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| * [[Hurler disease]] | | * [[Hurler disease]] |
| * [[Mucolipidoses]] | | * [[Mucolipidoses]] |
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| ==Overview==
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| '''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]].
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| There are three variants of Niemann-Pick disease based on the [[genetics|genetic]] cause and the symptoms exhibited by the patient.
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| ==Genetics==
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| Mutations in the [[NPC1]], [[NPC2]], and [[SMPD1]] [[gene]]s cause Niemann-Pick disease.
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| 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.
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| [[Image:autorecessive.svg|thumb|200px|left|Autosomal recessive inheritence]]
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| ==Types==
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| ===Types A and B===
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| 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 (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.
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| 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.
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| 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.
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| ===Type C===
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| 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.
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| 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.
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| ===Biochemical Transport===
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| 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.
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| * 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=}}</ref>
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| * 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.
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| 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>
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| 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.
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| == External links ==
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| [http://ghr.nlm.nih.gov The U.S. National Library of Medicine]''
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| ==References==
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| {{reflist|2}}
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| {{Metabolic pathology}}
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| [[de:Niemann-Pick-Krankheit]]
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| [[es:Enfermedad de Niemann-Pick]]
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| [[it:Malattia di Niemann-Pick]]
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| [[ru:Болезнь Ниманна — Пика]]
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| [[fi:Niemann–Pickin tauti]]
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| [[zh:尼曼匹克症]]
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| [[Category:Neurology]] | | [[Category:Neurology]] |