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Niemann-Pick disease type C

Friday 30 May 2003

Definition: Niemann-Pick disease type C (NPC) is a recessive lysosomal disorder of childhood probably caused by lysosomal storage of cholesterol. Niemann-Pick disease type C (NPC) is a neurovisceral disorder characterized by lysosomal sequestration of endocytosed LDL-cholesterol, premature and abnormal enrichment of cholesterol in trans Golgi cisternae and accompanying anomalies in intracellular sterol trafficking. In addition to cholesterol, the NPC lesion has also been shown to impact the metabolism of sphingolipids.

In NPC, the neuronal degeneration is characterized by prominent tau (TAU) pathology in the form of Alzheimer disease (AD)-like tau tangles (NFTs).

Mild adult-onset forms of NPC exist and then present as psychatric disease and presenile dementia.

Nieman-Pick Disease type C (NPC) is more common than types A and B combined.

Types

- Niemann-Pick disease type C1
- Niemann-Pick disease type C2

Clinical synopsis

- neonatal hepatitis
- hepatomegaly
- fetal ascites (2334227)
- rapidly fatal neonatal hepatitis
- neonatal cholestatic icterus

Physiopathology

In Niemann-Pick disease type C1, the affected gene NPC1 encodes a protein involved in cholesterol trafficking; therefore, in this disorder, cholesterol accumulates in the affected cells.

In the brain, NPC1 is present in astrocytic processes in close apposition to nerve terminals. With defective cholesterol trafficking, terminal axons and dendrites degenerate. NPC is clinically very heterogeneous.

It may present with hydrops fetalis and stillbirth, as neonatal hepatitis, or as a chronic form characterized by progressive neurologic damage. Most common, however, is presentation in childhood, which is marked by ataxia, supranuclear palsy, psychomotor regression, hepatosplenomegaly, and dysarthria.

Connections between cholesterol transport and intracellular-membrane transport

The study of Niemann-Pick disease type C provides interesting clues to the role of membrane cholesterol and membrane domains enriched with cholesterol and glycosphingolipids in vesicular transport and membrane-associated sorting events.

Niemann-Pick disease type C is characterized by the storage of lipids in various tissues, the clinical hallmark being severe neurodegeneration.

In the cells of patients with this disorder, free cholesterol is unable to exit lysosomes because of mutations in a gene that encodes NPC-1, a multimembrane-spanning protein found in late endocytic compartments.

The lysosomal accumulation of cholesterol and the resulting disturbance of cellular cholesterol homeostatic responses are likely to disrupt the organization of lipid microdomains in cellular membranes.

This effect may account for some of the observed disturbances in protein localization in affected patients and may constitute part of the molecular background of the neurodegenerative symptoms.

See also

- Cholesterol

  • cholesterol biosynthesis
  • cholesterol metabolism

- Niemann-Pick diseases

  • Niemann-Pick disease type A
  • Niemann-Pick disease type B

- lipids
- glycolipids
- cholesterol
- sphingomyelin
- gangliosides
- galactosylceramide
- myelin lipids
- ganglioside GM3
- ganglioside GM2
- lactosylceramide
- gangliotriaosylceramide (asialo-GM2)
- globotriaosylceramide
- globotetraosylceramide
- neutral glycolipids
- Niemann-Pick type A
- mucopolysaccharidoses

References

- Nixon RA. Niemann-Pick Type C disease and Alzheimer’s disease: the APP-endosome connection fattens up. Am J Pathol. 2004 Mar;164(3):757-61. PMID: 14982829

- Garver WS, Heidenreich RA. The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. Curr Mol Med. 2002 Aug;2(5):485-505. PMID: 12125814

- Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. N Engl J Med. 2000 Oct 12;343(15):1095-104. PMID: 11027745