Niemann–Pick disease is a group of inherited severe metabolic disorders in which sphingomyelin accumulates in lysosomes in cells. The lysosomes normally transport material through and out of the cell.
The prognosis is individual but the severe form is fatal in toddlerhood and the milder forms may even in some cases have a normal lifespan.
This disease involves dysfunctional metabolism of sphingolipids, which are fats found in cell membranes, so it is a kind of sphingolipidosis. Sphingolipidoses, in turn, are included in the larger family of lysosomal storage diseases.
Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension, and pain. Enlargement of the spleen (splenomegaly) may also cause low levels of platelets in the blood (thrombocytopenia).
Accumulation of sphingomyelin in the central nervous system (including the cerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria), and difficulty in swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk, and face (dystonia). Upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures causes gradual loss of intellectual abilities, causing dementia and seizures.
Bones can also be affected: symptoms can include enlarged bone marrow cavities, thinned cortical bone, or a distortion of the hip bone called coxa vara. Sleep-related disorders, such as sleep inversion, sleepiness during the day and wakefulness at night, can occur. Gelastic cataplexy, the sudden loss of muscle tone when the patient laughs, is also seen.
Mutations in the SMPD1 gene cause Niemann–Pick disease types A and B. They stop the body from making an enzyme, acid sphingomyelinase, that breaks down lipids.
Mutations in NPC1 or NPC2 cause Niemann–Pick disease, type C (NPC), which affects a protein used to transport lipids.
Type D was originally separated from type C to delineate a group of patients with otherwise identical disorders who shared a common Nova Scotian ancestry. Patients in this group are known to share a specific mutation in the NPC1 gene, so NPC is used for both groups. Before the molecular defects were described, the terms "Niemann–Pick type I" and "Niemann–Pick type II" were proposed to separate the high- and low-sphingomyelin forms of the disease in the early 1980s.
Niemann–Pick disease is inherited in an autosomal recessive pattern, which means both copies, or alleles, of the gene must be defective to cause the disease. "Defective" means they are altered in a way that impairs their function. Most often, the parents of a child with an autosomal recessive disorder are carriers: they have one copy of the altered gene, but are not affected because the other copy produces the enzyme. If both parents are carriers, each pregnancy has a 25% chance of producing an affected child. Genetic counseling and genetic testing are recommended for families who may be carriers of Niemann–Pick.
Type A Niemann–Pick disease (about 85% of cases) has an extremely poor prognosis, with most cases being fatal by the age of 18 months. Type B (adult onset) and type C (mutation affecting a different molecule) Niemann–Pick diseases have a better prognosis.
No specific treatment is known for type A, but symptoms are treated.
In adult patients with type B, physicians try to keep cholesterol levels down to normal levels. If statins are used, they monitor liver function. If the spleen is enlarged and platelet levels low, acute episodes of bleeding may require transfusions of blood products. If they have symptoms of interstitial lung disease, they may need oxygen.
Anecdotally, organ transplant has been attempted with limited success. Future prospects include enzyme replacement and gene therapy. Bone marrow transplant has been tried for type B.
In January 2009, Actelion announced the drug miglustat (Zavesca) had been approved in the European Union for the treatment of progressive neurological manifestations in adult patients and pediatric patients with NPC. The drug is available to patients in the United States on an experimental basis. In March 2010, the FDA requested additional preclinical and clinical information regarding Zavesca from Actelion before making a final decision on approving the drug in the United States for NPC.
Experimental use of 2-hydroxypropyl-β-cyclodextrin
Researchers at the University of Texas Southwestern Medical Center found, when Niemann–Pick type C mice were injected with 2-hydroxypropyl-β-cyclodextrin (HPbCD) when they were 7 days old, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life occurred. These results suggest HPbCD acutely reverses the storage defect seen in NPC.
In April 2009, the FDA approved investigational new drug (IND) applications for eight-year-old identical twins, Addison and Cassidy Hempel of Reno, Nevada, to receive intravenous infusions of HPbCD. The twins are the first in the United States to receive experimental treatment at Renown Regional Medical Center in Nevada. The twins received HPbCD, 2500 mg/kg, administered as an eight-hour infusion, twice weekly.
In February 2010, the parents of the twins with the support of Children's Hospital Oakland, filed an orphan drug application with the Office of Orphan Product Development at the FDA for Trappsol brand HPbCD for the treatment of NPC. On May 17, 2010, the FDA granted HPbCD orphan drug status and designated it as a promising treatment for NPC.
On July 14, 2010, Children's Hospital Oakland filed IND applications with the FDA on behalf of the Hempel twins, based on promising new animal data. Physicians proposed to deliver hydroxy-propyl-beta-cyclodextrin intrathecally and directly into the central nervous system of the twins in an attempt to deliver the compound across the blood–brain barrier and arrest neurodegeneration. The drug was to be administered twice per month and dosing would start at 175 mg (1 mM) and would be increased steadily to reach 875 mg (5 mM) by day 60.
The INDs were approved on September 23, 2010, and bimonthly intrathecal injections of HPbCD into the spine were administered starting in October 2010. Additional filings have been made to the FDA by Children's Hospital Research Center Oakland requesting approval to surgically implant Medtronic SynchroMed pumps into the twins to deliver continuous doses of HPbCD into their brains.
In April 2011, the U.S. National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they are developing a clinical trial using HPbCD for Niemann–Pick type C patients. The clinical trial is in the planning phase, not yet approved by the FDA.
On September 20, 2011, the European Medicines Agency granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.