Niemann-Pick+Disease,+Type+C

=Niemann-Pick Disease, Type C= Niemann-Pick C (NP-C) is caused by a mutation in either the //NPC1// or //NPC2// genes. These genes code for the NPC1 and NPC2 proteins, respectively. When there is a defect in either of these two proteins, the process of intracellular cholesterol transport is disrupted. This leads to an accumulation of unesterified cholesterol and other lipids in late endosomes and lysosomes (Vanier, 2010).
 * Root Cause**

NP-C primarily affects the spleen, liver, brain, and, more rarely, the lungs (Vanier, 2010).
 * Affected Organs**

NP-C takes its name from Albert Niemann and Ludwig Pick, both of whom wrote about the disease in the early 1900's. The designations (A, B, and C) came about in 1961 (Vanier, 2010).
 * Historical Background**

Symptoms of NP-C are generally divided into two categories: systemic and neurological. Systemic symptoms do not always occur, but when present can include spleno-, hepato-, or hepatosplenomegaly, jaundice, and, more rarely, respiratory problems. The neurological conditions are more severe than the systemic, and can include dysphagia, VSGP (vertical supranuclear gaze palsy), cataplexy, dystonia, cerebellar ataxia, dysarthria, seizures, and gradual dementia (Vanier, 2010).
 * Common Symptoms**

Currently, there is no cure for NP-C, only methods for controlling the symptoms. Antiepileptics can be used to control seizures. Cataplexy is managed with modafinil, clomipramine, or protripyline. Anticholinergic agents may be used for dystonia. Miglustat has been approved for use in treating NP-C in Europe and certain other countries; N-butyl-deoxynojirimycin is also used for treatment. Cyclodextrins have recently been used in certain cases, although this is not yet an approved treatment (Vanier, 2010).
 * Standard Treatments**

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 * Current Research**
 * Matsuo //et al//.'s work focuses on investigating the effectiveness of cyclodextrin as a treatment for NP-C. Cyclodextrins are already used in pharmaceuticals and have low toxicity, which gives them an advantage over other novel compounds that have not been tested in living subjects. Using extensive testing and clinical monitoring, two patients with NP-C were given regular doses of cyclodextrins. Matsuo //et al//.'s work shows that there were moderate reductions in systemic symptoms, but only a minor reduction in neurological symptoms. Further research might focus on developing a better method of delivering cyclodextrins to the brain, which might increase its effectiveness (Matsuo, 2012).
 * Ribas //et al.//'s work similarly focuses on oxidative stress in NP-C patients. Lipid and protein oxidation was measured using thiobarbituric acid-reactive species. One group was treated with N-butyl-deoxynojirimycin, which inhibits glycosphingolipid synthesis and is an approved treatment for NP-C, and one group was not. The levels of oxidative stress in the two groups were compared. Their data indicate that oxidative stress is increased in NP-C patients and that N-butyl-deoxynojirimycin provides some protection against the increased stress (Ribas, 2012).
 * Deffieu and Pfeffer focused on discerning the functions of the NPC1 and NPC2 proteins, rather than the effects of compounds. The exact functions of the NPC1 and NPC2 proteins are not clearly defined, and so it is important to perform research into that area of the disease as well as into potential cures and treatments. Using a synthesized part of the NPC1 protein, they were able investigate the binding properties of NPC1 and NPC2, and found that binding between the two depended on the presence of cholesterol (Deffieu, 2011).
 * References**


 * Deffieu, Maika S. and Suzanne R. Pfeffer** (2011) Niemann-Pick type C1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding. Proceedings of the National Academy of Sciences 108: 18932 – 18936


 * Matsuo, Muneaki //et al//.** (2012) Effects of cyclodextrin in two patients with Niemann-Pick Type C Disease. Molecular Genetics and Metabolism (2012)


 * Ribas, Graziela S., //et al.//** (2012) Oxidative stress in Niemann-Pick type C patients: a protective role of N-butyl-deoxynojirimycin therapy. International Journal of Developmental Neuroscience 30: 439 - 444


 * Vanier, Marie T** (2010) Niemann-Pick disease type C. Orphanet Journal of Rare Diseases 5: 16