Niemann-Pick disease type A (NPA) Niemann-Pick disease and B (NPB) refer to two related diseases that are characterized by lysosomal accumulation of sphingomyelin resulting from an inherited deficiency of sphingomyelinase.

In the past, these two conditions were grouped with an unrelated disorder, called Niemann-Pick disease type C (NBC), described separately below.

Niemann-Pick disease type A is the severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, and progressive wasting and early death within the first 3 years of life.

In Niemann-Pick disease type type B, patients have organomegaly but generally no central nervous system involvement. They usually survive into adulthood. As with Tay-Sachs disease, Niemann-Pick disease types A and B are common in Ashkenazi Jews. In the classic infantile type A variant, a missense mutation causes almostcomplete deficiency of sphingomyelinase.

Synopsis

 accumulation of sphingomyelin in reticuloendothelial system (RES)

• foamy macrophages accumulation many organs (liver, spleen)

 hepatic Niemann-Pick diseases

• foamy Kupffer cells in sinusoids
• increase of histiocytic storage cells within hepatic sinusoids
• uniform, birefringent cytoplasmic droplets
• foamy portal macrophages
• brown granular lipofuscin
• hepatocellular giant cell transformation (GCT)
• cirrhosis
• multiple hepatocellular adenomas (hepatocellular adenomatosis)
• possible cytoplasmic globules of alpha-1-antitrypsin (A-1-AT) (4083008)

Types

 Niemann-Pick disease type I (sphingomyelinase deficiency)

• Niemann-Pick disease type A (NPA)
• Niemann-Pick disease type B (NPB) (mutation of the acid sphingomyelinase (ASM) gene SMPD1)

 Niemann-Pick disease type II (defect in cholesterol esterification and intracellular trafficking)

• Niemann-Pick disease type C (NPC )
  • Niemann-Pick disease type C1 (NPC1)
  • Niemann-Pick disease type C2 (NPC2)

• Niemann-Pick disease type D (NPCD)

 Niemann-Pick disease type E (NPCE)
 Niemann-Pick disease type F (NPCF)

Physiopathology

Sphingomyelin is a ubiquitous component of cellular (including organellar) membranes, and so the enzyme deficiency blocks degradation of the lipid, resulting in its progressive accumulation within lysosomes, particularly within cells of the mononuclear phagocyte system.

Affected cells become enlarged, sometimes to 90 ?m in diameter, secondary to the distention of lysosomes with sphingomyelin and cholesterol. Innumerable small vacuoles of relatively uniform size are created, imparting a foaminess to the cytoplasm.

In frozen sections of fresh tissue, the vacuoles stain for fat with Sudan black B and oil red O. Electron microscopy confirms that the vacuoles are engorged secondary lysosomes that often contain membranous cytoplasmic bodies resembling concentric lamellated myelin figures. Sometimes the lysosomal configurations take the form of parallel palisaded lamellae, creating so-called zebra bodies.

The lipid-laden macrophages (phagocytic foam cells) are widely distributed in the spleen, liver, lymph nodes, bone marrow, tonsils, gastrointestinal tract, and lungs.

The involvement of the spleen generally produces massive enlargement, sometimes to 10 times its normal weight, but the hepatomegaly is usually not quite so striking. The lymph nodes are generally moderately to markedly enlarged throughout the body.

Involvement of the brain and eye deserves special mention. In the brain, the gyri are shrunken and the sulci widened. The neuronal involvement is diffuse, affecting all parts of the nervous system. Vacuolation and ballooning of neurons constitute the dominant histologic change, which in time leads to cell death and loss of brain substance.

A retinal cherry-red spot similar to that seen in Tay-Sachs disease is present in about one third to one half of affected individuals. Its origin is similar to that described in Tay-Sachs disease except that the accumulated metabolite is sphingomyelin.

Clinical manifestations may be present at birth but almost invariably become evident by age 6 months. Infants typically have a protuberant abdomen because of the hepatosplenomegaly. Once the manifestations appear, they are followed by progressive failure to thrive, vomiting, fever, and generalized lymphadenopathy as well as progressive deterioration of psychomotor function. Death comes as a release, usually within the first or second year of life.

Pathogeny

Cellular cholesterol homeostasis is maintained through activation of the designated sterol regulatory element binding proteins and liver X receptor transcriptional pathways.

Insight into the molecular mechanisms that regulate these pathways has come from the study of Niemann-Pick C (NPC) disease. Mutations in the NPC1 and NPC2 disease genes lead to lysosomal accumulation of cholesterol and defects in regulation of sterol homeostatic responses.

NPC1 and NPC2 are key participants in intracellular cholesterol trafficking and are required for production of low-density lipoprotein cholesterol-derived oxysterols.

In this review, the function of NPC1 and NPC2 in sterol trafficking and regulation of cholesterol homeostasis is examined. Study of the NPC proteins will further understanding of the mechanisms involved in atherogenesis.

See also

 metabolic diseases

• genetic metabolic diseases (inborn errors of metabolism)