Materiały źródłowe

• #1 Niemann–Pick disease – Wikipedia

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

  NiemannPick disease is inherited in an autosomal recessive pattern, which means both copies or both 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 and genetic testing are recommended for families who may be carriers of the disease.

• #2 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  All types of Niemann-Pick are autosomal recessive. This means that both parents are carriers. Each parent has one copy of the variant gene without having any signs of the disease themselves. […] When both parents are carriers, there is a 25% chance that their child will have the disease and a 50% chance that their child will be a carrier. […] Carrier detection testing is only possible if the genetic defect is identified. The defects involved in types A and B have been well-studied. DNA tests for these forms of Niemann-Pick are available. […] Genetic defects have been identified in the DNA of many people with type C. It may be possible to diagnose people who carry the abnormal gene.

• #3 Niemann-Pick Disease – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hereditary-metabolic-disorders/niemann-pick-disease

  Niemann-Pick disease is type of lysosomal storage disorder. Types A and B are sphingolipidoses and are caused by a buildup of sphingomyelin in the tissues. Type C is a lipidosis that is caused by a build up of cholesterol and other fats (lipids) in the cells. […] Niemann-Pick disease occurs when parents pass on to their children the defective genes that cause this disease. […] Niemann-Pick disease types A and B occur when the body lacks enzymes needed to break down sphingomyelin. […] Niemann-Pick disease type C occurs when the body is not able to break down cholesterol and other lipids. […] In Niemann-Pick disease, both parents of the affected child carry 1 copy of the abnormal gene. Because usually 2 copies of the abnormal (recessive) gene are necessary for the disorder to occur, usually neither parent has the disorder.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

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

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

  Niemann-Pick disease (NPD) types A and B result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene, located on bands 11p15.1-11p15.4. […] To date, more than 180 mutations have been described. […] Various types of mutations have been reported, including, most frequently, missense mutations (65.3%), with others including frameshift mutations (19%), nonsense mutations (7%), frame deletions, intronic variants, mutant alleles, duplication, and indel mutations. […] Frameshift mutations usually result in little or no enzyme activity and typically produce the type A phenotype. […] With missense mutations, significant residual activity is retained, so such mutations are related to the type B phenotype. […] The complete sphingomyelinase genomic region has been isolated and sequenced.

• #6 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. […] Type C1 disease is caused by mutations in the NPC1 gene (at position 18q11.2), while type C2 disease results from mutations in the NPC2 gene, located on the long arm of chromosome 14 (at position 14q24.3). […] Niemann-Pick type C disease is inherited in a classic autosomal recessive pattern, which means that both copies of the NPC1 or NPC2 gene must be deficient in order for the individual to be afflicted.

• #7 Niemann-Pick Disease | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4591

  Niemann-Pick disease types A and B is caused by mutations in the SMPD1 gene. This gene provides instructions for producing an enzyme called acid sphingomyelinase. This enzyme is found in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Acid sphingomyelinase is responsible for the conversion of a fat (lipid) called sphingomyelin into another type of lipid called ceramide. Mutations in SMPD1 lead to a shortage of acid sphingomyelinase, which results in reduced break down of sphingomyelin, causing this fat to accumulate in cells. This fat buildup causes cells to malfunction and eventually die. Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A and B.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

• #9 What is Acid Sphingomyelinase Deficiency (ASMD)

  https://www.asmdfacts.com/what-is-asmd

  ASMD is an inherited condition caused by genetic variants (changes in your genes). […] The gene involved in ASMD is called SMPD1. […] In people with ASMD, the body is unable to make enough of the ASM enzyme. […] Without regular levels of ASM, sphingomyelin cannot be broken down efficiently, and instead builds up in major organs such as the liver, lungs, and spleen. […] Low ASM enzyme activity from ASMD leads to buildup of sphingomyelin in cells of the body, causing symptoms and potential damage to multiple organs. […] Over time, the buildup of sphingomyelin can result in serious health consequences including organ damage.

• #10 Niemann-Pick disease // Middlesex Health

  https://middlesexhealth.org/learning-center/diseases-and-conditions/niemann-pick-disease

  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 (sfing-go-MY-uh-lin-ase) 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.

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

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

  Niemann-Pick disease (NPD) types A and B result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene, located on bands 11p15.1-11p15.4. […] To date, more than 180 mutations have been described. […] Various types of mutations have been reported, including, most frequently, missense mutations (65.3%), with others including frameshift mutations (19%), nonsense mutations (7%), frame deletions, intronic variants, mutant alleles, duplication, and indel mutations. […] Frameshift mutations usually result in little or no enzyme activity and typically produce the type A phenotype. […] With missense mutations, significant residual activity is retained, so such mutations are related to the type B phenotype. […] The complete sphingomyelinase genomic region has been isolated and sequenced.

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

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

  Niemann-Pick disease (NPD) types A and B result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene, located on bands 11p15.1-11p15.4. […] To date, more than 180 mutations have been described. […] Various types of mutations have been reported, including, most frequently, missense mutations (65.3%), with others including frameshift mutations (19%), nonsense mutations (7%), frame deletions, intronic variants, mutant alleles, duplication, and indel mutations. […] Frameshift mutations usually result in little or no enzyme activity and typically produce the type A phenotype. […] With missense mutations, significant residual activity is retained, so such mutations are related to the type B phenotype. […] The complete sphingomyelinase genomic region has been isolated and sequenced.

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

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

  Three common mutation variants (p.R498L, p.L304P, p.P333Sfs*52) are associated with NPD type A. […] The delta-R608 mutation is a common mutation that results in NPD type B. […] In addition, p.P323A, p.P330R, and p.W393G variants are associated with NPD type B. […] Mutation variants p.Q294K and p.W393G are associated with an intermediate phenotype. […] Regional distribution of mutations causing NPD varies. […] SMPD1 gene defects have also been reported as strong risk factors for Parkinson disease, with variants p.L304P and p.R591C having particularly been associated with such risk in the Ashkenazi Jewish and Chinese populations.

• #14 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. […] Type C1 disease is caused by mutations in the NPC1 gene (at position 18q11.2), while type C2 disease results from mutations in the NPC2 gene, located on the long arm of chromosome 14 (at position 14q24.3). […] Niemann-Pick type C disease is inherited in a classic autosomal recessive pattern, which means that both copies of the NPC1 or NPC2 gene must be deficient in order for the individual to be afflicted.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

• #16 Invitae Niemann-Pick Disease Type C Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06176

  Niemann-Pick disease, type C (NPC), is a lipid storage disorder. Biallelic variants in either of the two genes result in the same clinical disease. […] NPC is due not to an enzymatic defect, but rather to a disorder of intracellular lipid trafficking. […] Of individuals with a clinical diagnosis of NPC, 95% will have two pathogenic variants in NPC1 and approximately 4% will have biallelic pathogenic variants in NPC2. Less than 1% of cases with clinical and biochemical findings will have pathogenic variants in neither NPC1 or NPC2.

• #17 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 disease 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. […] 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.

• #18 Niemann-Pick disease type C1 | Myriad Foresight® Carrier Screen

  https://myriad.com/womens-health/diseases/niemann-pick-disease-type-c1/

  Niemann-Pick disease type C can be caused by mutations in two different genes. Type C1 is caused by mutations in the NPC1 gene, and type C2 is caused by mutations in the NPC2 gene. […] Of the known cases of Niemann-Pick disease type C, 95% have been type C1 and 5% have been C2.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

• #20 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  More than 400 mutations in the NPC1 gene have been identified. […] The authors predicted that severe mutations, whether in the homozygous form or the compound heterozygous form, result in a severe phenotype. Because the present patient presented with a severe phenotype, the two novel mutations (c.1145CG [p.Ser382*] and c.2231_2233del [p.Val744del]) in this patient are likely to be severe mutations. […] NPC must be considered in infants who present with neonatal cholestasis. In addition, the neonatal cholestasis gene panel may be crucial in the diagnostic process.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  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.

• #22 Niemann–Pick disease type C – Wikipedia

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

  NiemannPick disease, type C is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. […] Approximately 95% of NiemannPick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2. […] The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes. […] The NPC2 gene encodes a protein that binds and transports cholesterol. It has been shown to closely interact with NPC1. […] 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 disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes. […] Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  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.

• #24 Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium | Nature Medicine

  https://www.nature.com/articles/nm.1876

  Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. […] The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. […] Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.

• #25 Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. — Department of Pharmacology

  https://www.pharm.ox.ac.uk/publications/106497

  Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. […] Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.

• #26 Niemann-Pick Disease | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4591

  Niemann-Pick disease types A and B is caused by mutations in the SMPD1 gene. This gene provides instructions for producing an enzyme called acid sphingomyelinase. This enzyme is found in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Acid sphingomyelinase is responsible for the conversion of a fat (lipid) called sphingomyelin into another type of lipid called ceramide. Mutations in SMPD1 lead to a shortage of acid sphingomyelinase, which results in reduced break down of sphingomyelin, causing this fat to accumulate in cells. This fat buildup causes cells to malfunction and eventually die. Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A and B.

• #27 Niemann-Pick Disease | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4591

  Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease type C. The proteins produced from these genes are involved in the movement of lipids within cells. Mutations in these genes lead to a shortage of functional protein, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells. Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired. The accumulation of lipids as well as the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease types C1 and C2.

• #28 What is Acid Sphingomyelinase Deficiency (ASMD)

  https://www.asmdfacts.com/what-is-asmd

  ASMD is an inherited condition caused by genetic variants (changes in your genes). […] The gene involved in ASMD is called SMPD1. […] In people with ASMD, the body is unable to make enough of the ASM enzyme. […] Without regular levels of ASM, sphingomyelin cannot be broken down efficiently, and instead builds up in major organs such as the liver, lungs, and spleen. […] Low ASM enzyme activity from ASMD leads to buildup of sphingomyelin in cells of the body, causing symptoms and potential damage to multiple organs. […] Over time, the buildup of sphingomyelin can result in serious health consequences including organ damage.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

• #30 Niemann-Pick disease | Newborn Screening

  https://newbornscreening.hrsa.gov/conditions/niemann-pick-disease

  Niemann-Pick disease is a term used to describe a family of inherited (genetic) conditions that prevent the body from processing fatty substances normally. […] A change in the SMPD1 gene causes ASMD. This gene gives the body instructions for making the ASM enzyme that breaks down sphingomyelin. […] A changed SMPD1 gene prevents the body from breaking down sphingomyelin properly. Sphingomyelin then builds up in special processing compartments of the cells called lysosomes. When lysosomes get too full, cells do not function properly. ASMD most seriously affects the cells of the brain, lungs, spleen, and liver. […] ASMD is a genetic condition. Babies inherit it from their biological (birth) parents. […] ASMD is an autosomal recessive condition. Babies inherit type A or B when each parent passes down a nonworking SMPD1 gene to their baby. Only babies with two nonworking SMPD1 genesone from the mom and one from the dadhave this condition.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

• #32 Niemann-Pick Disease | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4591

  Niemann-Pick disease types A and B is caused by mutations in the SMPD1 gene. This gene provides instructions for producing an enzyme called acid sphingomyelinase. This enzyme is found in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Acid sphingomyelinase is responsible for the conversion of a fat (lipid) called sphingomyelin into another type of lipid called ceramide. Mutations in SMPD1 lead to a shortage of acid sphingomyelinase, which results in reduced break down of sphingomyelin, causing this fat to accumulate in cells. This fat buildup causes cells to malfunction and eventually die. Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A and B.

• #33 Niemann-Pick Disease Type A | Boston Children’s Hospital

  https://www.childrenshospital.org/conditions/niemann-pick-disease-type

  Niemann-Pick disease type A is caused by a mutation in a gene known as SMPD1, which provides instructions for the production of an enzyme called acid sphingomyelinase. […] Genetic mutations in the SMPD1 gene result in a deficiency of acid sphingomyelinase, leading to an accumulation of fat molecules in cells that eventually causes cells to malfunction. […] This genetic condition is inherited in an autosomal recessive pattern, which means that an affected child has received one defective copy of the SMPD1 gene from each of their parents.

• #34 Invitae Niemann-Pick Disease Type C Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06176

  Niemann-Pick disease, type C (NPC), is a lipid storage disorder. Biallelic variants in either of the two genes result in the same clinical disease. […] NPC is due not to an enzymatic defect, but rather to a disorder of intracellular lipid trafficking. […] Of individuals with a clinical diagnosis of NPC, 95% will have two pathogenic variants in NPC1 and approximately 4% will have biallelic pathogenic variants in NPC2. Less than 1% of cases with clinical and biochemical findings will have pathogenic variants in neither NPC1 or NPC2.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  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.

• #36

  https://omim.org/entry/257220

  A number sign (#) is used with this entry because Niemann-Pick disease type C1 and Niemann-Pick disease type D, also known as the Nova Scotian type, are caused by homozygous or compound heterozygous mutation in the NPC1 gene (607623) on chromosome 18q11. […] Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2 (607625). […] Vanier and Millat (2003) stated that approximately 95% of patients with Niemann-Pick disease type C have mutations in the NPC1 gene, which encodes a large membrane glycoprotein primarily located to late endosomes, and the remainder have mutations in the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggested that the 2 proteins function in a coordinate fashion. The NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids, and other cargo. […] Caused by mutation in the NPC intracellular cholesterol transporter 1 gene (NPC1, 607623.0001)

• #37 Niemann-Pick Disease | Encyclopedia MDPI

  https://encyclopedia.pub/entry/4591

  Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease type C. The proteins produced from these genes are involved in the movement of lipids within cells. Mutations in these genes lead to a shortage of functional protein, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells. Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired. The accumulation of lipids as well as the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease types C1 and C2.

• #38 Orphanet: Niemann-Pick disease type C

  https://www.orpha.net/en/disease/detail/646

  Most patients (95%) have mutations in the NPC1 gene (localized to 18q11.2), which encodes a membrane glycoprotein. […] The remainder have mutations in the NPC2 gene (localized to 14q24.3), which encodes a soluble lysosomal protein that binds cholesterol. […] The loss of function of those proteins blocks cholesterol egress from lysosomes leading to accumulation of lipid membrane components (unesterified cholesterol, glucosylceramide, and gangliosides) in the late endosomal/lysosomal compartment of the cell.

• #39 Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium | Nature Medicine

  https://www.nature.com/articles/nm.1876

  Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. […] The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. […] Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.

• #40 Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. — Department of Pharmacology

  https://www.pharm.ox.ac.uk/publications/106497

  Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. […] Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

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

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

  Niemann-Pick disease (NPD) types A and B result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene, located on bands 11p15.1-11p15.4. […] To date, more than 180 mutations have been described. […] Various types of mutations have been reported, including, most frequently, missense mutations (65.3%), with others including frameshift mutations (19%), nonsense mutations (7%), frame deletions, intronic variants, mutant alleles, duplication, and indel mutations. […] Frameshift mutations usually result in little or no enzyme activity and typically produce the type A phenotype. […] With missense mutations, significant residual activity is retained, so such mutations are related to the type B phenotype. […] The complete sphingomyelinase genomic region has been isolated and sequenced.

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

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

  Niemann-Pick disease (NPD) types A and B result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene, located on bands 11p15.1-11p15.4. […] To date, more than 180 mutations have been described. […] Various types of mutations have been reported, including, most frequently, missense mutations (65.3%), with others including frameshift mutations (19%), nonsense mutations (7%), frame deletions, intronic variants, mutant alleles, duplication, and indel mutations. […] Frameshift mutations usually result in little or no enzyme activity and typically produce the type A phenotype. […] With missense mutations, significant residual activity is retained, so such mutations are related to the type B phenotype. […] The complete sphingomyelinase genomic region has been isolated and sequenced.

• #46 The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

  https://www.mdpi.com/2218-273X/14/2/211

  Small deletions or nonsense mutations that result in a truncated ASM polypeptide, as well as missense mutations that render the enzyme noncatalytic, are characteristic of ASMD type A. These mutations result in a severely deficient or non-functional ASM enzyme. As a result, sphingomyelin cannot be properly metabolized, leading to the buildup of sphingomyelin in cells. […] The common pathogenetic process involves the accumulation of Niemann–Pick cells in the alveolar septa, bronchial walls, and pleura, leading to a progressively restrictive pattern that can be detected with pulmonary function tests. […] Niemann–Pick Disease type C is a rare autosomal recessive genetic disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene (NPD type C1); 5% are caused by mutations in NPC2 (NPD type C2). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. […] The NPC1 gene, in particular, exhibits significant genetic variability, with around 300 identified disease-causing mutations and over 60 polymorphisms described.

• #47 The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

  https://www.mdpi.com/2218-273X/14/2/211

  Small deletions or nonsense mutations that result in a truncated ASM polypeptide, as well as missense mutations that render the enzyme noncatalytic, are characteristic of ASMD type A. These mutations result in a severely deficient or non-functional ASM enzyme. As a result, sphingomyelin cannot be properly metabolized, leading to the buildup of sphingomyelin in cells. […] The common pathogenetic process involves the accumulation of Niemann–Pick cells in the alveolar septa, bronchial walls, and pleura, leading to a progressively restrictive pattern that can be detected with pulmonary function tests. […] Niemann–Pick Disease type C is a rare autosomal recessive genetic disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene (NPD type C1); 5% are caused by mutations in NPC2 (NPD type C2). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. […] The NPC1 gene, in particular, exhibits significant genetic variability, with around 300 identified disease-causing mutations and over 60 polymorphisms described.

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

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

  Three common mutation variants (p.R498L, p.L304P, p.P333Sfs*52) are associated with NPD type A. […] The delta-R608 mutation is a common mutation that results in NPD type B. […] In addition, p.P323A, p.P330R, and p.W393G variants are associated with NPD type B. […] Mutation variants p.Q294K and p.W393G are associated with an intermediate phenotype. […] Regional distribution of mutations causing NPD varies. […] SMPD1 gene defects have also been reported as strong risk factors for Parkinson disease, with variants p.L304P and p.R591C having particularly been associated with such risk in the Ashkenazi Jewish and Chinese populations.

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

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

  Three common mutation variants (p.R498L, p.L304P, p.P333Sfs*52) are associated with NPD type A. […] The delta-R608 mutation is a common mutation that results in NPD type B. […] In addition, p.P323A, p.P330R, and p.W393G variants are associated with NPD type B. […] Mutation variants p.Q294K and p.W393G are associated with an intermediate phenotype. […] Regional distribution of mutations causing NPD varies. […] SMPD1 gene defects have also been reported as strong risk factors for Parkinson disease, with variants p.L304P and p.R591C having particularly been associated with such risk in the Ashkenazi Jewish and Chinese populations.

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

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

  Three common mutation variants (p.R498L, p.L304P, p.P333Sfs*52) are associated with NPD type A. […] The delta-R608 mutation is a common mutation that results in NPD type B. […] In addition, p.P323A, p.P330R, and p.W393G variants are associated with NPD type B. […] Mutation variants p.Q294K and p.W393G are associated with an intermediate phenotype. […] Regional distribution of mutations causing NPD varies. […] SMPD1 gene defects have also been reported as strong risk factors for Parkinson disease, with variants p.L304P and p.R591C having particularly been associated with such risk in the Ashkenazi Jewish and Chinese populations.

• #51

  https://omim.org/entry/257220

  A number sign (#) is used with this entry because Niemann-Pick disease type C1 and Niemann-Pick disease type D, also known as the Nova Scotian type, are caused by homozygous or compound heterozygous mutation in the NPC1 gene (607623) on chromosome 18q11. […] Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2 (607625). […] Vanier and Millat (2003) stated that approximately 95% of patients with Niemann-Pick disease type C have mutations in the NPC1 gene, which encodes a large membrane glycoprotein primarily located to late endosomes, and the remainder have mutations in the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggested that the 2 proteins function in a coordinate fashion. The NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids, and other cargo. […] Caused by mutation in the NPC intracellular cholesterol transporter 1 gene (NPC1, 607623.0001)

• #52 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  More than 400 mutations in the NPC1 gene have been identified. […] The authors predicted that severe mutations, whether in the homozygous form or the compound heterozygous form, result in a severe phenotype. Because the present patient presented with a severe phenotype, the two novel mutations (c.1145CG [p.Ser382*] and c.2231_2233del [p.Val744del]) in this patient are likely to be severe mutations. […] NPC must be considered in infants who present with neonatal cholestasis. In addition, the neonatal cholestasis gene panel may be crucial in the diagnostic process.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

• #55 The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

  https://www.mdpi.com/2218-273X/14/2/211

  Small deletions or nonsense mutations that result in a truncated ASM polypeptide, as well as missense mutations that render the enzyme noncatalytic, are characteristic of ASMD type A. These mutations result in a severely deficient or non-functional ASM enzyme. As a result, sphingomyelin cannot be properly metabolized, leading to the buildup of sphingomyelin in cells. […] The common pathogenetic process involves the accumulation of Niemann–Pick cells in the alveolar septa, bronchial walls, and pleura, leading to a progressively restrictive pattern that can be detected with pulmonary function tests. […] Niemann–Pick Disease type C is a rare autosomal recessive genetic disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene (NPD type C1); 5% are caused by mutations in NPC2 (NPD type C2). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. […] The NPC1 gene, in particular, exhibits significant genetic variability, with around 300 identified disease-causing mutations and over 60 polymorphisms described.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

• #58 The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

  https://www.mdpi.com/2218-273X/14/2/211

  Small deletions or nonsense mutations that result in a truncated ASM polypeptide, as well as missense mutations that render the enzyme noncatalytic, are characteristic of ASMD type A. These mutations result in a severely deficient or non-functional ASM enzyme. As a result, sphingomyelin cannot be properly metabolized, leading to the buildup of sphingomyelin in cells. […] The common pathogenetic process involves the accumulation of Niemann–Pick cells in the alveolar septa, bronchial walls, and pleura, leading to a progressively restrictive pattern that can be detected with pulmonary function tests. […] Niemann–Pick Disease type C is a rare autosomal recessive genetic disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene (NPD type C1); 5% are caused by mutations in NPC2 (NPD type C2). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. […] The NPC1 gene, in particular, exhibits significant genetic variability, with around 300 identified disease-causing mutations and over 60 polymorphisms described.

• #59 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  More than 400 mutations in the NPC1 gene have been identified. […] The authors predicted that severe mutations, whether in the homozygous form or the compound heterozygous form, result in a severe phenotype. Because the present patient presented with a severe phenotype, the two novel mutations (c.1145CG [p.Ser382*] and c.2231_2233del [p.Val744del]) in this patient are likely to be severe mutations. […] NPC must be considered in infants who present with neonatal cholestasis. In addition, the neonatal cholestasis gene panel may be crucial in the diagnostic process.

• #60 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. […] This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. […] NPC disease is a progressive neurovisceral autosomal recessive LSD caused by loss of function variants in the NPC1 or NPC2 genes. […] Most NPC patients (up to 95%) have mutations in NPC1, with the remaining few (less than 5%) in NPC2. […] 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.

• #61 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. […] This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. […] NPC disease is a progressive neurovisceral autosomal recessive LSD caused by loss of function variants in the NPC1 or NPC2 genes. […] Most NPC patients (up to 95%) have mutations in NPC1, with the remaining few (less than 5%) in NPC2. […] 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.

• #62 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 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. […] 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.

• #63 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 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. […] 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.

• #64 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 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. […] 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.

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

• #66 Niemann-Pick disease, SMPD1-related | Myriad Foresight® Carrier Screen

  https://myriad.com/womens-health/diseases/niemann-pick-disease-smpd1-related/

  Niemann-Pick disease (NPD), SMPD1-Related is an inherited disease in which the body cannot properly metabolize a certain fatty substance called sphingomyelin due to a deficient enzyme called acid sphingomyelinase. […] Mutations in the SMPD1 gene can cause either the type A form or the type B form of NPD. […] NPD-A causes intellectual disability, loss of motor skills, and enlargement of the liver and spleen, among other symptoms. […] The disease is often fatal by the age of two or three. […] NPD-B is most common in the Maghreb region of North Africa, which includes Algeria, Morocco, and Tunisia. […] There is no treatment to address the cause of NPD-B. […] The prognosis for an individual with NPD-A is poor. […] It is a severe disease that is typically fatal by the age of two or three.

• #67 Niemann-Pick Disease | SpringerLink

  https://link.springer.com/10.1007/978-3-319-66816-1_1778-1

  Wasserstein MP, Aron A, Brodie SE, Simonaro C, Desnick RJ, McGovern MM (2006) Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. J Pediatr 149:554559. https://doi.org/10.1016/j.jpeds.2006.06.034 […] McGovern MM, Avetisyan R, Sanson BJ, Lidove O (2017a) Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis 12:41. https://doi.org/10.1186/s13023-017-0572-x […] McGovern MM et al (2017b) Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genet Med 19:967974. https://doi.org/10.1038/gim.2017.7

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

  https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-25882/

  Niemann-Pick disease (NPD) is inherited in an autosomal recessive pattern, which means both copies of the gene must have mutations for the manifestation of the disease. NPD types A and B are caused by missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. Over 180 mutations in SMPD1 have been identified. NPD type C is caused by mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 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. […] 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.

• #69 Niemann-Pick disease // Middlesex Health

  https://middlesexhealth.org/learning-center/diseases-and-conditions/niemann-pick-disease

  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.

• #70 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. […] This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. […] NPC disease is a progressive neurovisceral autosomal recessive LSD caused by loss of function variants in the NPC1 or NPC2 genes. […] Most NPC patients (up to 95%) have mutations in NPC1, with the remaining few (less than 5%) in NPC2. […] 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.

• #71 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 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. […] 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.

• #72 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  Niemann-Pick disease (NPD) is a group of diseases passed down through families (inherited) in which fatty substances called lipids collect in the cells of the spleen, liver, and brain. […] NPD types A and B occur when cells in the body do not have an enzyme called acid sphingomyelinase (ASM). This substance helps break down (metabolize) a fatty substance called sphingomyelin, which is found in every cell in the body. […] If ASM is missing or does not work properly, sphingomyelin builds up inside cells. This kills your cells and makes it hard for organs to work properly. […] Type C occurs when the body cannot properly break down cholesterol and other fats (lipids). This leads to too much cholesterol in the liver and spleen and too much of other lipids in the brain. […] Type C1 is a variant of type C. It involves a defect that interferes with how cholesterol moves between brain cells. This type has only been seen in French Canadian people in Yarmouth County, Nova Scotia.

• #73 Niemann–Pick disease – Wikipedia

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

  NiemannPick disease is inherited in an autosomal recessive pattern, which means both copies or both 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 and genetic testing are recommended for families who may be carriers of the disease.

• #74 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  All types of Niemann-Pick are autosomal recessive. This means that both parents are carriers. Each parent has one copy of the variant gene without having any signs of the disease themselves. […] When both parents are carriers, there is a 25% chance that their child will have the disease and a 50% chance that their child will be a carrier. […] Carrier detection testing is only possible if the genetic defect is identified. The defects involved in types A and B have been well-studied. DNA tests for these forms of Niemann-Pick are available. […] Genetic defects have been identified in the DNA of many people with type C. It may be possible to diagnose people who carry the abnormal gene.

• #75 Niemann–Pick disease – Wikipedia

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

  NiemannPick disease is inherited in an autosomal recessive pattern, which means both copies or both 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 and genetic testing are recommended for families who may be carriers of the disease.

• #76 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  All types of Niemann-Pick are autosomal recessive. This means that both parents are carriers. Each parent has one copy of the variant gene without having any signs of the disease themselves. […] When both parents are carriers, there is a 25% chance that their child will have the disease and a 50% chance that their child will be a carrier. […] Carrier detection testing is only possible if the genetic defect is identified. The defects involved in types A and B have been well-studied. DNA tests for these forms of Niemann-Pick are available. […] Genetic defects have been identified in the DNA of many people with type C. It may be possible to diagnose people who carry the abnormal gene.

• #77 Niemann–Pick disease – Wikipedia

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

  NiemannPick disease is inherited in an autosomal recessive pattern, which means both copies or both 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 and genetic testing are recommended for families who may be carriers of the disease.

• #78 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. […] Type C1 disease is caused by mutations in the NPC1 gene (at position 18q11.2), while type C2 disease results from mutations in the NPC2 gene, located on the long arm of chromosome 14 (at position 14q24.3). […] Niemann-Pick type C disease is inherited in a classic autosomal recessive pattern, which means that both copies of the NPC1 or NPC2 gene must be deficient in order for the individual to be afflicted.

• #79 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  All types of Niemann-Pick are autosomal recessive. This means that both parents are carriers. Each parent has one copy of the variant gene without having any signs of the disease themselves. […] When both parents are carriers, there is a 25% chance that their child will have the disease and a 50% chance that their child will be a carrier. […] Carrier detection testing is only possible if the genetic defect is identified. The defects involved in types A and B have been well-studied. DNA tests for these forms of Niemann-Pick are available. […] Genetic defects have been identified in the DNA of many people with type C. It may be possible to diagnose people who carry the abnormal gene.

• #80 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  All types of Niemann-Pick are autosomal recessive. This means that both parents are carriers. Each parent has one copy of the variant gene without having any signs of the disease themselves. […] When both parents are carriers, there is a 25% chance that their child will have the disease and a 50% chance that their child will be a carrier. […] Carrier detection testing is only possible if the genetic defect is identified. The defects involved in types A and B have been well-studied. DNA tests for these forms of Niemann-Pick are available. […] Genetic defects have been identified in the DNA of many people with type C. It may be possible to diagnose people who carry the abnormal gene.

• #81 Niemann–Pick disease – Wikipedia

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

  NiemannPick disease is inherited in an autosomal recessive pattern, which means both copies or both 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 and genetic testing are recommended for families who may be carriers of the disease.

• #82 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  Niemann-Pick disease is rare, and its symptoms can be similar to those of other health conditions, so testing is needed to get the right diagnosis. […] DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B and C. […] The gene change can be passed on to children. […] Questions to ask may include: What is likely causing these symptoms? […] Are there any other possible causes for these symptoms? […] Should family members be tested for the gene changes that can cause this condition?

• #83 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  Niemann-Pick disease is rare, and its symptoms can be similar to those of other health conditions, so testing is needed to get the right diagnosis. […] DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B and C. […] The gene change can be passed on to children. […] Questions to ask may include: What is likely causing these symptoms? […] Are there any other possible causes for these symptoms? […] Should family members be tested for the gene changes that can cause this condition?

• #84 Niemann-Pick Disease | LSDSS India

  https://lsdssindia.org/about-lysosomal-storage-disorders/niemann-pick-disease/

  Niemann-Pick is caused by mutations in specific genes that are responsible for the production of enzymes that help to break down and metabolize fats in the body. […] The genetic mutations that cause Niemann-Pick are inherited in an autosomal recessive pattern, which means that a person must inherit two copies of the mutated gene (one from each parent) in order to develop the condition. […] Niemann-Pick is a genetic disorder, which means that it is caused by mutations in specific genes that are passed down from a persons parents. […] The genetic mutations that cause Niemann-Pick are inherited in an autosomal recessive pattern, which means that a person must inherit two copies of the mutated gene (one from each parent) in order to develop the condition. […] People who have a family history of Niemann-Pick disease are at an increased risk of developing the condition, as are people who are of Ashkenazi Jewish ancestry, as this population has a higher rate of carrier status for the mutated genes that cause Niemann-Pick disease.

• #85 Niemann-Pick disease, SMPD1-related | Myriad Foresight® Carrier Screen

  https://myriad.com/womens-health/diseases/niemann-pick-disease-smpd1-related/

  Niemann-Pick disease (NPD), SMPD1-Related is an inherited disease in which the body cannot properly metabolize a certain fatty substance called sphingomyelin due to a deficient enzyme called acid sphingomyelinase. […] Mutations in the SMPD1 gene can cause either the type A form or the type B form of NPD. […] NPD-A causes intellectual disability, loss of motor skills, and enlargement of the liver and spleen, among other symptoms. […] The disease is often fatal by the age of two or three. […] NPD-B is most common in the Maghreb region of North Africa, which includes Algeria, Morocco, and Tunisia. […] There is no treatment to address the cause of NPD-B. […] The prognosis for an individual with NPD-A is poor. […] It is a severe disease that is typically fatal by the age of two or three.

• #86 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  Niemann-Pick disease (NPD) is a group of diseases passed down through families (inherited) in which fatty substances called lipids collect in the cells of the spleen, liver, and brain. […] NPD types A and B occur when cells in the body do not have an enzyme called acid sphingomyelinase (ASM). This substance helps break down (metabolize) a fatty substance called sphingomyelin, which is found in every cell in the body. […] If ASM is missing or does not work properly, sphingomyelin builds up inside cells. This kills your cells and makes it hard for organs to work properly. […] Type C occurs when the body cannot properly break down cholesterol and other fats (lipids). This leads to too much cholesterol in the liver and spleen and too much of other lipids in the brain. […] Type C1 is a variant of type C. It involves a defect that interferes with how cholesterol moves between brain cells. This type has only been seen in French Canadian people in Yarmouth County, Nova Scotia.

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

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

  Three common mutation variants (p.R498L, p.L304P, p.P333Sfs*52) are associated with NPD type A. […] The delta-R608 mutation is a common mutation that results in NPD type B. […] In addition, p.P323A, p.P330R, and p.W393G variants are associated with NPD type B. […] Mutation variants p.Q294K and p.W393G are associated with an intermediate phenotype. […] Regional distribution of mutations causing NPD varies. […] SMPD1 gene defects have also been reported as strong risk factors for Parkinson disease, with variants p.L304P and p.R591C having particularly been associated with such risk in the Ashkenazi Jewish and Chinese populations.

• #88 Gene therapy shows promise for treating Niemann-Pick disease type C1

  https://www.genome.gov/news/news-release/Gene-therapy-shows-promise-for-treating-Niemann-Pick-disease-type-C1

  For the first time, National Institutes of Health (NIH) researchers have demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). […] Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. […] „The gene therapy is treating the root of the problem, the defective gene.” […] „For NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient’s life span.”

• #89 Gene therapy shows promise for treating Niemann-Pick disease type C1

  https://www.genome.gov/news/news-release/Gene-therapy-shows-promise-for-treating-Niemann-Pick-disease-type-C1

  For the first time, National Institutes of Health (NIH) researchers have demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). […] Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. […] „The gene therapy is treating the root of the problem, the defective gene.” […] „For NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient’s life span.”

• #90 Gene therapy shows promise for treating Niemann-Pick disease type C1

  https://www.genome.gov/news/news-release/Gene-therapy-shows-promise-for-treating-Niemann-Pick-disease-type-C1

  For the first time, National Institutes of Health (NIH) researchers have demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). […] Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. […] „The gene therapy is treating the root of the problem, the defective gene.” […] „For NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient’s life span.”

• #91 Gene therapy shows promise for treating Niemann-Pick disease type C1

  https://www.genome.gov/news/news-release/Gene-therapy-shows-promise-for-treating-Niemann-Pick-disease-type-C1

  For the first time, National Institutes of Health (NIH) researchers have demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). […] Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. […] „The gene therapy is treating the root of the problem, the defective gene.” […] „For NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient’s life span.”

• #92 Gene therapy shows promise for treating Niemann-Pick disease type C1

  https://www.genome.gov/news/news-release/Gene-therapy-shows-promise-for-treating-Niemann-Pick-disease-type-C1

  For the first time, National Institutes of Health (NIH) researchers have demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). […] Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. […] „The gene therapy is treating the root of the problem, the defective gene.” […] „For NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient’s life span.”

• #93 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 disease 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. […] 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.

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

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

  The exact functions of the NPC1 and NPC2 proteins are still unclear, which greatly complicates understanding of the pathophysiology. […] The Niemann-Pick type C disease variation database listed by January 2010 244 NPC1 and 18 NPC2 gene sequence variants. […] In early genetic complementation studies, it was stated that about 95% of the families had mutations in the NPC1 gene. […] The NPC1 gene, mapped to chromosome 18q11-q12, spans 56 kb and contains 25 exons. […] The few genotype-phenotype studies published so far in NP-C1 patients generally showed good correlation between nonsense or frameshift mutations and the most severe neurologic course. […] The NPC2 gene (initially known as HE1), mapped to chromosome 14q24.3, spans 13.5 Kb and contains 5 exons.

• #95 Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium | Nature Medicine

  https://www.nature.com/articles/nm.1876

  Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. […] The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. […] Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.

• #96 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. […] This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. […] NPC disease is a progressive neurovisceral autosomal recessive LSD caused by loss of function variants in the NPC1 or NPC2 genes. […] Most NPC patients (up to 95%) have mutations in NPC1, with the remaining few (less than 5%) in NPC2. […] 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.

• #97 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These mutations cause the accumulation of unesterified cholesterol and other lipids in the lysosomes. […] Niemann-Pick disease type C (NPC, OMIM#257220, OMIM#607625) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These genes encode NPC1 and NPC2, which are proteins that mediate cholesterol transport in cells. Defective proteins cause the accumulation of lipids in lysosomes, such as unesterified cholesterol, sphingomyelin, and glycolipids. […] Genetic analysis of the NPC1 and NPC2 genes provides a definitive diagnosis of NPC. […] The neonatal cholestasis gene panel revealed two novel likely pathogenic variants in the NPC1 gene: c.1145CG (p.Ser382*) and c.2231_2233del (p.Val744del), leading to a diagnosis of NPC.

• #98 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These mutations cause the accumulation of unesterified cholesterol and other lipids in the lysosomes. […] Niemann-Pick disease type C (NPC, OMIM#257220, OMIM#607625) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These genes encode NPC1 and NPC2, which are proteins that mediate cholesterol transport in cells. Defective proteins cause the accumulation of lipids in lysosomes, such as unesterified cholesterol, sphingomyelin, and glycolipids. […] Genetic analysis of the NPC1 and NPC2 genes provides a definitive diagnosis of NPC. […] The neonatal cholestasis gene panel revealed two novel likely pathogenic variants in the NPC1 gene: c.1145CG (p.Ser382*) and c.2231_2233del (p.Val744del), leading to a diagnosis of NPC.

• #99 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  More than 400 mutations in the NPC1 gene have been identified. […] The authors predicted that severe mutations, whether in the homozygous form or the compound heterozygous form, result in a severe phenotype. Because the present patient presented with a severe phenotype, the two novel mutations (c.1145CG [p.Ser382*] and c.2231_2233del [p.Val744del]) in this patient are likely to be severe mutations. […] NPC must be considered in infants who present with neonatal cholestasis. In addition, the neonatal cholestasis gene panel may be crucial in the diagnostic process.

• #100 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  More than 400 mutations in the NPC1 gene have been identified. […] The authors predicted that severe mutations, whether in the homozygous form or the compound heterozygous form, result in a severe phenotype. Because the present patient presented with a severe phenotype, the two novel mutations (c.1145CG [p.Ser382*] and c.2231_2233del [p.Val744del]) in this patient are likely to be severe mutations. […] NPC must be considered in infants who present with neonatal cholestasis. In addition, the neonatal cholestasis gene panel may be crucial in the diagnostic process.

• #101 First therapy to treat two types of Niemann-Pick disease, a rare genetic metabolic disorder | European Medicines Agency (EMA)

  https://www.ema.europa.eu/en/news/first-therapy-treat-two-types-niemann-pick-disease-rare-genetic-metabolic-disorder

  Historically referred to as Niemann-Pick disease types A (NPD A) and B (NPD B), ASMD is a genetic disorder. […] ASMD is seriously debilitating and life threatening since the build-up of fatty substances can cause brain damage and swelling of organs such as liver and spleen. […] The most common causes of death are respiratory disease, liver problems and complications due to the excessive size of multiple organs. […] Xenpozyme was designated as an orphan medicinal product for the treatment of Niemann-Pick disease type B on 19 September 2001. […] The Committee for Orphan Medicinal Products (COMP) accepted broadening the orphan designation to NPD including subtypes A, B, and C.

• #102 First therapy to treat two types of Niemann-Pick disease, a rare genetic metabolic disorder | European Medicines Agency (EMA)

  https://www.ema.europa.eu/en/news/first-therapy-treat-two-types-niemann-pick-disease-rare-genetic-metabolic-disorder

  Historically referred to as Niemann-Pick disease types A (NPD A) and B (NPD B), ASMD is a genetic disorder. […] ASMD is seriously debilitating and life threatening since the build-up of fatty substances can cause brain damage and swelling of organs such as liver and spleen. […] The most common causes of death are respiratory disease, liver problems and complications due to the excessive size of multiple organs. […] Xenpozyme was designated as an orphan medicinal product for the treatment of Niemann-Pick disease type B on 19 September 2001. […] The Committee for Orphan Medicinal Products (COMP) accepted broadening the orphan designation to NPD including subtypes A, B, and C.

• #103 First therapy to treat two types of Niemann-Pick disease, a rare genetic metabolic disorder | European Medicines Agency (EMA)

  https://www.ema.europa.eu/en/news/first-therapy-treat-two-types-niemann-pick-disease-rare-genetic-metabolic-disorder

  Historically referred to as Niemann-Pick disease types A (NPD A) and B (NPD B), ASMD is a genetic disorder. […] ASMD is seriously debilitating and life threatening since the build-up of fatty substances can cause brain damage and swelling of organs such as liver and spleen. […] The most common causes of death are respiratory disease, liver problems and complications due to the excessive size of multiple organs. […] Xenpozyme was designated as an orphan medicinal product for the treatment of Niemann-Pick disease type B on 19 September 2001. […] The Committee for Orphan Medicinal Products (COMP) accepted broadening the orphan designation to NPD including subtypes A, B, and C.

• #104 First therapy to treat two types of Niemann-Pick disease, a rare genetic metabolic disorder | European Medicines Agency (EMA)

  https://www.ema.europa.eu/en/news/first-therapy-treat-two-types-niemann-pick-disease-rare-genetic-metabolic-disorder

  Historically referred to as Niemann-Pick disease types A (NPD A) and B (NPD B), ASMD is a genetic disorder. […] ASMD is seriously debilitating and life threatening since the build-up of fatty substances can cause brain damage and swelling of organs such as liver and spleen. […] The most common causes of death are respiratory disease, liver problems and complications due to the excessive size of multiple organs. […] Xenpozyme was designated as an orphan medicinal product for the treatment of Niemann-Pick disease type B on 19 September 2001. […] The Committee for Orphan Medicinal Products (COMP) accepted broadening the orphan designation to NPD including subtypes A, B, and C.

• #105 Niemann-Pick Disease Type C (NPC) – IntraBio

  https://intrabio.com/disease-information/niemannpickdiseasetypec/

  Niemann-Pick disease Type C (NPC) is a rare genetic disorder, occurring in approximately 1 in 100,000 live births. It is an autosomal recessive, lysosomal storage disorder caused by mutations in either the NPC1 or NPC2 genes. […] These mutations lead to lysosomal and mitochondrial dysfunction, resulting in progressive neurodegeneration.

• #106 Niemann-Pick Disease Type C (NPC) – IntraBio

  https://intrabio.com/disease-information/niemannpickdiseasetypec/

  Niemann-Pick disease Type C (NPC) is a rare genetic disorder, occurring in approximately 1 in 100,000 live births. It is an autosomal recessive, lysosomal storage disorder caused by mutations in either the NPC1 or NPC2 genes. […] These mutations lead to lysosomal and mitochondrial dysfunction, resulting in progressive neurodegeneration.

• #107 Niemann-Pick disease – Medizinonline

  https://medizinonline.com/en/niemann-pick-disease/

  Niemann-Pick disease is a genetic lysosomal storage disorder named after the German pediatrician Albert Niemann (1880-1921) and the German pathologist Ludwig Pick (1868-1944). […] Type A and B are due to deficient activity of a lysosomal enzyme encoded by the SMPD1 gene. The genetic defect causes sphingomyelin to be unable to be broken down and to accumulate in the cells of various organs. […] Type C is a cholesterol metabolism disorder in which mutations are detectable in the NPC-1 gene (18q11) or the NPC-2 gene (14q24.3). […] Reduced or absent acid sphingomyelinase activity can be detected in leukocyte and fibroblast cultures, and the cause of Niemann-Pick type A and B disease is. […] The underlying genetic defects are currently not treatable (as of 2022).

• #108 Niemann-Pick – Causes, Symptoms and Treatment | Apollo Hospitals

  https://www.apollohospitals.com/diseases-and-conditions/niemann-pick-causes-symptoms-and-treatment/

  Niemann-Pick disease is a rare metabolic disorder caused by changes in the structures of specific genes. The disease is inherited only when both the parents pass on the defective gene to their child. […] Types A and B occur due to the mutations in the SMPD1 gene that helps WBCs to produce acid sphingomyelinase (ASM). […] SMPD1 mutations (changes in the structure of genes) lead to ASM deficiency, and fat starts building up in the cells. […] Type C develops due to the mutations in NPC1 and NPC2 genes that affect a protein used to transport cholesterol and other lipids. […] Mutations lead to a shortage of protein, and cholesterol starts building up in the spleen and the liver. […] Ultimately, it results in cell death and organ failure. […] Niemann-Pick disease is an inherited disease that disrupts the metabolization of fats and lipids in the body. […] Unfortunately, it is an incurable disease, and over time, causes death.

• #109 Niemann-Pick disease – Medizinonline

  https://medizinonline.com/en/niemann-pick-disease/

  Niemann-Pick disease is a genetic lysosomal storage disorder named after the German pediatrician Albert Niemann (1880-1921) and the German pathologist Ludwig Pick (1868-1944). […] Type A and B are due to deficient activity of a lysosomal enzyme encoded by the SMPD1 gene. The genetic defect causes sphingomyelin to be unable to be broken down and to accumulate in the cells of various organs. […] Type C is a cholesterol metabolism disorder in which mutations are detectable in the NPC-1 gene (18q11) or the NPC-2 gene (14q24.3). […] Reduced or absent acid sphingomyelinase activity can be detected in leukocyte and fibroblast cultures, and the cause of Niemann-Pick type A and B disease is. […] The underlying genetic defects are currently not treatable (as of 2022).

• #110 Niemann-Pick – Causes, Symptoms and Treatment | Apollo Hospitals

  https://www.apollohospitals.com/diseases-and-conditions/niemann-pick-causes-symptoms-and-treatment/

  Niemann-Pick disease is a rare metabolic disorder caused by changes in the structures of specific genes. The disease is inherited only when both the parents pass on the defective gene to their child. […] Types A and B occur due to the mutations in the SMPD1 gene that helps WBCs to produce acid sphingomyelinase (ASM). […] SMPD1 mutations (changes in the structure of genes) lead to ASM deficiency, and fat starts building up in the cells. […] Type C develops due to the mutations in NPC1 and NPC2 genes that affect a protein used to transport cholesterol and other lipids. […] Mutations lead to a shortage of protein, and cholesterol starts building up in the spleen and the liver. […] Ultimately, it results in cell death and organ failure. […] Niemann-Pick disease is an inherited disease that disrupts the metabolization of fats and lipids in the body. […] Unfortunately, it is an incurable disease, and over time, causes death.

• #111 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. […] This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. […] NPC disease is a progressive neurovisceral autosomal recessive LSD caused by loss of function variants in the NPC1 or NPC2 genes. […] Most NPC patients (up to 95%) have mutations in NPC1, with the remaining few (less than 5%) in NPC2. […] 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.

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