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. With early infantile onset, there’s
usually low muscle tone, and delay in developmental motor milestones, like lifting the head or
crawling. Later, these children experience developmental regression. Infantile and childhood
onset often begins with clumsiness, and learning difficulties, and progresses to unsteady gait,
difficulty swallowing and slurred speech. Some children experience seizures or cataplexy,
which is a sudden loss of muscle tone provoked by something perceived as amusing. With teenage
or adult onset, there can be psychiatric symptoms and progressive cognitive impairment. Jaundice
is more common in newborns, but rare in older children or adults. Late in the illness, patients
lose the ability to walk, talk and swallow, and respiratory failure is a frequent cause
of death. Diagnosis of NPC is based on the clinical
examination and history, and blood tests to detect biomarkers like bile acid metabolites
and oxysterols. Finally, genetic analysis of the NPC1 and NPC2 genes confirms the diagnosis. Treatment involves supportive therapy, and
in many countries, miglustat is used to slow neurological decline. Even though there is
no cure for NPC yet, research is going strong, and several medications that target different
steps in the pathology of NPC have shown promise in animal models of the disease, and have
progressed to clinical trials in humans. Alright, as a quick recap… Niemann-Pick
disease type C is a rare genetically inherited condition, caused by mutations in the NPC1
or NPC2 genes, which impair intracellular cholesterol transport. This causes cholesterol
to accumulate in lysosomes, resulting in brain, bone marrow, liver, spleen and lung damage.
Diagnosis includes blood tests and genetic sequencing, and treatment is mostly supportive.