| Niemann–Pick disease | |
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| Child with Niemann–Pick disease | |
| Pronunciation | |
| Specialty | Medical genetics |
Niemann–Pick disease (NP), also known asacid sphingomyelinase deficiency, is a group of rare genetic diseases of varying severity. These are inheritedmetabolic disorders in whichsphingomyelin accumulates inlysosomes in cells of many organs. NP types A, A/B, and B are caused by mutations in theSMPD1 gene, which causes a deficiency of anacid sphingomyelinase (ASM).NP type C is now considered a separate disease, asSMPD1 is not involved, and there is no deficiency in ASM.
These disorders involve the dysfunctional metabolism ofsphingolipids, which are fats found in cell membranes. They can be considered as a kind ofsphingolipidosis, which is included in the larger family oflysosomal storage diseases.[2]
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 ofplatelets in the blood (thrombocytopenia).[citation needed]
Accumulation ofsphingomyelin in thecentral nervous system (including thecerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria), and difficulty 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 thecerebral cortex and subcortical structures causes gradual loss of intellectual abilities, causingdementia andseizures.[citation needed]
Bones also may be affected, with the disease-causing enlargedbone marrow cavities, thinnedcortical bone, or a distortion of the hip bone calledcoxa vara. Sleep-related disorders also occur with the condition, such assleep inversion, sleepiness during the day and wakefulness at night.Gelasticcataplexy, the sudden loss of muscle tone when the affected patient laughs, is also seen.[citation needed]
Mutations in theSMPD1gene cause Niemann–Pick disease types A and B. They produce a deficiency in the activity of thelysosomalenzymeacid sphingomyelinase, that breaks down the lipidsphingomyelin.[3]
Mutations inNPC1 orNPC2 causeNiemann–Pick disease, type C (NPC), which affects a protein used to transport lipids.[3]
Type D originally was separated from type C to delineate a group of patients with otherwise identical disorders who shared a commonNova 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.[citation needed]
Niemann–Pick disease is inherited in anautosomal recessive pattern,[4][5] which means both copies orboth 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 andgenetic testing are recommended for families who may be carriers of the disease.[citation needed]
Niemann–Pick diseases are a subgroup oflipid storage disorders calledsphingolipidoses in which harmful quantities of fatty substances, orlipids, accumulate in thespleen,liver,lungs,bone marrow, andbrain.[citation needed]
In the classic infantile type-A variant, amissense mutation causes complete deficiency ofsphingomyelinase. Sphingomyelin is a component of the cell membrane including the organellar membrane, so the enzyme deficiency blocks the degradation of lipids, resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte lineage. Affected cells become enlarged, sometimes up to 90 μm 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.[citation needed]
For types A and B, levels of sphingomyelinase can be measured from a blood sample. To diagnose type C, a skin sample can help determine whether the transporter is affected via the Filipin test which detects build-up of unesterified cholesterol via fluorescent staining.[6][7]
The four types of Niemann–Pick disease are divided into categories. People with ASM deficiency are classified into types A and B. Type A patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement and are unable to survive beyond two years of age. Type B patients also show hepatosplenomegaly and pathologic alterations of their lungs, but usually without the involvement of their central nervous system. Some can develop significant life-threatening complications, including liver failure, hemorrhage, oxygen dependency, pulmonary infections, and splenic rupture. Some develop coronary arterial or valvular heart disease. In a longitudinal natural history study, nearly 20% of the patients died. For those classified into type C, they may have mild hepatosplenomegaly, but their central nervous system is profoundly affected.[8]
Niemann–Pick disease type D (or Nova Scotia form) is now believed to be the same condition as Niemann–Pick disease type C.[10] Two poorly characterized forms of Niemann–Pick disease have also been described as types E and F.[11]
In adults with type B, physicians try to keep cholesterol levels down to normal levels. 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.[12]
Possible treatments includeenzyme replacement therapy andgene therapy.Bone marrow transplant has been tried for type B.[8]
In January 2009,miglustat (Zavesca) was authorized in the European Union for the treatment of progressive neurological manifestations in people with Niemann-Pick type C disease.[13][14] The medication is available to people in the United States on an experimental basis. In March 2010, the USFood and Drug Administration (FDA) requested additional pre-clinical and clinical information regarding miglustat from Actelion before making a final decision on approving it in the United States for Niemann-Pick type C disease.[15]
Olipudase alfa (Xenpozyme) was approved for medical use in Japan in March 2022.[16]
Arimoclomol (Miplyffa) was approved for medical use in the United States in September 2024.[17] It is the first medication approved by the FDA to treat Niemann-Pick Disease, Type C.[17]
Levacetylleucine (Aqneursa) was approved for medical use in the United States in September 2024.[18] Levacetylleucine is the second medication approved by the FDA for the treatment of Niemann-Pick disease type C.[18]
Highly variable, infantile neurovisceral Niemann–Pick disease (type A ASMD) is usually fatal before 3 years of age. In Type B, severity is highly variable, and many patients live well into adulthood and may reach a normal lifespan. Diagnoses have been made in the 7th decade of life.[19][20][21]
Type C is an entirely different disorder, which also has a highly variable prognosis.[citation needed]
Theincidence amongAshkenazi Jews is estimated to be about one 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 one in 250,000.[3] The incidence of Niemann–Pick disease type C is estimated to be one in 150,000.[3]
Albert Niemann published the first description of what now is 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.[22][23][24]
In 1961, the classification of Niemann–Pick disease into types A, B, and C was introduced, and also contained a type D,[25][26] 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.[3]
Research has been ongoing to better understand the disease and treatments for it, however, at present, there is no cure.[27]
The loss ofmyelin in the central nervous system is considered to be a main pathogenic factor. The research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in theNPC1 gene as seen in Niemann–Pick type C disease. In this model, the expression ofmyelin gene regulatory factor (MRF) is significantly decreased.[28] MRF is atranscription factor of critical importance in the development and maintenance ofmyelin sheaths.[29] A perturbation of oligodendrocyte maturation and the myelination process might, therefore, be an underlying mechanism of neurological deficits.[28]
Curiously, in 2011fibroblast cells derived from patients with Niemann–Pick type C1 disease were shown to be resistant toEbola virus because of mutations in the NPC1 protein, which is needed for viral escape from the vesicular compartment.[30]
Other studies have uncovered small molecules that inhibit the receptor and may be a potential therapeutic strategy.[31]
In 2014, theEuropean Medicines Agency granted orphan drug designation toarimoclomol for the treatment of Niemann–Pick type C.[32] This was followed in 2015 by theU.S. Food & Drug Administration.[33] Dosing in aplacebo-controlled phase II/IIIclinical trial to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016.[34]
Researchers at the University of Arizona first proposed the use of 2-hydroxypropyl-β-cyclodextrins for the treatment of Niemann–Pick Type C1 in 2001.[35] Researchers noted that HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage in a Niemann–Pick mouse model. Later, researchers at theUniversity of Texas Southwestern Medical Center found that when Niemann–Pick type C mice were injected with 2-hydroxypropyl-β-cyclodextrin (HPbCD) when they were seven days old, they showed marked improvement in liver function, much lessneurodegeneration, and ultimately, they lived longer lives than the mice that did not receive this treatment. These results suggest HPbCD acutely reverses the storage defect seen in NPC.[36]
In April 2011, the U.S.National Institutes of Health, in collaboration with the Therapeutics for Rare and Neglected Diseases Program,[37] announced they were developing aclinical trial using HPbCD for Niemann–Pick type C1 patients. A clinical trial conducted by Vtesse, LLC began in January 2013 and was completed in March 2017.[38]
On 26 April 2013, the European Medicines Agency granted International Niemann–Pick Disease Alliance, the United Kingdom, orphan designation for HPbCD for the treatment of Niemann–Pick disease, type C.[39]
Gene therapy is being used clinically to treat genetic diseases, includinghemophilia andspinal muscular atrophy. It has been used preclinically, in a mouse model of Niemann–Pick type C, using anadeno-associated virus-derivedviral vector, and has been shown to extend lifespan following injection into the lateralventricles of the neonatal brain.[40] In a separate proof-of-concept study, a similar vector, but with a modifiedcapsid, was injected intravenously into Niemann–Pick type C mice around four weeks of age; this resulted in extended lifespan and improved weight gain.[41] Gene therapy has also been used preclinically in a mouse model of Niemann–Pick type A. Injection into thecisterna magna at seven weeks of age prevented motor and memory impairment andneuronal cell death.[42]
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