Abstract
Niemann-Pick C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids within the lysosomes due to mutation in NPC1 or NPC2 genes. A feline model of NPC carrying a mutation in NPC1 gene has been previously described. We have identified two kittens affected by NPC disease due to a mutation in NPC2 gene. They manifested with tremors at the age of 3 months, which progressed to dystonia and severe ataxia. At 6 months of age cat 2 was unable to stand without assistance and had bilaterally reduced menace response. It died at the age of 10 months. Post-mortem histological analysis of the brain showed the presence of neurons with cytoplasmic swelling and vacuoles, gliosis of the substantia nigra and degeneration of the white matter. Spheroids with accumulation of ubiquitinated aggregates were prominent in the cerebellar cortex. Purkinje cells were markedly reduced in number and they showed prominent intracytoplasmic storage. Scattered perivascular aggregates of lymphocytes and microglial cells proliferation were present in the thalamus and midbrain. Proliferation of Bergmann glia was also observed. In the liver, hepatocytes were swollen because of accumulation of small vacuoles and foamy Kupffer cells were also detected. Foamy macrophages were observed within the pulmonary interstitium and alveoli as well. At 9 months cat 1 was unable to walk, developed seizures and it was euthanized at 21 months. Filipin staining of cultured fibroblasts showed massive storage of unesterified cholesterol. Molecular analysis of NPC1 and NPC2 genes showed the presence of a homozygous intronic mutation (c.82+5G>A) in the NPC2 gene. The subsequent analysis of the mRNA showed that the mutation causes the retention of 105 bp in the mature mRNA, which leads to the in frame insertion of 35 amino acids between residues 28 and 29 of NPC2 protein (p.G28_S29ins35).
Highlights
Niemann Pick C [Niemann-Pick C disease (NPC)-MIM 257220; MIM607625] disease is a neurodegenerative lysosomal storage disorder due to mutations in NPC1 or NPC2 genes
In this study we describe two kittens from the same litter affected by NPC disease caused by a mutation in the NPC2 gene
Niemann pick type C disease is a rare neurovisceral lysosomal storage disorder caused by mutations in either NPC1 or NPC2 genes
Summary
Niemann Pick C [NPC-MIM 257220; MIM607625] disease is a neurodegenerative lysosomal storage disorder due to mutations in NPC1 or NPC2 genes. Apart from patients affected by the perinatal form of the disease, which manifests at birth or within the first month of life with severe visceral involvement (fetal hydrops, ascites, neonatal cholestasis, liver failure and/or specific pulmonary disease), often leading to death [5], [6], most patients develop a progressive and fatal neurological disease In these patients, even if initial manifestations may be systemic, with liver and spleen enlargement, neurological, or psychiatric, the disease has been classified according to the age at onset of neurological symptoms in a severe infantile form (onset before 2 y of age), a late infantile form (onset between 3–5 y of age), a juvenile form (onset between 5 and 16 y) and an adult form (onset at age. y) [1], [7]
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