Niemann-Pick disease type C, or NPC, is a rare genetically inherited condition caused by mutations in either the NPC1 or NPC2 genes.
These mutations impair intracellular transport of cholesterol and other molecules, which causes progressive neurologic and developmental problems.
Now, cholesterol reaches the cells packed in lipoproteins, which bind to low density lipoprotein, or LDL, receptors on the cell membrane, to get inside the cell.
Then, cholesterol reaches the early-endosome, which is an intracellular organelle that eventually matures into a late-endosome, and finally into a lysosome.
Inside the lysosome, cholesterol is processed and recycled, so that it can be incorporated into the cell membrane.
To get out of the lysosome, first, cholesterol gets a little help from the NPC2 gene product, a protein that carries cholesterol up to the lysosomal membrane.
And on this membrane, cholesterol is greeted by the NPC1 gene product, which is a glycoprotein that moves cholesterol out of the lysosome and into the cell.
So with NPC1 or NPC2 mutations, intracellular cholesterol transport is impaired, so cholesterol accumulates inside lysosomes instead. Mutations can affect people of all ethnic backgrounds, and they’re inherited in an autosomal recessive pattern, which means that an affected individual must have two copies of the mutated gene, one from each parent.
Cholesterol buildup affects almost all cells, so it causes a variety of symptoms.
The brain and bone marrow are often affected.
The liver and spleen can be affected too, in which case, they enlarge.
Liver enlargement disrupts bile flow, causing bilirubin to accumulate in the blood.
This leads to jaundice, or yellow pigmentation of the skin and whites of the eye.
An enlarged spleen, on the other hand, may trap platelets, which causes easy bruising and bleeding issues.
Finally, when this buildup occurs in macrophages, they develop a characteristic lipid-laden appearance under microscopy and are called “foam cells.”
The most common symptoms are progressive neurologic symptoms, which occur in almost all affected individuals.