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

Cross-species summary: CLN4A

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: