OMIA 001503-9615 : Neuronal ceroid lipofuscinosis, 4A in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 204300

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2010

Species-specific description: The neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules and early neuronal death. Dogs with NCL4A have late-onset and slowly progressive behavioral changes, cognitive and motor degeneration, ataxia, seizures, and premature death. There is a genetic test available.

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.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ARSG arylsulfatase G Canis lupus familiaris 9 NC_006591.3 (15048563..15115095) ARSG Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
American Staffordshire terrier Neuronal ceroid lipofuscinosis, 4A ARSG missense 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

References


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.
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 :, 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.
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.
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.
2004 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.

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