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.