Niemann-Pick disease type C


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Niemann-Pick disease type C


Population genetics

Mendelian genetics and punnett squares

Hardy-Weinberg equilibrium

Inheritance patterns

Independent assortment of genes and linkage

Evolution and natural selection

Genetic disorders

Down syndrome (Trisomy 21)

Edwards syndrome (Trisomy 18)

Patau syndrome (Trisomy 13)

Fragile X syndrome

Huntington disease

Myotonic dystrophy

Friedreich ataxia

Turner syndrome

Klinefelter syndrome

Prader-Willi syndrome

Angelman syndrome

Beckwith-Wiedemann syndrome

Cri du chat syndrome

Williams syndrome

Alagille syndrome (NORD)


Polycystic kidney disease

Familial adenomatous polyposis

Familial hypercholesterolemia

Hereditary spherocytosis

Huntington disease

Li-Fraumeni syndrome

Marfan syndrome

Multiple endocrine neoplasia

Myotonic dystrophy


Treacher Collins syndrome

Tuberous sclerosis

von Hippel-Lindau disease


Polycystic kidney disease

Cystic fibrosis

Friedreich ataxia

Gaucher disease (NORD)

Glycogen storage disease type I

Glycogen storage disease type II (NORD)

Glycogen storage disease type III

Glycogen storage disease type IV

Glycogen storage disease type V


Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)

Krabbe disease


Niemann-Pick disease types A and B (NORD)

Niemann-Pick disease type C

Primary ciliary dyskinesia

Phenylketonuria (NORD)

Sickle cell disease (NORD)

Tay-Sachs disease (NORD)



Wilson disease

Fragile X syndrome

Alport syndrome

X-linked agammaglobulinemia

Fabry disease (NORD)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency


Mucopolysaccharide storage disease type 2 (Hunter syndrome) (NORD)

Lesch-Nyhan syndrome

Muscular dystrophy

Ornithine transcarbamylase deficiency

Wiskott-Aldrich syndrome

Mitochondrial myopathy

Autosomal trisomies: Pathology review

Muscular dystrophies and mitochondrial myopathies: Pathology review

Miscellaneous genetic disorders: Pathology review


Niemann-Pick disease type C

USMLE® Step 1 questions

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USMLE® Step 1 style questions USMLE

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A 5-month-old girl undergoes evaluation for failure to thrive. The parents are concerned that she is no longer able to sit or roll over on her own, despite being able to a few weeks ago. She was born at term with a birth weight of 2.5-kg (5.5-lb). Her current height and weight are below the 10th percentile, while at her previous visit 2 months ago, she was in the 40th percentile for both. Vitals are within normal limits. Physical examination reveals marked hypotonia throughout, with decreased deep tendon reflexes noted bilaterally in the upper and lower extremities. Abdominal examination is notable for hepatosplenomegaly. Fundoscopic examination is shown below:

By Achim Fieß, Ömer Cal, Stephan Kehrein, Sven Halstenberg, Inez Frisch, Ulrich Helmut Steinhorst
Reproduced from Wikimedia Commons" style="max-height: 25px; max-width: 25px;">Wikimedia Commons

If further testing is performed, which of the following enzymes is most likely to be deficient in this patient?  



Charles Davis, MD

Jerry Ferro

Salma Ladhani, MD

Kaia Chessen, MScBMC

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.


Niemann-Pick disease type C is a rare genetically inherited condition, caused by mutations in the NPC1 or NPC2 genes. These mutations impair intracellular transport of cholesterol and other molecules, which causes progressive neurologic and developmental problems. This causes cholesterol to accumulate in lysosomes, resulting in brain, bone marrow, liver, spleen and lung damage.

Symptoms of Niemann-Pick disease type C typically begin in childhood and may include difficulty with movement and balance, difficulty swallowing, developmental delays, and progressive intellectual disability. There may also be hepatosplenomegaly, and liver failure.


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