In other species: domestic cat , sheep

Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601780 (trait) , 606725 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0011144: ceroid lipofuscinosis, neuronal, 6A

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Cross-species summary: One of several variants of neuronal ceroid lipofuscinosis (NCL) or Batten disease: CLN6; NCL6

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 NCL6 have early-onset, progressive disease that results in blindness and premature death. A genetic test is available.

Mapping: CFA30

Molecular basis: The causative variant in Australin Shepherd dogs is a c.829T>C transition in exon 7 of CLN6 leading to p.W277R on the protein level (Katz et al., 2011). Affected dogs have CLN6 deficiency. The function of CLN6 is unknown, but is likely an intrinsic membrane protein with 7 transmembrane domains (Katz et al., 2011).
Bellamy et al. (2024) "describe a 19-month-old Schapendoes dog, where clinical signs were indicative of lysosomal storage disease, which was corroborated by pathological findings consistent with NCL. Whole genome sequencing of the affected dog and both parents, followed by variant calling and visual inspection of known NCL genes, identified a missense variant in CLN6 (c.386T>C)."
Mhlanga-Mutangadura et al. (2024) identified 'a homozygous C to T substitution that altered the intron 3–exon 4 splice site of CLN6' as likely causal variant in a mixed breed dog with neuronal ceroid lipofuscinosis. "The CLN6 protein was undetectable with immunolabeling in the tissues of the proband." 

Clinical features: Affected dogs present with visual deficits which progress to complete blindness, as well as progressive anxiety, cognitive and motor degeneration, circling, and incoordination (Katz et al., 2011).

Pathology: Cerebellar hypoplasia and enlarged lateral ventricles are present. Large amounts of autofluorescent substance are present in the retina, cerebral cortex, and cerebellum, which is most prevalent in the cerebellar Purkinje and granular layers and the retinal ganglion cell layer (Katz et al., 2011).

Prevalence: The prevalence of this condition appears to be very low in Australian Shepherd dogs, as only two affected dogs have been definitively identified thus far (Katz et al., 2011).

Control: Relatives of affected dogs should be tested. Avoid breeding affected or carrier dogs.

Genetic testing: A genetic test is available.

Breeds: Australian Shepherd (Dog) (VBO_0200095), Schapendoes (Dog) (VBO_0201181).
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: