Niemann-Pick Disease

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What is Niemann-Pick disease?

Niemann-Pick disease is an inherited condition involving lipid metabolism (the breakdown and use of fats and cholesterol in the body) in which harmful amounts of lipids accumulate in the spleen, liver, lungs, bone marrow, and brain.

This disorder is divided into four main types based on the genetic cause and the signs and symptoms exhibited by the patient. Type A Niemann-Pick disease begins during infancy and is characterized by an enlarged liver and spleen (hepatosplenomegaly), failure to thrive, and progressive deterioration of the nervous system. Children affected by this condition generally do not survive past early childhood. Type B disease may include signs of hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as abnormal cholesterol and lipid levels, and low numbers of blood cells involved in clotting (platelets). People affected by this type of Niemann-Pick disease usually survive into adulthood.

Niemann-Pick disease, type C is further subdivided into types C1 and C2, each caused by a different gene mutation. Both types C1 and C2 Niemann-Pick disease are most commonly characterized by onset in childhood, although infant and adult onsets are possible. Other signs include severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically. People with this disorder can survive into adulthood.

How common is Niemann-Pick disease?

Niemann-Pick disease, type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in the general population. The incidence within the Ashkenazi population is approximately 1 in 40,000 people. The incidence for other populations is unknown.

Niemann-Pick disease, type B occurs in all populations; however, the incidence is unknown.

The incidence of Niemann-Pick disease, type C is estimated to be 1 in 150,000 people. The disease occurs more frequently in people of French-Acadian descent in Nova Scotia. They were previously designated as having Niemann-Pick disease, type D. This term is no longer used since it was shown that these patients have mutations in the gene that cause type C Niemann-Pick disease.

What genes are related to Niemann-Pick disease?

Mutations in the NPC1, NPC2, and SMPD1 genes cause Niemann-Pick disease.

Mutations in the SMPD1 gene cause Niemann-Pick disease, types A and B. This gene carries instructions for cells to produce an enzyme called acid sphingomyelinase. This enzyme is found in the lysosomes (compartments that digest and recycle materials in the cell), where it processes lipids such as sphingomyelin. Mutations in this gene lead to a deficiency of acid sphingomyelinase and the accumulation of sphingomyelin, cholesterol, and other kinds of lipids within the cells and tissues of affected individuals.

Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease, type C. The NPC1 gene produces a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal storage of lipids within cells. The NPC2 gene produces a protein that binds and transports cholesterol, although its exact function is not fully understood. Extremely low levels or absence of this protein leads to the abnormal accumulation of lipids and cholesterol in the cells of people with this condition.

How do people inherit Niemann-Pick disease?

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.

Source: National Institutes of Health

Findings from University of North Carolina, Research Center in fibrosis cell biology reported

"CF cells accumulate free cholesterol similar to Niemann-Pick disease type C cells. We show that this lipid alteration is caused by the presence of misassembled mutant CFTR proteins, including DeltaF508, in the distal secretory pathway rather than the absence of functional CFTR. By contrast, cholesterol distribution is not changed by either D572N CFTR, which does not mature even at low temperature, or G551D, which is processed normally but is inactive. On expression of the DeltaF508 mutant, cholesterol and glycosphingolipids accumulate in punctate endosomal structures and cholesterol esters are reduced, indicating a block in the translocation of cholesterol to the ER for esterification. This is overcome by Rab9 overexpression, resulting in clearance of accumulating intracellular cholesterol. Similar but less pronounced alterations in intracellular cholesterol distribution are observed on expression of a temperature-rescued mutant variant of the related ATP-binding cassette (ABC) protein multidrug resistance-associated protein 1 (MRP1)," wrote M. Gentzsch and colleagues, University of North Carolina, Research Center.

The researchers concluded: "Thus, on escape from ER quality control, misassembled mutants of CFTR and MRP1 impair lipid homeostasis in endocytic compartments."

Gentzsch and colleagues published their study in the Journal of Cell Science (Misassembled mutant DeltaF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. Journal of Cell Science, 2007;120(Pt 3):447-55).

For additional information, contact M. Gentzsch, University of North Carolina, Dept. of Cell and Developmental Biology and Cystic Fibrosis Research Center, Chapel Hill, NC 27599 USA.

The publisher's contact information for the Journal of Cell Science is: Company of Biologists Ltd., Bidder Building Cambridge Commercial Park Cowley Rd., Cambridge CB4 4DL, Cambs, England.

Keywords: United States, Chapel Hill, Fibrosis Cell Biology, Cell Biology, Cell Science, Cystic Fibrosis, Fibrosis, Genetics, Hepatology, Pulmonology.

This article was prepared by Life Science Weekly editors from staff and other reports. Copyright 2007, Life Science Weekly via NewsRx.com.