In other species: sheep

Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 256730 (trait) , 600722 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009744: neuronal ceroid lipofuscinosis 1

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: One of several variants of neuronal ceroid lipofuscinosis (NCL) or Batten disease: CLN1; NCL1

Species-specific description: The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules, early neuronal death, and progressive neurodegeneration of the central nervous system. NCL1 is a rare disorder of dachshunds caused by severely deficient palmitoyl protein thioesterase (PPT1) activity. Signs appear as early as nine months of age, and include behavioral changes, nervousness, disorientation, ataxia, weakness, kyphosis, stiffness of gait, uncontrolled rhythmic head movements, and visual impairment. Fundic examination may show diffuse retinal thinning and retinal vessel degeneration. The mode of inheritance is autosomal recessive. There is no effective treatment. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Mapping: CFA15

Molecular basis: A causative mutation in Dachshunds is a single nucleotide insertion (c.736-737insC) in exon 8 of PPT1, which causes a frameshift in amino acid codons and a premature stop codon. The resultant truncated PPT1 protein lacks a hydrophobic region that is key to enzyme activity, such that the affected dachshund brain has only 3% activity of normal dogs (Sanders et al., 2010). Whole-genome sequencing of an affected Cane Corso dog by Kolicheski et al. (2017) revealed the likely causal variant to be "a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos."

Clinical features: Diffuse retinal thinning and severe retinal vessel degeneration were present at 7 months of age, followed by complete blindness at 8 months of age (Sanders et al., 2010). Additional signs appeared at nine months of age, including disorientation, ataxia, weakness, visual impairment, and behavioral changes. These progressed to kyphosis and stiffness in gait, uncontrolled rhythmic head movements, inability to recognize the owner, severe vision loss, sensitivity to loud noise, inappropriate vocalization, circling, loss of coordination and general weakness. There is no effective treatment.

Pathology: The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules, early neuronal death, and progressive neurodegeneration of the central nervous system. Affected dogs are severely deficient in palmitoyl protein thioesterase (PPT1), a key enzyme in creating hydrophobic regions in proteins, allowing them to interact with membranes, participate in vesicular transport and signal transduction, and maintain cellular architecture. As a result of severely deficient PPT1 activity, autofluorescent material accumulates in neuronal lysosomes of the retina, cerebellum, and cerebral cortex, followed by progressive neurodegeneration (Sanders et al., 2010). The central retina maintains its normal thickness and structure, and has inclusions in many retinal layers, including photoreceptor inner segments, outer nuclear layer, and ganglion cell layer. The peripheral retina appears significantly thinned with loss of the photoreceptor cell layer and absence of normal structural layering (Sanders et al., 2010). Storage material is widely abundant in the cerebral cortex and cerebellum. In the latter, increased concentration was identified in the granular layer with little or no accumulation in Purkinje cells (Sanders et al., 2010).

Prevalence: Thus far, one affected animal and three carriers from the same pedigree have been identified (Sanders et al., 2010).

Control: Parents of affected dogs are obligate carriers. Siblings of affected animals should be tested. Breeding of affected or carrier dogs is not recommended.

Genetic testing: A test is available to detect the causative mutation in Dachshunds.

Breeds: Dachshund (Dog) (VBO_0200406), Italian Cane Corso (Dog) (VBO_0200712).
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: