In other species: dog , domestic cat

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: 2020

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.

Species-specific description: Woolley et al. (2020) report clinical signs, pathology, fibroblast cell culture analysis and identification of a likely disease causing mutation for Niemann-Pick type C disease in Australian Angus/Angus-cross calves.

History: Woolley et al. (2020) describe that "the herd consisted originally of various beef cattle breeds, but the use of purebred Angus bulls over multiple years resulted in a predominantly Angus/Angus-cross population. ...In 2005, three affected half-siblings (calf 1, calf 2 and calf 3) were reported. ...Detailed pedigree information was not available for these paternal half-siblings, although the possibility of sire daughter matings was recorded. ...The same three Angus bulls were used repetitively for at least 5 years."

Molecular basis: "After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. ...The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves." (Woolley et al. 2020)

Clinical features: Woolley et al. (2020) describe that "onset of disease in affected animals was observed from three months of age and animals died or were euthanised at about seven months of age. Clinical signs included hind limb weakness, dysmetria, incoordination, a wide based stance, walking sideways or falling over and recumbency followed by death. Head tremors were observed in at least one animal. The condition was described to be exacerbated by stress, and animals were reported to be in good body condition at onset of disease."

Pathology: "Histopathology revealed degenerated neurons and widespread foamy vacuolation of the cytoplasm and glia of the CNS in all three affected calves. The accumulation of storage material within the CNS and peripheral organs in the affected calves resulted in a diagnosis of a LSD." (Woolley et al. 2020). "After identification of a possible causative mutation in NPC1 in the affected calves, central to the diagnosis of NPC in this study was the characterisation of fibroblast cell cultures from affected calves." (Woolley et al. 2020)

Prevalence: Woolley et al. (2020) report that several affected calves were born in one herd between 2002 and 2005. "Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%" for the identified mutation in the NPC1 gene.

Breed: Angus (Cattle) (VBO_0000104).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: