Niemann-Pick Disease Type C1

Niemann-Pick disease type C1 (NPC1) is an autosomal recessive inherited pathology that causes abnormal accumulation of unesterified cholesterol and other lipids in late endosomes and lysosomes due to a defect in the transport and metabolism of these lipids. This accumulation leads to a series of progressive neurological symptoms.

Symptoms

Symptoms of the disease begin to develop around the 8th and 12th week of life. Early neurological signs include tremors, which rapidly worsen, leading to lack of coordination and severe mobility problems. In addition, cats often have low birth weight, enlarged liver and spleen, and often die prematurely between 8 and 10 months of age.

Disease Management

Disease management focuses on alleviating symptoms and improving quality of life, as there is currently no definitive cure. The strategies employed include dietary, pharmacological and supportive care therapies. On the pharmacological side, sphingomyelinase inhibitors, which have demonstrated the ability to delay disease progression in human studies and animal models, are being investigated.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the cat, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected cat must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between cats carrying genetic variants that may cause disease, even if they do not show symptoms, is not recommended.

Technical report

Niemann-Pick disease type C1 (NPC1) is a lysosomal storage pathology, characterized by an alteration in the transport and metabolism of unesterified cholesterol and sphingomyelin. This dysfunction causes the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. The gene responsible for this disease is NPC1, which encodes a transmembrane protein essential for the transport of endocytosed material in lysosomes and endosomes. Two genetic variants in the NPC1 gene related to Niemann-Pick disease have been identified. Here, we analyzed a base substitution (c.2864G>C), which causes the substitution of a highly conserved cysteine amino acid in multiple species, including humans. This cysteine is crucial for the structure and function of the NPC1 protein, so its mutation compromises the functionality of this transport protein, contributing to the pathogenesis of the disease.

Most affected breeds

Domestic Shorthair

Bibliography

Brown DE, Thrall MA, Walkley SU, et al. Feline Niemann-Pick disease type C. Am J Pathol. 1994 Jun