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 buildup 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
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.
Genealogical 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. Pathophysiology
Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal 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.
The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND through Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both have since begun intrathecal treatments beginning in January 2012.In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients.On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012.Due to unprecedented collaboration between individual physicians and parents of children affected by NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy.