Harmful amounts of lipids accumulate in the spleen, liver, lungs, bone marrow, and brain
Autosomal recessive pattern of inheritance (two copies of the gene must be present)
Four variants: A, B, C1, and C2
Clinical feature include: severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone, lack of coordination, problems feeding, and inability to move eyes vertically.
Types A and B: mutated SMPD1 gene
SMPD gene carries instructions for cells to produce, sphingomyelinase, which processes lipids.
Mutations lead to deficiency of sphingomyelinase and accumulations of cholesterol and lipids.
Types C1 and C2: mutated NCP1 or NCP2 gene
NCP1 gene produces a protein involved in the movement of cholesterol and lipids within a cell.
May be a cholesterol pump, which is why its mutation leads to the buildup of lipids and cholesterol in the cell membrane.
Plays a critical role in regulation of intracellular cholesterol trafficking
NCP2 gene produces protein that binds and transports cholesterol (not fully understood).
NCP1 v. NCP2 Gene
95% of patients have mutations in the NPC1 gene
Mapped at chromosome 18q11
NPC1 encodes a 1278 amino acid glycoprotein with 13 transmembrane domains.
Remainder of patients have mutations in the NPC2 gene (or HE1 gene)
Mapped at chromosome 14q24.3
Encodes a small soluble lysosomal protein involved in cholesterol binding.
Both genes have identical biochemical patterns suggesting that the two proteins function together in cellular transport of cholesterol, glycolipids, etc.
Work together to facilitate the intracellular transport of lipids from the lysosome to other cellular sites.
Their precise functions and relationship remain unclear and are currently the subject of intense investigation.