In other species: dog , taurine cattle

Categories: Lysosomal storage disease , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 257220 (trait) , 607623 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009757: Niemann-Pick disease, type C1

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2003

Cross-species summary: Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disease (LSD) characterised by impaired un-esterified cholesterol and sphingomyelin transport and metabolism, resulting in the accumulation of un-esterified cholesterol and glycosphingolipids within late endosomes and lysosomes. Affected animals present with hepatosplenomegaly, neurological degeneration and premature death.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Somers et al. (2003) showed that this disorder is due to a 2864G>C base substitution in the NPC1 gene, resulting in a C955S amino-acid substitution. In an excellent example of Precision Medicine (and the first time this term has appeared in the 24,392 papers currently [29 Oct 2016] included in OMIA), Mauler et al. (2017) identified a novel likely causal (missense) variant (c.1322A>C; p.H441P) in the NPC1 gene by 25x whole-genome sequencing an affected cat and comparing its variants to those in the 99 Lives Cat Genome Sequencing database.

Clinical features: NPC1 disease is a fatal neurovisceral lysosomal storage disease characterised by progressive neurological dysfunction. From around 8 to 12 weeks of age, head and whole-body intention tremors are observable and neurologic symptoms rapidly progress to severe dysmetria and ataxia (Munana et al., 1994). Other clinical features include low birth weight, hepatosplenomegaly and premature death, typically around 8 to 10 months of age (Brown et al., 1994; Vite et al., 2008). Serum biochemical abnormalities (elevations in liver enzymes, cholesterol, bile acids and total bilirubin and decreased albumin) are suggestive of hepatic disease but signs of jaundice and liver failure have not been observed in affected cats (Brown et al., 1994; Vite et al., 2008). IT thanks DVM student Daisy Lau, who provided the basis of this contribution in May 2023.

Pathology: Neuropathological features include diffuse neuronal cytoplasmic vacuolisation with intracellular cholesterol accumulation, severe Purkinje cell loss, GABAergic neuroaxonal dystrophy, ectopic dendritogenesis and central myelin deficits (Munana et al., 1994; Vite et al., 2008). Examination of liver histologic samples revealed extensively severe cytoplasmic vacuolisation of hepatocytes and Kupffer cells accompanied by marked accumulation of unesterified cholesterol (Vite et al., 2008). Multifocal histiocytosis with vacuolated macrophages were present in spleen and lung samples (Vite et al., 2008; Roszell et al., 2013). IT thanks DVM student Daisy Lau, who provided the basis of this contribution in May 2023.

Associated gene: