Materiały źródłowe

• #1 Niemann-Pick Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556129/

  Niemann-Pick disease (NPD) is a lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine. As a result, SM and its precursor lipids begin to accumulate in lysosomes, mainly in macrophages. These lipid-laden macrophages deposit in the liver, spleen, lungs, and brain causing hepatosplenomegaly, cytopenias, lung disease, and neurologic symptoms.[1] […] Niemann-Pick disease types A and B are caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, leading to a strongly decreased activity of acid sphingomyelinase (ASM). The enzyme ASM is mainly present in lysosomes and converts sphingomyelin (SM) to ceramide and phosphocholine. In ASMD, SM and its precursor lipids accumulate in lysosomes and cause cellular damage. There are over 180 mutations of the SMPD1 gene some with residual ASM activity up to 30%. Due to a dramatic reduction of the protein half-life, the condition may phenotypically be type A. Allelic heterogeneity is responsible for most of the variability in severity between types A and B. The mutations can be missense, frameshift, nonsense, and frame deletions. The predominant mutation varies by region.

• #2 The pathogenesis of Niemann-Pick type C disease: a role for autophagy?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2662713/

  Niemann-Pick type C disease (NPC) is a sphingolipid storage disorder that results from inherited deficiencies of intracellular lipid trafficking proteins, and is characterized by an accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. […] How impaired lipid trafficking leads to neurodegeneration is largely unknown. […] Recent studies have established that NPC is associated with an induction of autophagy, a regulated and evolutionarily conserved process by which cytoplasmic proteins are sequestered within autophagosomes and targeted for degradation. […] We summarize evidence showing that autophagy induction and flux are increased in NPC by signaling through the class III-PI3K/Beclin-1 complex. […] We propose that an imbalance between induction and flux through the autophagic pathway contributes to cell stress and neuronal loss in NPC and related sphingolipid storage disorders.

• #3 Niemann-Pick disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/symptoms-causes/syc-20355887

  Niemann-Pick disease is caused by changes in specific genes related to how the body breaks down and uses fats. These fats include cholesterol and lipids. The gene changes are passed from parents to children in a pattern called autosomal recessive inheritance. This means that both the mother and the father must pass on a changed gene for the child to have the condition. […] Niemann-Pick disease types A and B are both caused by changes in the SMPD1 gene. The condition is sometimes called acid sphingomyelinase deficiency (ASMD). With these gene changes, an enzyme called sphingomyelinase is missing or doesn’t work well. This enzyme is needed to break down and use lipids called sphingomyelin inside cells. A buildup of these fats causes cell damage, and over time, the cells die. […] Niemann-Pick disease type C is caused by changes in the NPC1 and NPC2 genes. With these changes, the body doesn’t have the proteins it needs to move and use cholesterol and other lipids in cells. Cholesterol and other lipids build up in the cells of the liver, spleen or lungs. Over time, the nerves and brain also are affected. This causes problems with eye movements, walking, swallowing, hearing and thinking. Symptoms vary widely, can appear at any age and get worse over time.

• #4 Sphingomyelinase Deficiency: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/951564-overview

  Niemann-Pick disease (NPD) types A and B result from genetic mutations in the SMPD1 gene, which produce a deficiency of acid sphingomyelinase (ASM) and lysosomal accumulation of sphingomyelin. […] The enzymatic defect results in the pathologic accumulation of sphingomyelin (which is a ceramide phospholipid) and other lipids in the monocyte-macrophage system, the primary site of pathology in patients with NPD. […] Progressive deposition of sphingomyelin in the central nervous system (CNS) results in the neurodegenerative course observed in NPD type A, which shares systemic disease manifestations with NPD type B. The severity of systemic involvement which includes progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia varies in affected individuals.

• #5 Niemann–Pick disease – Wikipedia

  https://en.wikipedia.org/wiki/Niemann%E2%80%93Pick_disease

  NiemannPick disease 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 is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM. […] NiemannPick 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 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 m 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.

• #6 Niemann-Pick disease pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Niemann-Pick_disease_pathophysiology

  NiemannPick 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.

• #7 Niemann-Pick disease and genetics | EBSCO Research Starters

  https://www.ebsco.com/research-starters/consumer-health/niemann-pick-disease-and-genetics

  Niemann-Pick disease is primarily caused by genetic mutations affecting the SMPD1, NPC1, and NPC2 genes, which play crucial roles in lipid metabolism. […] Niemann-Pick disease types A and B result from mutations in the SMPD1 gene, which is found on the short arm of chromosome 11 at position 11p15.4p15.1. This gene encodes a protein known as sphingomyelin phosphodiesterase 1, acid lysosomal, or more simply acid sphingomyelinase. Found in the lysosomes (cellular organelles that digest and recycle molecules), this catalyzes the conversion of sphingomyelin into ceramide (two different lipid molecules). This lipid conversion is essential for normal cell function, since its absence results in the accumulation of sphingomyelin, cholesterol, and other lipids to toxic levels. […] Inheritance of Niemann-Pick disease types A and B is quite unusual and follows a pattern known as genomic imprinting. Only the gene inherited from the mother is active; the paternal copy is permanently inactivated. Therefore the child will be healthy or affected depending upon whether the maternal gene copy is normal or mutated.

• #8 Niemann-Pick Disease, Types A and B | Hereditary Ocular Diseases

  https://disorders.eyes.arizona.edu/disorders/niemann-pick-disease-types-and-b

  Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration. […] This is an autosomal recessive neurodegenerative disorder resulting from homozygous mutations in SMPD1 (11p15.4-p15.1) encoding sphingomyelin phosphodiesterase-1. […] Such parent-specific gene activation is called gene imprinting. […] Types A and B are allelic disorders. […] Niemann-Pick diseases designated types C1 and D (257220) are caused by mutations in the NPC1 gene (18q11-q12) and type C2 (607625) from mutations in the NPC2 gene (14q24.3).

• #9 Niemann-Pick Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556129/

  Niemann-Pick disease type C (NPC) is further classified as type C1 or type C2 based on the pathogenic mutations in the NPC1 or NPC2 genes, respectively. NPC1 is the predominant subtype affecting about 95% of the patient population with over 30 different sequence alterations detected. NPC1 and NPC2 proteins are present in late endosomes and lysosomes and are involved in the transport and intracellular mobilization of cholesterol and sterols. The loss of function of NPC1 and/or NPC2 proteins blocks cholesterol egress from lysosomes, resulting in an excessive build-up of cholesterol in lysosomes. Consequently, toxic cholesterol accumulation results in cellular and organ damage.[5][6]

• #10 Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-16

  Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. […] NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. […] Mutations in either of the two genes, NPC1 or NPC2, may cause the disease. Approximately 95% of patients have mutations in the NPC1 gene, which encodes a large membrane glycoprotein with mostly a late endosomal localization. The remainder have mutations in the NPC2 gene, which encodes a small soluble lysosomal protein that binds cholesterol with high affinity. Mutations in the NPC1 or NPC2 genes result in a similar cellular lesion, including a unique impairment in processing and utilization of endocytosed cholesterol that could explain cholesterol storage and secondary alterations of sphingomyelin metabolism in extra neural tissues.

• #11 Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine | npj Genomic Medicine

  https://www.nature.com/articles/s41525-023-00365-w

  Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. […] The biological factors accounting for the broad phenotypic spectrum of LSDs, including the different ages of symptoms onset, rates of disease progressions, severity, degrees of organ involvement, and response to the pharmacological treatments, remain poorly studied. […] NPC disease is a progressive neurovisceral autosomal recessive LSD caused by loss of function variants in the NPC1 or NPC2 genes. […] NPC1 is a highly glycosylated protein of 1278 amino acids located in late endosomes and lysosomes (LE/Lys). […] Cholesterol and sphingomyelin are the major lipids stored in peripheral tissues.

• #12 Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-16

  Initial studies by Peter Pentchev and associates and further work from several laboratories demonstrated, in cultured skin fibroblasts of Niemann-Pick C disease patients, a disruption in intracellular transport of endocytosed cholesterol. Endocytosed low density lipoproteins are delivered to late endosomes/lysosomes, where they are hydrolyzed, so that free cholesterol is released. In normal cells, this cholesterol is transported rapidly out of endosomes to the plasma membrane and the endoplasmic reticulum. In Niemann-Pick C disease cells (either NPC1 or NPC2), the cholesterol does not exit the endocytic pathway but accumulates within lysosomes. This anomaly constitutes the cellular hallmark of the disease. […] This unique impairment in processing and utilization of endocytosed cholesterol obviously plays a key role in the pathogenesis of Niemann-Pick C disease, and, at least in extraneural organs, could actually explain a more general dysfunction of intracellular metabolism of lipids. […] The pathogenesis of the neuronal dysfunction appears by far more complex, since brain cholesterol is synthesized locally, mostly by oligodendroglial cells and to a lesser extent by astrocytes and neurons.

• #13 Niemann–Pick disease type C – Wikipedia

  https://en.wikipedia.org/wiki/Niemann%E2%80%93Pick_disease_type_C

  NiemannPick type C is biochemically, genetically and clinically distinct from NiemannPick Types A or B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In NiemannPick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes. […] Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In NiemannPick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.

• #14 Niemann-Pick Disease And Lipid Metabolism: The Role Of Lipid Accumulation In The Pathogenesis Of The Disease – Klarity Health Library

  https://my.klarity.health/niemann-pick-disease-and-lipid-metabolism-the-role-of-lipid-accumulation-in-the-pathogenesis-of-the-disease/

  The accumulation of sphingomyelin disrupts cellular membranes and impairs the function of lysosomes, which are critical for degrading and recycling cellular components. This lysosomal dysfunction triggers a cascade of pathological events, including inflammation, oxidative stress, and cell death, which contribute to the clinical manifestations of the disease. […] Mutations in NPC1 or NPC2 disrupt this transport process, leading to the accumulation of unesterified cholesterol (free cholesterol) and other lipids within lysosomes. This accumulation interferes with the normal trafficking and distribution of lipids, causing secondary storage of sphingolipids, glycosphingolipids, and other lipids. The resultant lipid storage leads to lysosomal dysfunction, altered cellular signalling, and impaired autophagy, contributing to cellular damage and neurodegeneration. […] Understanding the intricate relationship between lipid metabolism and Niemann-Pick disease pathogenesis is essential for developing effective treatments and improving the lives of those affected by this challenging condition.

• #15 Niemann–Pick disease type C – Wikipedia

  https://en.wikipedia.org/wiki/Niemann%E2%80%93Pick_disease_type_C

  Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein. Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network. Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form. Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1. Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation.

• #16 The pathogenesis of Niemann–Pick type C disease: a role for autophagy? | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/pathogenesis-of-niemannpick-type-c-disease-a-role-for-autophagy/982E3560C95F0B5E63FC9A535D9D32DE

  NiemannPick type C disease (NPC) is a sphingolipid-storage disorder that results from inherited deficiencies of intracellular lipid-trafficking proteins, and is characterised by an accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. […] How impaired lipid trafficking leads to neurodegeneration is largely unknown. […] Recent studies have established that NPC is associated with an induction of autophagy, a regulated and evolutionarily conserved process by which cytoplasmic proteins are sequestered within autophagosomes and targeted for degradation. […] We summarise evidence showing that autophagy induction and flux are increased in NPC by signalling through a complex of the class III phosphoinositide 3-kinase and beclin-1. […] We propose that an imbalance between induction and flux through the autophagic pathway contributes to cell stress and neuronal loss in NPC and related sphingolipid-storage disorders.

• #17 The pathogenesis of Niemann-Pick type C disease: a role for autophagy?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2662713/

  The induction of autophagy in NPC1 deficiency is not mediated by signaling through the Akt-mTor-p70 S6K pathway, but rather by the class III-PI3K/Beclin-1 complex. […] While NPC1 deficiency is characterized by elevated induction and flux through the autophagic pathway, ubiquitinated proteins accumulate in the mutant mouse brain. […] The paradoxical accumulation of ubiquitinated proteins in the setting of increased autophagic degradation suggests that flux though this pathway is not sufficient to handle the quantity of proteins targeted for degradation. […] Disproportionate induction and flux through the autophagic pathway can lead to cell stress (so-called autophagic stress) and may trigger cell death, with dire consequences for NPC patients.

• #18 Restarting stalled autophagy a potential approach to treating Niemann-Pick disease | Whitehead Institute

  https://wi.mit.edu/news/restarting-stalled-autophagy-potential-approach-treating-niemann-pick-disease

  CAMBRIDGE, Mass. Whitehead Institute researchers have determined that the lipid storage disorder Niemann-Pick type C1 (NPC1) disease is caused not only by defects in cholesterol processing but also in autophagy a key cellular degradation pathway that malfunctions in many neurodegenerative diseases. Targeting both the cholesterol accumulation and stalled autophagy found in NPC1 with combination therapy could represent a viable treatment strategy. […] Our research indicates that if you improve autophagy, you can somewhat improve the phenotype. […] the research conducted at Whitehead reveals for the first time that impaired autophagy in the cells of NPC1 patients is contributing to disease pathology. […] Whitehead researchers observed that cells of mice carrying a mutated copy of the human NPC1 gene not only had the characteristic cholesterol accumulations seen in patients, but also abnormalities in the autophagosomes necessary for non-starvation (basal) autophagy. The conclusion: that in NPC1, autophagy is interrupted, causing the process to stall and certain intermediary products of autophagy, including autophagosomes, to amass.

• #19 Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine | npj Genomic Medicine

  https://www.nature.com/articles/s41525-023-00365-w

  The accumulation of unesterified cholesterol in peripheral tissues (mainly in the liver and the spleen) is associated with the infiltration of activated macrophages, which leads to the production of proinflammatory cytokines and plays a critical role in cell death. […] The buildup of gangliosides in the CNS causes structural and functional damage to neurons, particularly in the cerebellar Purkinje neurons, triggering the characteristic motor dysfunction observed in the disease. […] The dysfunction of non-neuronal cells in the brain, such as microglia and astrocytes, also contributes to neurodegeneration. […] The presence of substantial phenotypic variability among familial NPC cases suggests a contribution from various factors such as epigenetic variations, post-zygotic mutagenesis, modifier genes, or environmental influences.

• #20 Niemann–Pick disease – Wikipedia

  https://en.wikipedia.org/wiki/Niemann%E2%80%93Pick_disease

  The loss of myelin in the central nervous system is considered to be a main pathogenic factor. The research uses animal models carrying the underlying mutation for NiemannPick disease, e.g. a mutation in the NPC1 gene as seen in NiemannPick type C disease. In this model, the expression of myelin gene regulatory factor (MRF) is 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 neurological deficits.

• #21 Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment – touchNEUROLOGY

  https://touchneurology.com/alzheimers-disease-dementia/journal-articles/niemann-pick-type-c-disease-pathophysiology-and-future-perspectives-for-treatment/

  For example, cholesterol synthesis is increased in the liver in NPC disease, apparently in response to lack of cholesterol egress from the late endosomal/lysosomal system. […] Cellular accumulation of these unmetabolized products is manifested as polymembranous cytoplasmic bodies, a common hallmark of NPC disease. […] The impact of axonal spheroids on the normal function of neurons is not well understood, but it is likely that these focal swellings interfere with both transport of materials between the cell body and axon terminals and with propagation of action potentials. […] Neurofibrillary tangles (NFTs), which consist of paired helical filaments and are a hallmark of Alzheimers disease (AD) and other tauopathies, are also routinely observed in NPC disease. […] Since there is evidence indicating that disruption of the ubiquitin-proteasome system (UPS) may be involved in altered protein degradation leading to NFTs and Lewy body formation, the presence of these two pathologies suggests that compromise of UPS function, in addition to the well-known endosomal/lysosomal abnormalities, may be occurring in NPC disease.

• #22 Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment – touchNEUROLOGY

  https://touchneurology.com/alzheimers-disease-dementia/journal-articles/niemann-pick-type-c-disease-pathophysiology-and-future-perspectives-for-treatment/

  NPC disease is known to have a prominent neuro-inflammatory component, similar to many other neurodegenerative diseases. […] Although many neurons are able to survive the above myriad morphological changes and cellular insults for years, neurodegeneration does occur in NPC disease, the most notable example being the patterned cell death of PCs in the cerebellum. […] The biochemical changes caused by defective NPC1 or NPC2 proteins lead to massive intracellular accumulation of cholesterol and GSLs, adversely affecting many cells of the body.

• #23 Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine | npj Genomic Medicine

  https://www.nature.com/articles/s41525-023-00365-w

  The term modifier gene refers to a locus where DNA sequence variation changes the phenotypes typically linked to target genes that act independently. […] Variations in modifier genes and pathways may explain why some patients with the same NPC1 mutation exhibit heterogeneous phenotypes and disease progression. […] The primary molecular mechanism responsible for NPC symptomatology is the intra-lysosomal buildup of cholesterol and GSLs. […] Several NPC mouse models have been described in different genetic backgrounds. […] The results of the studies performed so far lead to the general conclusion that NPC phenotypic expression can be modified by many factors, which include, but are probably not limited to, such as the level of residual function of the defective protein, genetic background, sex, environment, and splicing factors.

• #24 Overview of acid sphingomyelinase deficiency and Niemann-Pick disease type C – UpToDate

  https://www.uptodate.com/contents/overview-of-acid-sphingomyelinase-deficiency-and-niemann-pick-disease-type-c

  Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick disease type C (NPC) are autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of lipids including sphingomyelin and cholesterol. […] Niemann-Pick disease type C (NPC) is caused by pathogenic variants of the NPC1 and NPC2 genes that result in impaired cellular processing and transport of low-density lipoprotein (LDL) cholesterol and other macromolecules, including glycosphingolipids.

• #25 KEGG DISEASE: Niemann-Pick disease type A/B

  https://www.genome.jp/dbget-bin/www_bget?ds:H00137

  Niemann-Pick disease (NPD) is an autosomal recessive lysosomal storage disorder caused by deficient acid sphingomyelinase (ASM) activity, resulting in accumulation of sphingomyelin and cholesterol in many organs. […] ASM plays an important role in normal membrane turnover and is one of the key enzymes responsible for the production of ceramide. […] The different clinical presentations of Types A and B NPD are likely due to small differences in the amount of residual, functional ASM activity. […] The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. […] Acid sphingomyelinase, cell membranes and human disease: lessons from Niemann-Pick disease.

• #26 Niemann-Pick Disease: Causes, Symptoms & Diagnosis

  https://www.healthline.com/health/niemann-pick-disease

  Niemann-Pick disease is an inherited disease that affects lipid metabolism, or the way fats, lipids, and cholesterol are stored in or removed from your body. […] People with Niemann-Pick disease have an abnormal lipid metabolism that causes a buildup of harmful amounts of lipids in various organs. […] Types A and B occur when acid sphingomyelinase (ASM) isn’t properly produced in the white blood cells. ASM is an enzyme that helps remove fats in all the cells of your body. […] Sphingomyelin, the fat that ASM removes, can build up in your cells when ASM isn’t properly breaking it down. […] Type C is primarily concerned with the body’s inability to efficiently remove excess cholesterol and other lipids. […] Without the proper breakdown, cholesterol builds up in the spleen and liver and excessive amounts of other fats accumulate in the brain. […] The formerly-called type D occurs when the body cannot properly move cholesterol between cells of the brain.

• #27 Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010007

  PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. […] The results indicate that PC loss in npc1/ mutants is a cell-autonomous process, i.e., Npc1 function is critical within PCs. […] Ultrastructural and biochemical analyses support the idea that this cell-autonomous loss is due to the activation of a particular genetic program, autophagy, that leads to cell death. […] The decline in neurological function in NPC patients is caused by mutations in either the npc1 or npc2 gene. […] The exact role of Npc1 in regulating lipid homeostasis and in maintaining neurological function is far from clear. […] Four broad categories of possible explanations for the PC degeneration have emerged. […] Npc1 is required within PCs and loss of the protein results in degeneration as a consequence of the toxic accumulation of lipids.

• #28 Niemann Pick Disease – Rivin | PPT

  https://www.slideshare.net/RivinduWickramanayake/niemann-pick-disease-rivin

  A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine. […] As a result, SM and its precursor lipids begin to accumulate in lysosomes, mainly in macrophages. These lipid-laden macrophages deposit in the liver, spleen, lungs, and brain causing hepatosplenomegaly, cytopenias, lung disease, and neurologic symptoms. […] Type A is known as infantile neurovisceral form with very low acid sphingomyelinase (ASM) activity is usually fatal before the age of three. […] Type B is less severe and is characterized by variable visceral symptoms and minimal neurological involvement. […] NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. […] The mutations in these genes lead to abnormal or defective formation of proteins, which impair the movement of lipids out of the cells, leading to their accumulation within the cells.

• #29 Niemann-Pick Disease | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/niemann-pick-disease

  In 1914 Albert Niemann, a German pediatrician who primarily studied infant metabolism, published a description of an Ashkenazi Jewish infant with jaundice, nervous system and brain impairments, swollen lymph nodes (lymphadenopathy), and an enlarged liver and spleen (hepatosplenomegaly). […] After extensively studying the abnormal characteristics of the infant, Niemann came to the conclusion that the disease was a variant of Gauchers disease. […] In contrast, Niemann and Picks patients presented a buildup of sphingomyelins, composed of sphingosine, choline, a fatty acid, and a phosphoric acid. […] From this point on, dysfunctional sphingomyelin storage was called Niemann-Pick disease (NPD) and is understood as a developmental disease. […] NPD type A, an acute neuronopathic form, is characterized by a deficiency of acid sphingomyelinase, an enzyme responsible for breaking down sphingomyelin into its derivatives.

• #30 Morbidity and mortality in type B Niemann–Pick disease | Genetics in Medicine

  https://www.nature.com/articles/gim20134

  Serious morbidities included significant neurological, hepatic, and cardiac disease. […] This study demonstrates that NiemannPick disease is a life-threatening disorder with significant morbidity and mortality, especially in the pediatric population. […] Given these findings and the observations noted in the patient population reported here, it is reasonable to conclude that liver disease is a significant cause of morbidity and mortality in NP-B. […] Cardiac disease included valvular heart disease as well as coronary artery disease. […] The pathophysiology of the pulmonary disease is presumably related to the accumulation of sphingomyelin in the alveolar macrophages, although studies in the ASM knockout mouse also have shown that inflammation, abnormal surfactant catabolism, and abnormal surfactant composition all contribute to lung abnormalities. […] In conclusion, this study demonstrates that NP-B is a life-threatening disorder associated with significant morbidity and mortality, especially in the pediatric population.

• #31 Niemann Pick Disease

  https://www.brainfacts.org/diseases-and-disorders/neurological-disorders-az/diseases-a-to-z-from-ninds/niemann-pick-disease

  Niemann-Pick disease (NP) refers to a group of inherited metabolic disorders known as lipid storage diseases. In Niemann-Pick disease, harmful quantities of lipids accumulate in the brain, spleen, liver, lungs, and bone marrow. In types A and B, insufficient activity of an enzyme called sphingomyelinase causes the build up of toxic amounts of sphingomyelin, a fatty substance present in every cell of the body. Type C may appear early in life or develop in the teen or adult years. It is caused by a lack of the NPC1 or NPC2 proteins. […] NINDS scientists are studying the mechanisms by which lipids accumulating in these storage diseases causes harm to the body.

• #32 Niemann Pick Disease – Rivin | PPT

  https://www.slideshare.net/RivinduWickramanayake/niemann-pick-disease-rivin

  The prognosis depends on the time of the initial presentation. […] Niemann-Pick disease is a progressive disease, and quite often, complications develop with time. […] Deterioration of lungs can result in respiratory insufficiency. […] Progressive neurodegeneration can cause dementia, seizures, and schizophrenia-like psychosis. […] Severe thrombocytopenia can result in internal or external bleeding.

• #33 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  The discovery of disease-specific biomarkers cholestane-3,5,6-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)] has led to development of non-invasive, blood-based diagnostics. […] A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy. […] The only approved drug for treatment of NPC is the glycosphingolipid synthesis inhibitor miglustat. […] The relatively modest disease-modifying effects of miglustat have prompted further drug development to address the unmet clinical needs. […] The insistence by regulatory bodies on a well-controlled trial, the lack of a validated, clinical endpoint accepted by regulators, and the rarity of the disease all contribute to the infeasibility of conducting a trial of shorter than 4-5 years duration. […] Thus, there is an urgent need for new biomarkers that could serve as surrogate endpoints to accelerate drug approval.

• #34 Niemann-Pick Disease Type C (NPC) – Rare Awareness Rare Education

  https://rareportal.org.au/rare-disease/niemann-pick-disease-type-c-npc/

  Diagnosis of Niemann-Pick disease type C (NPC) is made through biomarker profiling to look for increased levels of oxidised cholesterol products (oxysterols) and lyso-sphingolipids in the blood plasma, as well as bile acids in the blood plasma and urine, and genetic testing (for mutations in the NPC1 or NPC2 gene).

• #35 IntraBio Reports Positive Data from IB1001 Multinational Clinical Trial for the Treatment of Niemann-Pick disease Type C – IntraBio

  https://intrabio.com/news/intrabio-reports-positive-data-from-ib1001-multinational-clinical-trial-for-the-treatment-of-niemann-pick-disease-type-c/

  About Niemann-Pick disease Type C Niemann-Pick disease Type C (NPC) is a rare (1:120,000 live births), prematurely fatal, autosomal recessive, lysosomal storage disorder. The disease begins in early childhood and presents with systemic, psychiatric, and neurological symptoms, including cerebellar ataxia. NPC is chronic and progressive in nature and is characterized by rapid degeneration of the cerebellum and major organ systems which severely impacts the quality of life. There is no approved treatment for NPC in the United States. Treatment of NPC in the European Union and several other countries is limited to substrate reduction therapy drug miglustat (Zavesca™).

• #36 Niemann-Pick Disease

  https://lysosomalcenter.org/index.php/for-patients/disorders/niemann-pick-disease

  Niemann-Pick disease types A and B are part of a group of lysosomal storage disorders that affect the body’s ability to metabolize lipids (fats) properly. […] These conditions are caused by mutations in the SMPD1 gene, which leads to a deficiency in the enzyme acid sphingomyelinase. This deficiency results in the accumulation of sphingomyelin and other lipids in various organs of the body, leading to the symptoms and complications of the disease. […] Treatment has been supportive, focusing on symptom management, until the introduction of Xenpozyme (olipudase alfa) in August 2022. Xenpozyme (olipudase alfa), the first enzyme replacement therapy approved specifically for Niemann-Pick disease type B, addresses the enzyme deficiency at the disease’s root. […] Administered bi-weekly via intravenous infusion, Xenpozyme has shown efficacy in reducing spleen and liver size, improving lung function, and normalizing blood lipid levels in clinical trials.

• #37 Niemann-Pick Disease | Causes, signs, symptoms & treatment

  https://cpdonline.co.uk/knowledge-base/care/niemann-pick-disease/

  Niemann-Pick types A and B occur due to inheriting a faulty gene mutation of the SMPD1 gene. This causes a decreased level of a substance called acid sphingomyelinase, or ASM. This is an enzyme that is present in cell lysosomes. It converts a substance called sphingomyelin (SM) into phosphocholine and ceramide. The accumulation of SM causes damage to the cells. In total, there are around 180 different SMPD1 genetic mutations that affect ASM activity. […] In May 2022, the European Medicines Agency (EMA) recommended to the EU to grant marketing authorisation for Xenpozyme. This is a treatment for those with types A and B. This is the first specific treatment and is an enzyme replacement therapy. It is designed to replace the defective or deficient enzyme ASM so as to reduce the accumulation of fat within cells and relieve disease symptoms. This would be administered every two weeks intravenously.

• #38 Restarting stalled autophagy a potential approach to treating Niemann-Pick disease | Whitehead Institute

  https://wi.mit.edu/news/restarting-stalled-autophagy-potential-approach-treating-niemann-pick-disease

  This dual treatment may have more benefits in patients than using HP-beta-cyclodextrin alone, says Sovan Sarkar, a postdoctoral researcher in Jaenischs lab and the lead author of the Cell Reports article. […] Since rapamycin and other drugs that inhibit the metabolic mTOR pathway can possibly have side-effects pertaining to suppression of mTORs critical cellular functions, were suggesting that we need to stimulate autophagy, ideally by mTOR-independent autophagy activators, and remove cholesterol as a treatment strategy. […] Sarkar and others in the Jaenisch lab are currently searching for other potential therapeutics that correct the faulty mechanisms in NPC1. Such drugs may remedy the autophagy issues identified in other neurodegenerative and lipid/lysosomal storage diseases.

• #39 Niemann-Pick Disease – Focused Ultrasound Foundation

  https://www.fusfoundation.org/diseases-and-conditions/niemann-pick-disease/

  Focused ultrasound is a noninvasive, therapeutic technology with the potential to improve the quality of life and decrease the cost of care for patients with Niemann-Pick Disease. […] Patients with Niemann-Pick disease lack certain enzymes for the metabolism of fat. Where the focused ultrasound beams converge, transient opening of the blood-brain barrier (BBB) can allow enhanced penetration into the central nervous system of a synthetic replacement enzyme. […] Another area being explored is using focused ultrasound for transient BBB opening to allow modified RNA penetration into the central nervous system, enabling production of the needed enzyme. Preclinical research for both of these mechanisms is being evaluated.

• #40 IntraBio Reports Positive Data from IB1001 Multinational Clinical Trial for the Treatment of Niemann-Pick disease Type C – IntraBio

  https://intrabio.com/news/intrabio-reports-positive-data-from-ib1001-multinational-clinical-trial-for-the-treatment-of-niemann-pick-disease-type-c/

  IB1001, N-acetyl-L-leucine, is an orally administered modified amino acid. In vivo studies have identified N-acetyl-L-leucine to be the active isomer of N-acetyl-DL-leucine and can restore neuronal function and protect against/delay disease progression in multiple neurological circuits of the brain. The mechanism of N-acetyl-L-leucine is known to be multi-modal, including altered glucose and antioxidant metabolism, reduced lysosomal storage, and the reduction of neuroinflammation in the cerebellum, leading to the attenuation of cell death. […] Professor Antony Galione, FRS, FMedSci, Statutory Professor of Pharmacology, University of Oxford commented, “We are particularly excited from what we know from in vitro and in vivo studies into the cellular mechanisms that this drug has the potential to ameliorate not only rare genetic neurological diseases like NPC, but also some of the more common neurodegenerative diseases prevalent in society with large unmet medical needs.”

• #41

  https://omim.org/entry/257220

  Acyl-CoA:cholesterol acyltransferase activity was also normal in type C cell extracts. […] Fluorescent microscopy showed that type C cells grown in fetal calf serum stored much unesterified cholesterol. […] The partial expression of the esterification defect (50% of normal) in heterozygous mice indicated that it is the primary fault. […] Kruth et al. (1986) and Pentchev et al. (1986) discussed the abnormality of cholesterol metabolism in this disorder. […] In both heterozygous and homozygous type C Niemann-Pick fibroblasts, excessive uptake of LDL cholesterol and deficient esterification of the internalized cholesterol were observed. […] As reported by Pentchev et al. (1985), Liscum and Faust (1987) found that LDL does not stimulate cholesterol esterification in this disorder; however, they also showed that LDL does not down-regulate cholesterol synthesis or LDL receptor activity normally.

• #42

  https://omim.org/entry/257220

  They suggested that the intracellular processing of LDL-derived cholesterol may be defective in NPC fibroblasts. […] This suggestion was corroborated by the findings of Sokol et al. (1988), who examined the intracellular accumulation of unesterified cholesterol in normal and Niemann-Pick C fibroblasts. […] They found that the plasma membrane cholesterol of normal cells was more readily replenished by internalized LDL cholesterol than that of mutant fibroblasts. […] Their studies suggested that deficient translocation of exogenously derived cholesterol from lysosomes to other intracellular membrane sites may have an important pathophysiologic role in type C Niemann-Pick disease. […] Vanier et al. (1988) demonstrated that cultured homozygous NPC cells challenged with pure human low-density lipoproteins showed a pronounced deficiency in cholesterol esterification and that heterozygotes showed intermediate rates of esterification.

• #43

  https://omim.org/entry/257220

  All other pathologic conditions studied, including types A and B Niemann-Pick disease, gave normal results. […] There appeared to be a correlation between the clinical phenotype and severity of the biochemical lesion. […] Blanchette-Mackie et al. (1988) showed that incubation of fibroblasts from patients with type C Niemann-Pick disease with low density lipoprotein resulted in excessive intracellular accumulation of unesterified cholesterol not only in lysosomes but also at an early stage in the Golgi complex. […] They suggested that the Golgi complex may play a role in the intracellular translocation of exogenously derived cholesterol and that disruptions of the cholesterol transport pathway at the Golgi may, in part, be responsible for the deficiency in cholesterol utilization in this disorder.

• #44

  https://omim.org/entry/257220

  Lloyd-Evans et al. (2008) found that lysosomal sphingosine storage and reduced lysosomal calcium levels were early events in development of the NPC phenotype in normal human cells exposed to the NPC-inducing drug U18666A. […] In this model, accumulation of cholesterol, sphingomyelin, and glycerosphingolipid was a secondary event. […] Pharmacologic elevation of cytosolic calcium or reduction of sphingosine content reversed the NPC phenotype in several cellular models of NPC, and sphingosine alone induced the abnormal calcium phenotype in a concentration-dependent manner. […] Treatment of Npc1 -/- mice with curcumin, a weak SERCA (see 108730) antagonist that elevates cytosolic calcium levels, increased life expectancy by 35% and slowed the rate of disease progression by 3 weeks. […] Lloyd-Evans et al. (2008) concluded that NPC1 is involved in sphingosine efflux from lysosomes, and that lysosomal sphingosine accumulation in NPC alters intracellular calcium concentration and causes abnormal endocytic trafficking.

• #45 Niemann-Pick disease type C symptomatology: an expert-based clinical description | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-166

  In fact, impaired swallowing is associated with aspiration pneumonia, the most common cause of death in neurodegenerative disease including NP-C. […] Despite increasing research in the field, open questions remain regarding the exact function of NPC1 and NPC2 proteins, as well as the precise role of sphingosine and other lipids in the pathogenesis of NP-C. […] As such, further investigations are required to elucidate the biochemical and cellular mechanisms leading to the disease, in order to design new targeted therapies.

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