: This phene was initially called 'neuronal ceroid lipofusconosis, 4A' (NCL4) and included information about a lysosomal storage disease in dogs, which was caused by a mutation in the ARSG gene. Historically, NCL4 in humans related to variants of NCL with adult onset. In humans, adult onset variants of NCL include Kufs disease (or CLN4A - now to be known to be caused by mutations in the CLN6 gene) and Parry disease (or CLN4B - now to be known to be caused by mutations in the DNAJC5 gene). However, more recent findings suggest that this phene, caused by a mutation in the ARSG gene, is more likely a mucopolysaccharidosis.

Species-specific name: Cerebellar cortical abiotrophy, cerebellar cortical degeneration, neuronal ceroid lipofuscinosis

Species-specific description: Dogs with this lysosomal storage disorder have late-onset and slowly progressive behavioral changes, cognitive and motor degeneration, ataxia, seizures, and premature death.

History: The disease was first described as cerebellar cortical abiotrophy (Hanzliek et al., 2003) and cerebellar cortical degeneration (Olby et al., 2004; Buijtels et al. 2006) in American Staffordshire Terriers (see also OMIA000177-9615). Abitbol et al. (2010) reported a likely causative mutation for this disease in the ARSG gene and suggested - based on clinical signs and histopathology - that the disease is a neuronal ceroid lipofuscinosis with adult onset. However, Abitbol et al. (2010) did not identify the type of storage material. ARSG codes for arylsulfatase G, a lysosomal enzyme that functions in the degradation of heparan sulfate. Transgenic mice with ARSG deficiency were diagnosed with a mucopolysaccharidosis (Kowalewski et al., 2012, 2014, 2015) and it is likely that this lysosomal storage disorder in American Staffordshire Terriers is a mucopolysaccharidosis (Katz et al., 2017).

Mapping: CFA9

Molecular basis: Abitbol et al. (2010) reported a likely causative mutation in American Staffordshire Terriers as a c.296G>A transition in the gene encoding the lysosomal enzyme arylsulfatase G. The variant leads to the p.R99H substitution in the protein. Affected dogs are deficient in ARSG. Nolte et al. (2016) reported the same variant in another affected American Staffordshire Terrier.

Clinical features: Signs include late onset and slowly progressive behavioral changes, cognitive and motor degeneration, ataxia, seizures, and premature death.

Pathology: Lysosomal storage inhibits intracellular and membrane trafficking, autophagy, and calcium storage, impair vesicle formation, and leads to premature neuronal apoptosis (Abitbol et al., 2010, Bellettato et al., 2010). Lesions include severe cerebellar cortical abiotrophy and remodeling with loss of Purkinje cells. Remaining Purkinje cells contain autofluorescent cytoplasmic storage material.

Prevalence: In populations in the USA and France, 50% of American Staffordshire Terriers tested were carriers (Abitbol et al., 2010).

Control: Relatives to affected dogs should be tested. Avoid breeding affected dogs. Carriers should be bred only to noncarriers.

Genetic testing: A test is available.

Breed: American Staffordshire Terrier (Dog) (VBO_0200055).
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
ARSG arylsulfatase G Canis lupus familiaris 9 NC_051813.1 (16669828..16777722) ARSG Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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
67 American Staffordshire Terrier (Dog) Neuronal ceroid lipofuscinosis, 4A ARSG missense Naturally occurring variant CanFam3.1 9 g.15071276G>A c.296G>A p.(R99H) 2010 20679209 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. (2021). OMIA:001503-9615: 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 Jankelunas, L., Hoehne, S.N., Chen, A.V., Williams, L., Murthy, V.D. :
Cerebellar ataxia in a young dog. J Am Vet Med Assoc :1-4, 2023. Pubmed reference: 37290756. DOI: 10.2460/javma.23.04.0194.
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 Story, B.D., Miller, M.E., Bradbury, A.M., Million, E.D., Duan, D., Taghian, T., Faissler, D., Fernau, D., Beecy, S.J., Gray-Edwards, H.L. :
Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80, 2020. Pubmed reference: 32219101. DOI: 10.3389/fvets.2020.00080.
2017 Katz, M.L., Rustad, E., Robinson, G.O., Whiting, R.E.H., Student, J.T., Coates, J.R., Narfstrom, K. :
Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. Neurobiol Dis 108:277-87, 2017. Pubmed reference: 28860089. DOI: 10.1016/j.nbd.2017.08.017.
2016 Nolte, A., Bello, A., Drögemüller, M., Leeb, T., Brockhaus, E., Baumgärtner, W., Wohlsein, P. :
Neuronal ceroid lipofuscinosis in an adult American Staffordshire Terrier. Tierarztl Prax Ausg K Kleintiere Heimtiere 44, 2016. Pubmed reference: 27778018. DOI: 10.15654/TPK-150766.
2015 Kowalewski, B., Heimann, P., Ortkras, T., Lüllmann-Rauch, R., Sawada, T., Walkley, S.U., Dierks, T., Damme, M. :
Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III). Hum Mol Genet 24:1856-68, 2015. Pubmed reference: 25452429. DOI: 10.1093/hmg/ddu603.
2014 Kowalewski, B., Lübke, T., Kollmann, K., Braulke, T., Reinheckel, T., Dierks, T., Damme, M. :
Molecular characterization of arylsulfatase G: expression, processing, glycosylation, transport, and activity. J Biol Chem 289:27992-8005, 2014. Pubmed reference: 25135642. DOI: 10.1074/jbc.M114.584144.
2013 Bond, M., Holthaus, S.M., Tammen, I., Tear, G., Russell, C. :
Use of model organisms for the study of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1832:1842-65, 2013. Pubmed reference: 23338040. DOI: 10.1016/j.bbadis.2013.01.009.
Broeckx, B.J., Coopman, F., Verhoeven, G.E., Van Haeringen, W., van de Goor, L., Bosmans, T., Gielen, I., Saunders, J.H., Soetaert, S.S., Van Bree, H., Van Neste, C., Van Nieuwerburgh, F., Van Ryssen, B., Verelst, E., Van Steendam, K., Deforce, D. :
The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. PLoS One 8:e74811, 2013. Pubmed reference: 24069350. DOI: 10.1371/journal.pone.0074811.
2012 Kowalewski, B., Lamanna, W.C., Lawrence, R., Damme, M., Stroobants, S., Padva, M., Kalus, I., Frese, M.A., Lübke, T., Lüllmann-Rauch, R., D'Hooge, R., Esko, J.D., Dierks, T. :
Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice. Proc Natl Acad Sci U S A 109:10310-5, 2012. Pubmed reference: 22689975. DOI: 10.1073/pnas.1202071109.
2010 Abitbol, M., Thibaud, J.L., Olby, N.J., Hitte, C., Puech, J.P., Maurer, M., Pilot-Storck, F., Hédan, B., Dréano, S., Brahimi, S., Delattre, D., André, C., Gray, F., Delisle, F., Caillaud, C., Bernex, F., Panthier, J.J., Aubin-Houzelstein, G., Blot, S., Tiret, L. :
A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A 107:14775-80, 2010. Pubmed reference: 20679209. DOI: 10.1073/pnas.0914206107.
Bellettato, C.M., Scarpa, M. :
Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:347-62, 2010. Pubmed reference: 20429032. DOI: 10.1007/s10545-010-9075-9.
2006 Buijtels, J.J., Kroeze, E.J., Voorhout, G., Schellens, C.J., van Nes, J.J. :
[Cerebellar cortical degeneration in an American Staffordshire terrier]. Tijdschr Diergeneeskd 131:518-22, 2006. Pubmed reference: 16916197.
2004 Olby, N., Blot, S., Thibaud, JL., Phillips, J., O'Brien, DP., Burr, J., Berg, J., Brown, T., Breen, M. :
Cerebellar cortical degeneration in adult American Staffordshire Terriers. J Vet Intern Med 18:201-8, 2004. Pubmed reference: 15058771.
Sisó, S., Navarro, C., Hanzlícek, D., Vandevelde, M. :
Adult onset thalamocerebellar degeneration in dogs associated to neuronal storage of ceroid lipopigment. Acta Neuropathol 108:386-92, 2004. Pubmed reference: 15365721. DOI: 10.1007/s00401-004-0902-7.
2003 Hanzlicek, D., Kathmann, I., Bley, T., Srenk, P., Botteron, C., Gaillard, C., Jaggy, A. :
[Cerebellar cortical abiotrophy in American Staffordshire terriers: clinical and pathological description of 3 cases] Schweizer Archiv fur Tierheilkunde 145:369-75, 2003. Pubmed reference: 12951908.

Edit History

  • Created by Frank Nicholas on 21 Jul 2011
  • Changed by Vicki Meyers-Wallen on 18 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Tosso Leeb on 28 May 2013
  • Changed by Matthew Hobbs on 17 Dec 2014
  • Changed by Frank Nicholas on 28 Oct 2016
  • Changed by Imke Tammen2 on 08 Jan 2021