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Niemann Pick Type C is diagnosed by assaying cultured [[fibroblasts]] (skin cells) for cholesterol esterfication and staining for unesterified chlesterol with [[filipin]]. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the [[NPC1]] or [[NPC2]] genes in 80-90% of cases. This specialized testing is available at [[Thomas Jefferson University]] Lysosomal Disease Testing Lab<ref name="urlThomas Jefferson University - Lysosomal Diseases Testing Laboratory">{{cite web |url=http://www.jefferson.edu/lysolab/tests.cfm+ |title=Thomas Jefferson University - Lysosomal Diseases Testing Laboratory |format= |work= |accessdate=2008-10-27}}</ref> and the [[Mayo Clinic]].<ref name="urlNiemann Pick Diagnosis">{{cite web |url=http://www.mayoclinic.org/niemann-pick/diagnosis.html |title=Niemann Pick Diagnosis |format= |work= |accessdate=2008-10-27}}</ref>
Niemann Pick Type C is diagnosed by assaying cultured [[fibroblasts]] (skin cells) for cholesterol esterfication and staining for unesterified chlesterol with [[filipin]]. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the [[NPC1]] or [[NPC2]] genes in 80-90% of cases. This specialized testing is available at [[Thomas Jefferson University]] Lysosomal Disease Testing Lab<ref name="urlThomas Jefferson University - Lysosomal Diseases Testing Laboratory">{{cite web |url=http://www.jefferson.edu/lysolab/tests.cfm+ |title=Thomas Jefferson University - Lysosomal Diseases Testing Laboratory |format= |work= |accessdate=2008-10-27}}</ref> and the [[Mayo Clinic]].<ref name="urlNiemann Pick Diagnosis">{{cite web |url=http://www.mayoclinic.org/niemann-pick/diagnosis.html |title=Niemann Pick Diagnosis |format= |work= |accessdate=2008-10-27}}</ref>

==External Links==
*[http://www.clinicaltrials.gov/ct/show/NCT00344331?order=1// National Institutes of Health Clinical Center Study On Niemann Pick Type C]
*[http://podcasts.mayoclinic.org/2008/07/11/niemann-pick-disease-type-c/ Marc C. Patterson, MD, child neurologist, Mayo Clinic]
*[http://ccr.coriell.org/Sections/Collections/NIGMS/npc.aspx?PgId=247// Coriell Institute: Biobank that stores Niemann Pick Type C cells for research]
*[http://www.addiandcassi.com/ Addi and Cassi Hempel: Identical twins living with Niemann Pick Type C disease]
*[http://www.genetests.org/query?testid=116458 Testing labs for Niemann Pick Type C]
*[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=npc Clinical Description of Niemann Pick Type C]


==References==
==References==

Revision as of 03:04, 29 November 2008

Niemann–Pick disease type C
SpecialtyEndocrinology, neurology Edit this on Wikidata
Frequency0.000667%

Niemann-Pick type C is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes.

Niemann-Pick Type C strikes an estimated 1:150,000 people.[1] Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.

Pathophysiology

Niemann-Pick Type C is biochemically, genetically and clinically distinct from Niemann Pick Types A or and B. In Types A & B, there is complete or partial deficiency of an enzyme called acid sphingomyelinase. In Niemann Pick Type C, the protein product of the major mutated gene NPC1 is not an enzyme, but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally, but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.

Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann-Pick Type C, large amounts of free or unesterfied cholesterol accumulates in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.

Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein.

Neufeld et al hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi Network.[2]

  • 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.
  • Iouannou, et al have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.[3]
  • Recent evidence indicates that NPC-1 may play an important role in calcium regulation.[4]

Genetics and classification

Approximately 95% of Niemann-Pick Type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2.[5] The clinical manifestations of types Niemann Pick Type C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997.[6]

  • The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells.[7] A deficiency of this protein leads to the abnormal build up of lipids and cholesterol within cell membranes.
  • The NPC2 gene encodes a protein that binds and transports cholesterol.[8][9] It has been shown to closely interact with NPC1.[10][11]

"Type D" variant

File:Novascotiayarmouthcountydet.gif
Yarmouth County, Nova Scotia

Type D Niemann-Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann Pick Type C.

Genelogical research indicates that Joseph Muise (c. 1679 - 1729) and Marie Amirault (1684 - c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant.[12]

Prognosis

The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann Pick Type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years.

Symptoms

Niemann-Pick Type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen/liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen and/or liver does not occur for months or years - or not at all. Enlargement of the spleen and/or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann-Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.

Progressive neurological disease is the hallmark of Niemann-Pick Type C disease, and is responsible for disability and premature death in all cases beyond early childhood.[13] Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).

Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and atnagonist muscles across joints), most commonly begins with in turning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.

In the terminal stages of Niemann Pick Type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and has severe dementia.

Management

There is no known cure for Niemann Pick Type C, nor is there any FDA-standard approved disease modifying treatment.[14] Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, orthopedics, nutrition, physical therapy and occupational therapy. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube).[15]

An observational study is underway at the National Institutes of Health to better characterize the natural history of NPC and to attempt to identify markers of disease progression. For example, one drug that has been tried is Miglustat.[16][17] Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC.

Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include cholesterol mobilization, neurosteroid (a special type of hormone that effects brain and other nerve cells) replacement using allopregnanolone,[5][18] rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent.[4] The pregnane X receptor has been identified as a potential target.[19]

Neural stem cells have been investigated in an animal model, but there was no clear evidence of benefit.[20]

Low cholesterol diets are often used,[21] but there is no evidence of efficacy.[22]

Diagnosis

Niemann Pick Type C is diagnosed by assaying cultured fibroblasts (skin cells) for cholesterol esterfication and staining for unesterified chlesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80-90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab[23] and the Mayo Clinic.[24]

References

  1. ^ Chang TY, Reid PC, Sugii S, Ohgami N, Cruz JC, Chang CC (2005). "Niemann-Pick type C disease and intracellular cholesterol trafficking". The Journal of biological chemistry. 280 (22): 20917–20. doi:10.1074/jbc.R400040200. PMID 15831488. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  2. ^ Neufeld EB, Wastney M, Patel S; et al. (1999). "The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo". J. Biol. Chem. 274 (14): 9627–9635. doi:10.1074/jbc.274.14.9627. PMID 10092649. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  3. ^ Davies JP, Chen FW, Ioannou YA (2000). "Transmembrane molecular pump activity of Niemann-Pick C1 protein". Science. 290 (5500): 2295–2298. doi:10.1126/science.290.5500.2295. PMID 11125140.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b Lloyd-Evans E, Morgan AJ, He X; et al. (2008). "Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium". Nature medicine. doi:10.1038/nm.1876. PMID 18953351. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b Mellon SH, Gong W, Schonemann MD (2008). "Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease". Brain research reviews. 57 (2): 410–20. doi:10.1016/j.brainresrev.2007.05.012. PMC 2323675. PMID 17629950. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ "genome.gov". Retrieved 2008-10-27. {{cite web}}: Text "1997 News Release, Niemann-Pick Type C Gene" ignored (help)
  7. ^ Zhang JR, Coleman T, Langmade SJ; et al. (2008). "Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking". The Journal of clinical investigation. 118 (6): 2281–90. doi:10.1172/JCI32561. PMC 2381744. PMID 18483620. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Bjurulf B, Spetalen S, Erichsen A, Vanier MT, Strøm EH, Strømme P (2008). "Niemann-Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue". Medical science monitor : international medical journal of experimental and clinical research. 14 (8): CS71–5. PMID 18668002. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P (2006). "NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols". The Journal of biological chemistry. 281 (48): 36710–23. doi:10.1074/jbc.M608743200. PMID 17018531. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  10. ^ Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL (2008). "NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes". Proceedings of the National Academy of Sciences of the United States of America. 105 (40): 15287–92. doi:10.1073/pnas.0807328105. PMID 18772377. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Subramanian K, Balch WE (2008). "NPC1/NPC2 function as a tag team duo to mobilize cholesterol". Proceedings of the National Academy of Sciences of the United States of America. 105 (40): 15223–4. doi:10.1073/pnas.0808256105. PMID 18832164. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Winsor EJ, Welch JP (1978). "Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D)". American journal of human genetics. 30 (5): 530–8. PMC 1685594. PMID 736041. {{cite journal}}: Unknown parameter |month= ignored (help)
  13. ^ Rimkunas VM, Graham MJ, Crooke RM, Liscum L (2008). "TNF-alpha plays a role in hepatocyte apoptosis in Niemann Pick type C liver disease". Journal of lipid research. doi:10.1194/jlr.M800415-JLR200. PMID 18815434. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  14. ^ Pacheco CD, Lieberman AP (2008). "The pathogenesis of Niemann-Pick type C disease: a role for autophagy?". Expert reviews in molecular medicine. 10: e26. doi:10.1017/S146239940800080X. PMID 18782459.
  15. ^ "Niemann-Pick Disease Type C -- GeneReviews -- NCBI Bookshelf". Retrieved 2008-10-27.
  16. ^ Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (2007). "Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study". Lancet neurology. 6 (9): 765–72. doi:10.1016/S1474-4422(07)70194-1. PMID 17689147. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Santos ML, Raskin S, Telles DS; et al. (2008). "Treatment of a child diagnosed with Niemann-Pick disease type C with miglustat: A case report in Brazil". Journal of inherited metabolic disease. doi:10.1007/s10545-008-0923-9. PMID 18937049. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Ahmad I, Lope-Piedrafita S, Bi X; et al. (2005). "Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice". Journal of neuroscience research. 82 (6): 811–21. doi:10.1002/jnr.20685. PMID 16273542. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Langmade SJ, Gale SE, Frolov A; et al. (2006). "Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease". Proceedings of the National Academy of Sciences of the United States of America. 103 (37): 13807–12. doi:10.1073/pnas.0606218103. PMC 1564205. PMID 16940355. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ Ahmad I, Hunter RE, Flax JD, Snyder EY, Erickson RP (2007). "Neural stem cell implantation extends life in Niemann-Pick C1 mice". Journal of applied genetics. 48 (3): 269–72. PMID 17666780. Retrieved 2008-10-27.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ "eMedicine - Niemann-Pick Disease : Article by Robert A Schwartz". Retrieved 2008-10-27.
  22. ^ "Niemann-Pick Disease". Retrieved 2008-10-27.
  23. ^ "Thomas Jefferson University - Lysosomal Diseases Testing Laboratory". Retrieved 2008-10-27.
  24. ^ "Niemann Pick Diagnosis". Retrieved 2008-10-27.
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