| Niemann-Pick disease | |
|---|---|
| Classification and external resources | |
| ICD-10 | E75.2 (ILDS E75.230) |
| ICD-9 | 272.7 |
| OMIM | 257200 607616 257220 607625 |
| DiseasesDB | 9016 34341 33390 |
| eMedicine | derm/699 |
| MeSH | D009542 |
Niemann–Pick disease ( /niːmənˈpɪk/ nee-mən-pik)[1] refers to a group of fatal inherited metabolic disorders that are included in the larger family of lysosomal storage diseases (LSDs).[2]:536
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Symptoms are related to the organs in which they accumulate. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension and pain as well as thrombocytopenia secondary to splenomegaly.
Sphingomyelin accumulation 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) and upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures is responsible for gradual loss of intellectual abilities causing dementia and seizures.[3]
Bone marrow cavities may be enlarged and the cortical bone may be thinned. Coxa vara may be found.
Sleep related disorders are also seen, including gelastic cataplexy (sudden loss of muscle tone associated with laughter), and sleep inversion (sleepiness during the day and wakefulness at night).
Mutations in the SMPD1 gene cause Niemann–Pick disease types A and B, and mutations in NPC1 and NPC2 cause Niemann-Pick disease, type C (NPC). 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 now known to share a specific mutation in the NPC 1 gene, and NPC is now used to embrace both groups. 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, before the molecular defects were described.
Niemann–Pick disease is inherited in an autosomal recessive pattern, which means both copies, or alleles, of the gene must be mutated (altered in such a way that function is impaired, in contrast to a polymorphism, in which the nucleotide sequence is altered but causes no functional disruption) for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.
In 1961, the following classification was introduced:[4][5]
Now that the genetics are better understood, the condition can be classified as follows:
Niemann–Pick diseases are genetic diseases which are classified in 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 demonstrates lipid laden macrophages in the marrow, as well as "sea-blue histiocytes" on pathology. Numerous small vacuoles of relatively uniform size are created, imparting a foamy appearance to the cytoplasm.
Treatments for Niemann–Pick disease are limited with care being mostly supportive. Anecdotally, organ transplant has been attempted with limited success. Future prospects include enzyme replacement and gene therapy. Bone marrow transplant has been attempted for Type B. Supportive care through nutrition, medication, physical therapy and being followed by specialists can help with quality of life.[3]
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.
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.[6]
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 with HPbCD and are currently undergoing treatment at Renown Regional Medical Center in Nevada.
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 Investigational New Drug (INDs) applications with the FDA on behalf of the Hempel twins based on promising new animal data. Doctors requested to deliver hydroxy-propyl-beta-cyclodextrin intrathecally and directly into the central nervous system of the twins in an attempt to arrest neurodegeneration and deliver the compound across the blood-brain barrier. 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.
In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), 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.
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 has an extremely poor prognosis with most cases being fatal by the age of 18 months.[7] Type B and C Niemann Pick disease have a better prognosis, with many patients with these disorders living into their teens or adulthood.[8]
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.[9][10][11]
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