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39-449: Niemann–Pick disease ( NP ), also known as acid sphingomyelinase deficiency , is a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. NP types A, A/B, and B are caused by mutations in the SMPD1 gene, which causes a deficiency of an acid sphingomyelinase (ASM). NP type C

78-562: A placebo-controlled phase II/III clinical trial to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016. 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. Researchers noted that HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage in

117-506: A Niemann–Pick mouse model. Later, researchers at the University 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 less neurodegeneration, and ultimately, they lived longer lives than the mice that did not receive this treatment. These results suggest HPbCD acutely reverses

156-406: A defective gene causes an enzyme deficiency. These diseases, of which there are many subtypes, are known as inborn errors of metabolism. Metabolic diseases can also occur when the liver or pancreas do not function properly. The principal classes of metabolic disorders are: Metabolic disorders can be present at birth, and many can be identified by routine screening. If a metabolic disorder

195-408: A distortion of the hip bone called coxa vara . Sleep-related disorders also occur with the condition, such as sleep inversion , sleepiness during the day and wakefulness at night. Gelastic cataplexy , the sudden loss of muscle tone when the affected patient laughs, is also seen. Mutations in the SMPD1 gene cause Niemann–Pick disease types A and B. They produce a deficiency in the activity of

234-404: A highly variable prognosis. The incidence among Ashkenazi Jews is estimated to be about one in 40,000 for type A of Niemann–Pick disease. The incidence of both Niemann–Pick disease types A and B in all other populations is estimated to be one in 250,000. The incidence of Niemann–Pick disease type C is estimated to be one in 150,000. Albert Niemann published the first description of what now

273-453: A role in metabolic disorder related obesity . Metabolic disorder screening can be done in newborns via blood , skin , or hearing tests . Metabolic disorders can be treatable by nutrition management, especially if detected early. It is important for dieticians to have knowledge of the genotype to create a treatment that will be more effective for the individual. Lipid storage disorder A lipid storage disorder (or lipidosis )

312-480: 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 both alleles of the gene, must be defective to cause

351-552: Is a carrier. There are no specific treatments for lipid storage disorders; however, there are some highly effective enzyme replacement therapies for people with type 1 Gaucher disease and some patients with type 3 Gaucher disease. There are other treatments such as the prescription of certain drugs such as phenytoin and carbamazepine to treat pain for patients with Fabry disease . Furthermore, gene therapies and bone marrow transplantation may prove to be effective for certain lipid storage disorders. Diet restrictions do not help prevent

390-418: Is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or, they produce enzymes that do not work properly. Over time, the buildup of fats may cause permanent cellular and tissue damage, particularly in

429-441: Is available mainly to treat Fabry disease and Gaucher disease and people with these types of sphingolipidoses may live well into adulthood. Generally, the other types are fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile-onset or adult-onset forms. Alternatively, some of the sphingolipidoses may be classified into either GM1 gangliosidoses or GM2 gangliosidoses . Tay–Sachs disease belongs to

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468-440: 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. In 1961, the classification of Niemann–Pick disease into types A, B, and C was introduced, and also contained a type D, 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. The composer Maurice Ravel

507-456: Is not identified early, then it may be diagnosed later in life, when symptoms appear. Specific blood and DNA tests can be done to diagnose genetic metabolic disorders. The gut microbiota , which is a population of microbes that live in the human digestive system , also has an important part in metabolism and generally has a positive function for its host. In terms of pathophysiological/mechanism interactions, an abnormal gut microbiota can play

546-480: Is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM. These disorders involve the dysfunctional metabolism of sphingolipids , which are fats found in cell membranes. They can be considered as a kind of sphingolipidosis , which is included in the larger family of lysosomal storage diseases . Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of

585-704: Is profoundly affected. Niemann–Pick disease type D (or Nova Scotia form) is now believed to be the same condition as Niemann–Pick disease type C. Two poorly characterized forms of Niemann–Pick disease have also been described as types E and F. 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. Possible treatments include enzyme replacement therapy and gene therapy . Bone marrow transplant has been tried for type B. In January 2009, miglustat (Zavesca)

624-490: Is the second medication approved by the FDA for the treatment of Niemann-Pick disease type C. 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. Type C is an entirely different disorder, which also has

663-404: The brain , peripheral nervous system , liver , spleen , and bone marrow . Inside cells under normal conditions, lysosomes convert, or metabolize, lipids and proteins into smaller components to provide energy for the body. Disorders that store this intracellular material are part of the lysosomal storage diseases family of disorders. Many lipid storage disorders can be classified into

702-473: The lysosomal enzyme acid sphingomyelinase , that breaks down the lipid sphingomyelin . Mutations in NPC1 or NPC2 cause Niemann–Pick disease, type C (NPC), which affects a protein used to transport lipids. Type D originally was 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

741-547: The NPC1 protein, which is needed for viral escape from the vesicular compartment. Other studies have uncovered small molecules which inhibit the receptor and may be a potential therapeutic strategy. In 2014, the European Medicines Agency granted orphan drug designation to arimoclomol for the treatment of Niemann–Pick type C. This was followed in 2015 by the U.S. Food & Drug Administration . Dosing in

780-481: The United Kingdom, orphan designation for HPbCD for the treatment of Niemann–Pick disease, type C. Gene therapy is being used clinically to treat genetic diseases, including haemophilia and spinal muscular atrophy . It has been used preclinically, in a mouse model of Niemann–Pick type C, using an adeno-associated virus -derived viral vector , and has been shown to extend lifespan following injection into

819-658: The United States for Niemann-Pick type C disease. Olipudase alfa (Xenpozyme) was approved for medical use in Japan in March 2022. Arimoclomol (Miplyffa) was approved for medical use in the United States in September 2024. It is the first medication approved by the FDA to treat Niemann-Pick Disease, Type C. Levacetylleucine (Aqneursa) was approved for medical use in the United States in September 2024. Levacetylleucine

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858-482: The affected gene on the X chromosome that has determined the child's gender and passes it to her son. Sons of carriers have a 50 percent chance of inheriting the disorder. Daughters have a 50 percent chance of inheriting the X-linked chromosome, but usually are not severely affected by the disorder. Affected men do not pass the disorder to their sons, but their daughters will be carriers for the disorder. Diagnosis of

897-755: The cytoplasm a foamy appearance. For type A and B, levels of sphingomylinase 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. The four types of Niemann–Pick disease are divided into categories. Patients 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

936-413: The disease. Niemann–Pick diseases are a subgroup of lipid storage disorders called sphingolipidoses 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

975-465: 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

1014-417: The disorder. Each child born to these parents have a 25 percent chance of inheriting both copies of the defective gene, a 50 percent chance of being a carrier, and a 25 percent chance of not inheriting either copy of the defective gene. Children of either gender may be affected by an autosomal recessive this pattern of inheritance. X-linked recessive (or sex linked) inheritance occurs when the mother carries

1053-524: The expression of myelin gene regulatory factor (MRF) has been shown to be significantly decreased. MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths . A perturbation of oligodendrocyte maturation and the myelination process might, therefore, be an underlying mechanism of the neurological deficits. Curiously, in 2011 fibroblast cells derived from patients with Niemann–Pick type C1 disease were shown to be resistant to Ebola virus because of mutations in

1092-446: 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

1131-527: The lateral ventricles of the neonatal brain. In a separate proof-of-concept study, a similar vector, but with a modified capsid , was injected intravenously into Niemann–Pick type C mice around four weeks of age; this resulted in extended lifespan and improved weight gain. Gene therapy has also been used preclinically in a mouse model of Niemann–Pick type A. Injection into the cisterna magna at seven weeks of age prevented motor and memory impairment and neuronal cell death. Metabolic disorders Some of

1170-402: The latter. Other lipid storage disorders that generally are not classified as sphingolipidoses include fucosidosis , Schindler disease , and Wolman disease . Lipid storage diseases can be inherited two ways: Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent show signs and symptoms of the condition and is not affected by

1209-422: 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 also may be affected, with the disease causing enlarged bone marrow cavities, thinned cortical bone , or

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1248-408: The lipid storage disorders can be achieved through the use of several tests. These tests include clinical examination, biopsy, genetic testing , molecular analysis of cells or tissues, and enzyme assays. Certain forms of this disease also can be diagnosed through urine testing, which detects the stored material. Prenatal testing also is available to determine whether the fetus will have the disease or

1287-487: 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 swallowing ( dysphagia ). Basal ganglia dysfunction causes abnormal posturing of

1326-503: The organellar membrane, 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 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

1365-712: The storage defect seen in NPC. In April 2011, the U.S. National Institutes of Health , in collaboration with the Therapeutics for Rare and Neglected Diseases Program, announced they were developing a clinical 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. On 26 April 2013, the European Medicines Agency granted International Niemann–Pick Disease Alliance,

1404-508: The subgroup of sphingolipidoses , as they relate to sphingolipid metabolism. Members of this group include Niemann-Pick disease , Fabry disease , Krabbe disease , Gaucher disease , Tay–Sachs disease , metachromatic leukodystrophy , multiple sulfatase deficiency , and Farber disease . They are generally inherited in an autosomal recessive fashion, but Fabry disease is X-linked . Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000. Enzyme replacement therapy

1443-402: The symptoms that can occur with metabolic disorders are lethargy , weight loss , jaundice and seizures . The symptoms expressed would vary with the type of metabolic disorder. There are four categories of symptoms: acute symptoms, late-onset acute symptoms, progressive general symptoms and permanent symptoms. Inherited metabolic disorders are one cause of metabolic disorders, and occur when

1482-547: Was authorized in the European Union for the treatment of progressive neurological manifestations in people with Niemann-Pick type C disease. The medication is available to people in the United States on an experimental basis. In March 2010, the US Food and Drug Administration (FDA) requested additional pre-clinical and clinical information regarding miglustat from Actelion before making a final decision on approving it in

1521-515: Was diagnosed as having Picks disease after his death in 1937. Research has been ongoing to better understand the disease and treatments for it, however at present there is no cure. The 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,

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