- Niemann-Pick disease, type C
Niemann-Pick disease, type C Classification and external resources ICD-10 E75.2 (ILDS E75.230) ICD-9 272.7 OMIM 257220 607625 DiseasesDB 33390 eMedicine derm/699 MeSH D052556
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. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.
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.
- 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.
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. 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.
- 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. 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. It has been shown to closely interact with NPC1.
"Type D" variant
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.
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. 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 antagonist 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.
Niemann Pick Type C is diagnosed by assaying cultured fibroblasts for cholesterol esterfication and staining for unesterified cholesterol 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 and the Mayo Clinic.
There is no known cure for Niemann Pick Type C, nor is there any FDA-standard approved disease modifying treatment. 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).
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.
In April 2009, hydroxy-propyl-beta-cyclodextrin (HPBCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel, identical twin girls suffering from Niemann Pick Type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPBCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann Pick Type C mice and feline models. (This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. Over 20 years ago, HPBCD was used in a medical case involving a boy suffering from severe hypervitaminosis A.)
On May 17, 2010, the FDA granted hydroxy-propyl-beta-cyclodextrin orphan drug status and designated hydroxy-propyl-beta-cyclodextrin as a potential treatment for Niemann Pick Type C disease. On July 14, 2010, Dr. Caroline Hastings of Children's Hospital Research Center Oakland filed additional applications with the FDA requesting approval to deliver hydroxy-propyl-beta-cyclodextrin directly into the central nervous system of the twins in an attempt to get HPBCD across the blood-brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPBCD into the spine were started in October 2010. Additional filings have been made to the FDA by Children's Hospital Research Center Oakland requesting approval to surgically install Medtronic SynchroMed pumps into the twins to deliver continuous doses of HPBCD into their brains.
Other treatments under investigation
One drug that has been tried is Miglustat. 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, rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent. The pregnane X receptor has been identified as a potential target.
Low cholesterol diets are often used, but there is no evidence of efficacy. On March 22, 2011, scientists at the University of Notre Dame and Cornell University made a breakthrough in the cure for this disease. No known cure is known yet, but we are much closer to one.
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.
- GeneReviews/NCBI/NIH/UW entry on Niemann-Pick Disease Type C
- OMIM entries on Niemann-Pick Type C
- National Institutes of Health Clinical Center Study On Niemann Pick Type C
- Marc C. Patterson, MD, child neurologist, Mayo Clinic
- Coriell Institute: Biobank that stores Niemann Pick Type C cells for research
- Addi and Cassi Hempel: Identical twins living with Niemann Pick Type C disease
- Testing labs for Niemann Pick Type C
- Clinical Description of Niemann Pick Type C
- Hide & Seek Foundation for Lysosomal Disease Research
- Detailed information about Niemann Pick Type C for patients and Healthcare Professionals incl. Glossary
- Portuguese description of Niemann Pick Type C, support and resources
- ^ Chang TY, Reid PC, Sugii S, Ohgami N, Cruz JC, Chang CC (June 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. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15831488.
- ^ 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.
- ^ 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.
- ^ a b Lloyd-Evans E, Morgan AJ, He X, et al. (October 2008). "Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium". Nature medicine 14 (11): 1247–55. doi:10.1038/nm.1876. PMID 18953351.
- ^ a b Mellon SH, Gong W, Schonemann MD (March 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. http://linkinghub.elsevier.com/retrieve/pii/S0165-0173(07)00097-5.
- ^ "genome.gov". http://www.genome.gov/10000889+. Retrieved 2008-10-27. [dead link]
- ^ Zhang JR, Coleman T, Langmade SJ, et al. (June 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2381744.
- ^ Bjurulf B, Spetalen S, Erichsen A, Vanier MT, Strøm EH, Strømme P (August 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. http://www.medscimonit.com/fulltxt.php?ICID=865795.
- ^ Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P (December 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. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17018531.
- ^ Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL (October 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. PMC 2563079. PMID 18772377. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18772377.
- ^ Subramanian K, Balch WE (October 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. PMC 2563125. PMID 18832164. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18832164.
- ^ Winsor EJ, Welch JP (September 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1685594.
- ^ Rimkunas VM, Graham MJ, Crooke RM, Liscum L (September 2008). "TNF-alpha plays a role in hepatocyte apoptosis in Niemann Pick type C liver disease". Journal of lipid research 50 (2): 327–33. doi:10.1194/jlr.M800415-JLR200. PMC 2636917. PMID 18815434. http://www.jlr.org/cgi/pmidlookup?view=long&pmid=18815434.
- ^ "Thomas Jefferson University - Lysosomal Diseases Testing Laboratory". http://www.jefferson.edu/lysolab/tests.cfm+. Retrieved 2008-10-27. [dead link]
- ^ "Niemann Pick Diagnosis". http://www.mayoclinic.org/niemann-pick/diagnosis.html. Retrieved 2008-10-27.
- ^ 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. PMC 2662713. PMID 18782459. http://journals.cambridge.org/abstract_S146239940800080X.
- ^ "Niemann-Pick Disease Type C -- GeneReviews -- NCBI Bookshelf". http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=npc. Retrieved 2008-10-27.
- ^ Davidson CD, Ali NF, Micsenyi MC, et al. (2009). "Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression". PLoS ONE 4 (9): e6951. doi:10.1371/journal.pone.0006951. PMC 2736622. PMID 19750228. http://dx.plos.org/10.1371/journal.pone.0006951.
- ^ Ward S, O'Donnell P, Fernandez S, Vite CH (July 2010). "2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease". Pediatr. Res. 68 (1): 52–6. doi:10.1203/PDR.0b013e3181df4623. PMC 2913583. PMID 20357695. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0031-3998&volume=68&issue=1&spage=52.
- ^ Carpenter TO, Pettifor JM, Russell RM, et al. (October 1987). "Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake". J. Pediatr. 111 (4): 507–12. doi:10.1016/S0022-3476(87)80109-9. PMID 3655980.
- ^ Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (September 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. http://linkinghub.elsevier.com/retrieve/pii/S1474-4422(07)70194-1.
- ^ Santos ML, Raskin S, Telles DS, et al. (October 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. ISBN 1054500809239. PMID 18937049.
- ^ Ahmad I, Lope-Piedrafita S, Bi X, et al. (December 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.
- ^ Langmade SJ, Gale SE, Frolov A, et al. (September 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. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16940355.
- ^ 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. doi:10.1007/BF03195222. PMID 17666780. http://jag.igr.poznan.pl/2007-Volume-48/3/abstracts/403.html. Retrieved 2008-10-27.
- ^ "eMedicine - Niemann-Pick Disease : Article by Robert A Schwartz". http://www.emedicine.com/derm/topic699.htm. Retrieved 2008-10-27.
- ^ "Niemann-Pick Disease". http://my.clevelandclinic.org/disorders/Niemann-Pick_Disease_NP/hic_Niemann-Pick_Disease.aspx. Retrieved 2008-10-27.
(LSD) Inborn error of lipid metabolism: lipid storage disorders (E75, 272.7–272.8) Sphingolipidoses
(to ceramide)From globosideGlobotriaosylceramide: Fabry's diseaseFrom sphingomyelinTo sphingosine
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