Niemann-Pick disease
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2008-07-07T16:36:04Z
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{{Infobox_Disease |
Name = Niemann-Pick disease |
Image = |
Caption = |
DiseasesDB = |
ICD10 = {{ICD10|E|75|2|e|70}} ([[ILDS]] E75.230) |
ICD9 = {{ICD9|272.7}} |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
MeshID = D009542 |
}}
'''Niemann-Pick disease''' is an [[autosomal recessive]] disorder affecting [[lipid]] metabolism (the breakdown and use of fats and [[cholesterol]] in the body), in a way which causes harmful amounts of lipids to accumulate in the [[spleen]], [[liver]], [[lungs]], [[bone marrow]], and [[brain]].
There are three variants of Niemann-Pick disease based on the [[genetics|genetic]] cause and the symptoms exhibited by the patient.
This disease is extremely rare; in fact, under 1,500 people have been diagnosed with Type C of this disease around the world.{{Fact|date=May 2008}}
==Genetics==
Mutations in the [[NPC1]], [[NPC2]], and [[SMPD1]] [[gene]]s cause 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. If both parents are carriers, there is a 25% chance with each pregnancy for an affected child. [[Genetic counseling]] and [[genetic testing]] is recommended for families who may be carriers of Niemann-Pick.
[[Image:autorecessive.svg|thumb|right|Autosomal recessive inheritence]]
==Types==
===Types A and B===
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. Niemann-Pick disease, type A occurs more frequently among individuals of [[Ashkenazi Jews|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.
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 cell]]s involved in clotting ([[platelets]]). People affected by this type of Niemann-Pick disease usually survive into adulthood. Niemann-Pick disease, type B occurs in all populations.
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.
===Type C===
Type C is 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. 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]].
Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease, type C.
* The NPC1 gene produces a [[membrane protein|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 build up of lipids and cholesterol within cell membranes.
* The NPC2 gene produces a protein that binds and transports cholesterol, although its exact function is not fully understood.
===Biochemical Transport===
The molecular basis for this disease is extremely complex due to the role that [[endosome]] formation has on affected patients. Recently, three theories have attempted to explain the buildup of cholesterol in the lysosomes of affected patients of Niemann-Pick Disease Type C due to the malfunction of the protein NPC-1.
* The contention by Neufel et al is that the buildup of [[mannose 6-phosphate receptor]]s (MPRs) in the late endosome suggests that the retrograde breakdown of cholesterol via the Trans [[Golgi]] Network cannot occur.<ref name="npp">{{cite journal |author=Neufeld EB, Wastney M, Patel S, et al |title=The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo |journal=J. Biol. Chem. |volume=274 |issue=14 |pages=9627–9635 |year=1999 |pmid=10092649 |doi=10.1074/jbc.274.14.9627}}</ref>
* Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the Trans [[Golgi]] Network cannot bud and form.
The support of these theories has considerable evidence using mutant proteins [[in vitro]] to determine the buildup of [[cholesterol]] in the [[lysosomes]]. Researchers have also discovered that the NPC-1 protein may function as a pump of cholesterol.<ref name="tmp">{{cite journal |author=Davies JP, Chen FW, Ioannou YA |title=Transmembrane molecular pump activity of Niemann-Pick C1 protein |journal=Science |volume=290 |issue=5500 |pages=2295–2298 |year=2000 |pmid=11125140 |doi=10.1126/science.290.5500.2295}}</ref>
The overall effect of a malfunction in NPC-1 is that low levels or an absence of the protein lead to the abnormal accumulation of lipids and cholesterol in the cells of people with this condition.
== External links ==
*[http://www.nnpdf.org/ National Niemann-Pick Disease Foundation]
*[http://www.parseghian.org/ Ara Parseghian Medical Research Foundation]
*[http://www.niemannpick.org.uk/ Niemann-Pick Disease Group (UK)]
:''This article incorporates public domain text from [http://ghr.nlm.nih.gov The U.S. National Library of Medicine]''
==References==
{{reflist}}
{{Lipid storage disorders}}
[[Category:Neurology]]
[[Category:Genetic disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Lysosomal storage diseases]]
[[Category:Ashkenazi Jews topics]]
[[de:Niemann-Pick-Krankheit]]
[[es:Enfermedad de Niemann-Pick]]
[[it:Malattia di Niemann-Pick]]
[[pl:Choroba Niemanna-Picka]]
[[ru:Болезнь Ниманна — Пика]]
[[fi:Niemann–Pickin tauti]]
[[zh:尼曼匹克症]]