Category: Lysosomal storage disease

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 619071 (gene) , 123830 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific description: Bullock et al. (2022) report a progressive neurological disorder in purebred Dalmatian dogs with similarities to the neuronal ceroid lipofuscinoses.

Molecular basis: Bullock et al. (2022): “ Whole genome sequences, generated with DNA from the two euthanized Dalmatians, both contained a rare, homozygous single-base deletion and reading-frame shift in CNP … . The late-onset disease was exhibited by five of seven related Dalmatians that were heterozygous for the deletion allele and over 8 years of age, whereas none of 16 age-matched reference-allele homozygotes developed neurologic signs.”

Clinical features: Bullock et al. (2022): “The disease is characterized by anxiety, pacing and circling, hypersensitivity, cognitive decline, sleep disturbance, loss of coordination, loss of control over urination and defecation, and visual impairment. Neurological signs first became apparent when the dogs were approximately 18 months of age and progressed slowly. Two affected littermates were euthanized at approximately 7 years, 5 months and 8 years, 2 months of age due to the severity of neurological impairment. The mother of the affected dogs and four other relatives exhibited milder, later-onset neurological signs.”

Pathology: Bullock et al. (2022): “Pronounced accumulations of autofluorescent intracellular inclusions were found in cerebral cortex, cerebellum, optic nerve, and cardiac muscle of the affected dogs. These inclusions co-localized with immunolabeling of the lysosomal marker protein LAMP2 and bound antibodies to mitochondrial ATPase subunit c, indicating that the dogs suffered from a lysosomal storage disease with similarities to the neuronal ceroid lipofuscinoses. Ultrastructural analysis indicated that the storage bodies were surrounded by a single-layer membrane, but the storage granules were distinct from those reported for other lysosomal storage diseases.”

Breed: Dalmatian.

Associated gene: