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Niemann-Pick disease

Not to be confused with Pick's disease.
Niemann–Pick disease
Classification and external resources
ICD-10 9 OMIM DiseasesDB MedlinePlus eMedicine MeSH D009542

Niemann–Pick disease (/nmənˈpɪk/ )[1] refers to a group of inherited severe metabolic disorders that allow sphingomyelin to accumulate in lysosomes, which are organelles in animal cells. The severe form is fatal in toddlerhood; people with milder forms may live into their teens or young adulthood. 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 (LSDs).[2]:536

Signs and symptoms

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 discoordinated 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 also occur. One is gelastic cataplexy sudden loss of muscle tone when the patient laughs. Another is sleep inversion, sleepiness during the day and wakefulness at night.

Cause and genetics

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.[3]

Mutations in NPC1 or NPC2 cause Niemann–Pick disease, type C (NPC), which affects a protein used to transport lipids.[3]

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. We now know that patients in this group 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 that 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.


  • Niemann–Pick disease type A: classic infantile
  • Niemann–Pick disease type B: visceral
  • Niemann–Pick disease, type C: subacute/juvenile, includes types C1 (95% of type C) and C2. Type C is the most common form of the disease[3] Type C2 is a rare form of the disease.[4]


The incidence among Ashkenazi Jews is estimated to be approximately 1 in 40,000 for type A of Niemann–Pick disease.[3] The incidence of both Niemann–Pick disease types A and B in all other populations is estimated to be 1 in 250,000.[3] The incidence of Niemann–Pick disease type C is estimated to be 1 in 150,000.[3]


Niemann–Pick diseases are a subgroup of LSDs called sphingolipidoses or lipid storage disorders in which harmful quantities of fatty substances, or lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain.

In the classic infantile type A variant, a missense mutation causes complete deficiency of sphingomyelinase. Sphingomyelin is a component of cell membrane including the organellar membrane and so the enzyme deficiency blocks degradation of lipid, resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte lineage. Affected cells become enlarged, sometimes up to 90 micrometres in diameter, secondary to the distention of lysosomes with sphingomyelin and cholesterol. Histology shows lipid-laden macrophages in the marrow and "sea-blue histiocytes" on pathology. Numerous small vacuoles of relatively uniform size are created, giving the cytoplasm a foamy appearance.


There is no specific treatment for Type A but symptoms are treated.

In adult patients with Type B, doctors 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.[5]

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 that the drug Zavesca (Miglustat) had been approved in the European Union for the treatment of progressive neurological manifestations in adult patients and pediatric patients with Niemann–Pick disease, type C (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 disease. [6]

Experimental Use of 2-hydroxypropyl-β-cyclodextrin or HPbCD

Researchers at the University of Texas Southwestern Medical Center found that when Niemann–Pick type C mice were injected with CYCLO (2-hydroxypropyl-β-cyclodextrin or 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 that 2-hydroxypropyl-β-cyclodextrin acutely reverses the storage defect seen in Niemann–Pick disease, type C.[7]

In April 2009, the Food and Drug Administration approved Investigational New Drug (INDs) 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 cyclodextrin for the treatment of NPC disease. On May 17, 2010, the FDA granted HPbCD orphan drug status and designated hydroxy-propyl-beta-cyclodextrin as a promising treatment for Niemann–Pick type C disease.

On July 14, 2010, Children's Hospital Oakland filed (INDs) applications[8] with the FDA on behalf of the Hempel twins, based on promising new animal data. Doctors 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 that dosing would start at 175 mg HPBCD (1mM)and would be increased steadily to reach 875 mg HPBCD (5mM) by day 60.[9]

The INDs were approved on September 23, 2010, and bi-monthly 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.[10]

In April 2011, the U.S. National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND),[11] announced they are developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients. The clinical trial is in the planning phase is not yet approved by the FDA.[12]

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.


Type A Niemann–Pick disease (approximately 85% of cases)[13] has an extremely poor prognosis with most cases being fatal by the age of 18 months.[14]

Type B (adult onset) and Type C (mutation affecting a different molecule) Niemann–Pick disease have a better prognosis, with many patients with these disorders living into their teens or adulthood.[3]


Albert Niemann published the first description of what is now known as Niemann–Pick disease, type A, in 1914. Ludwig Pick described the pathology of the disease in a series of papers in the 1930s.[15][16][17]

In 1961, the classification of Niemann–Pick disease into types A, B and C was introduced, and also contained a type D,[18][19] also called the "Nova Scotian type". Genetic studies showed that type D is caused by the same gene as type C1, and the type D designation is no longer used today.[3]

In 2011 it was discovered that subjects with Niemann-Pick type C1 disease were resistant to Ebola virus because of defects in the NPC1 protein which are needed for viral escape from the vesicular compartment.[20]

Research directions

Loss of myelin in the Central Nervous System is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the NPC1 gene as seen in Niemann-Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased.[21] MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths.[22] A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.[21]

See also


External links

  • National Institute of Neurological Diseaases and Strokes page on the disease
  • National Niemann–Pick Disease Foundation (U.S.)
  • Ara Parseghian Medical Research Foundation
  • Niemann–Pick Disease Group (UK)
  • GeneReviews/NCBI/NIH/UW entry on Acid Sphingomyelinase Deficiency Includes: Niemann–Pick Disease Type A, Niemann–Pick Disease Type B
  • OMIM entries on Acid Sphingomyelinase Deficiency
  • GeneReviews/NCBI/NIH/UW entry on Niemann–Pick Disease Type C
  • OMIM entries on Niemann–Pick Type C
  • Niemann–Pick Disease Group Canada
  • National Institutes of Health Clinical Center Study On Niemann–Pick Type C
  • Genetics Home Reference on Niemann–Pick Disease
  • Hide & Seek Foundation for Lysosomal Disease Research
  • Detailed information about Niemann–Pick Type C for patients and Healthcare Professionals
  • Pathology images and digital slides (HP:7983)
  • This article incorporates public domain text from The U.S. National Library of Medicine
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