Niemann-Pick Disease Type C2

Niemann-Pick disease type C2 (NPC2) 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

Cats affected by this disease are characterized by progressive neurological signs as early as three months of age. Initial symptoms include intention tremors and truncal ataxia, suggesting cerebellar involvement. As the disease progresses, a slow progression of these signs is observed, leading to dystonia and worsening gait. Affected cats may develop hindlimb hypermetria, and in advanced stages, may lose the ability to stand and show a bilateral reduction in the threat response.

Disease Management

Management of the disease focuses on alleviating symptoms and improving quality of life, since there is currently no definitive cure.

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 is not recommended, even if they do not show symptoms.

Technical report

Niemann-Pick disease type C2 (NPC2) is a lysosomal storage disorder characterized by alterations in the transport and metabolism of unesterified cholesterol and other lipids. This dysfunction leads to the accumulation of unesterified cholesterol and gangliosides in late endosomes and lysosomes, which adversely affects cell function. The gene responsible for this disease is NPC2, which encodes a protein that facilitates sterol mobilization in collaboration with NPC1, another protein crucial for cholesterol homeostasis. In Niemann-Pick disease type C2, two mutations have been identified in the NPC2 gene. One of the disease-causing variants is an intronic mutation that affects messenger RNA splicing, resulting in the insertion of 35 additional amino acids in the NPC2 protein. This alteration produces an aberrant protein that cannot adequately perform its cholesterol transport function, contributing to the pathogenesis of the disease.

Most affected breeds

Not specified

Bibliography

Zampieri S, Bianchi E, Cantile C, et al. Characterization of a spontaneous novel mutation in the NPC2 gene in a cat affected by Niemann Pick type C disease. PLoS One. 2014 Nov 14