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

Disease-related: 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: