Lysosomal storage disease in a Weimaraner

Lysosomal storage disease is a neurodegenerative disease. It shares similarities with neural ceroid lipofuscinosis but is a distinct entity with distinct pathological features. The disease is characterized by the accumulation of autofluorescent inclusions in lysosomes in the cerebral cortex, cerebellum, optic nerve, and cardiac muscle.

Clinical signs are progressive and primarily involve the central nervous system. In Weimaraners, the first clinical signs are observed from approximately five years of age and include fecal incontinence, lethargy, paraparesis, pelvic limb ataxia with impaired proprioception, falls, cognitive impairment, uncoordinated movements, decreased interest in food, changes in posture, and episodes of trance-like behavior. The disease causes generalized brain atrophy with white matter involvement, leading to severe neurological impairment and the need for euthanasia.

The cause of the disease in Weimaraners is the c.125C>T mutation in the CNP gene. The mutation leads to disruption of myelin integrity and accumulation of autofluorescent material in lysosomes.

Inheritance is described as autosomal, incompletely dominant with variable expressivity. Heterozygous individuals who inherit the mutation from only one parent may have milder, later-onset, or variable clinical signs. In contrast, homozygotes who inherit the mutation from both parents usually show a more severe or earlier-onset form of the disease. The manifestations of the disease therefore depend on the genotype as well as the individual expressivity and penetrance of the mutation.

A genetic test can clearly reveal the genotype of the animal and is a suitable tool for breeders to avoid unintentional breeding of affected puppies.

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References:

Keller, S.H., Johnson, G.S., Bullock, G., Mhlanga-Mutangadura, T., Schwartz, M., Pattridge, S.G., Guo, J., Kortz, G.D., Katz, M.L. : Homozygous CNP mutation and neurodegeneration in Weimaraners: Myelin abnormalities and accumulation of lipofuscin-like inclusions. Genes (Basel) 15:246, 2024. Pubmed reference: 38397235