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Tirelli, C.; Rondinone, O.; Italia, M.; Mira, S.; Belmonte, L.A.; De Grassi, M.; Guido, G.; Maggioni, S.; Mondoni, M.; Miozzo, M.R.; et al. Niemann–Pick Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/55267 (accessed on 27 June 2026).
Tirelli C, Rondinone O, Italia M, Mira S, Belmonte LA, De Grassi M, et al. Niemann–Pick Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/55267. Accessed June 27, 2026.
Tirelli, Claudio, Ornella Rondinone, Marta Italia, Sabrina Mira, Luca Alessandro Belmonte, Mauro De Grassi, Gabriele Guido, Sara Maggioni, Michele Mondoni, Monica Rosa Miozzo, et al. "Niemann–Pick Disease" Encyclopedia, https://encyclopedia.pub/entry/55267 (accessed June 27, 2026).
Tirelli, C., Rondinone, O., Italia, M., Mira, S., Belmonte, L.A., De Grassi, M., Guido, G., Maggioni, S., Mondoni, M., Miozzo, M.R., & Centanni, S. (2024, February 21). Niemann–Pick Disease. In Encyclopedia. https://encyclopedia.pub/entry/55267
Tirelli, Claudio, et al. "Niemann–Pick Disease." Encyclopedia. Web. 21 February, 2024.
Niemann–Pick Disease
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This entry is adapted from the peer-reviewed paper 10.3390/biom14020211

Niemann–Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure.

Niemann–Pick Disease acid sphingomyelinase deficiency SMPD1 NPC1 NPC2 Olipudase α miglustat lung transplant

1. Introduction

Niemann–Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder. NPD comprises three different pathologies, namely NPD type A, B, and C. NPD type A and B are now most commonly categorized as acid sphingomyelinase deficiencies (ASMDs), as they are caused by mutations in the gene SMPD1, which codes for sphingomyelin phosphodiesterase 1. However, NPD type C is a neurological disorder caused by mutations in the NPC1 or NPC2 genes, leading to defects in cholesterol trafficking and esterification. In ASMD types A and B, defects in sphingomyelin phosphodiesterase 1 result in a lack of acid sphingomyelinase activity, leading to the accumulation of sphingomyelin, cholesterol, and other lipids in lysosomes (Figure 1). 
Biomolecules 14 00211 g001
Figure 1. Molecular pathogenetic mechanisms in ASMD (NPD type A and B) and NPD type C. ASMDs (NPD type A and B) are due to acid sphingomyelinase (ASMase) deficiency. This leads to accumulation of sphingomyelin in lysosomes. As a consequence, a secondary sequestration of cholesterol in lysosomes occurs. ASMase acts as a trigger for endoplasmic reticulum stress. The consequent reduced endoplasmic reticulum stress signaling causes a decrease in reactive oxygen species (ROS) in mitochondria. NPD type C is characterized by defects of NPC1 and NPC2. This leads to accumulation of cholesterol in lysosomes, which is sustained by decreased activity of acid ceramidase (ACDase). As a consequence, via a poorly understood mechanism involving endoplasmic reticulum signals, mitochondrial cholesterol levels increase. The mitochondrial cholesterol accumulation determines an increase in ROS-induced oxidative stress.
Table 1. Main characteristics of ASMD (NPD type A and B) and NPD type C.
  ASMD Type A ASMD Type B NPD Type C
Age of onset Childhood Childhood and adulthood Mainly childhood, adulthood (underecognized)
Lung involvement Present Frequent Rare
Hepato-splenomegaly Frequent Frequent Frequent
Liver disease Present Frequent Present
Neurodegeneration Frequent and rapidly progressive Present and slowly progressive Present and rapidly progressive (in younger patients)
Atherosclerosis Present Frequent Not described
Growth delay Frequent Frequent Not frequently described
Hypotonia Frequent Rare Present

2. The Genetic Basis of Niemann–Pick Disease Type A and B: Disease-Causing Mutations and Genotype–Phenotype Relationships

ASMD is a group of inherited metabolic disorders caused by genetic mutations that affect the processing and transport of lipids, especially sphingomyelin and cholesterol, within cells. These mutations disrupt the function of specific enzymes or proteins involved in lipid metabolism, resulting in the abnormal accumulation of lipids in various tissues and organs.
The genetics of Niemann–Pick Disease are complex and involve several types, including types A, B, C1, and C2, each with distinct genetic causes. NPD types A and B (ASMD) are caused by mutations in the SMPD1 gene, which is located on 11p15.1-p15.4. This gene provides instructions for producing an enzyme called acid sphingomyelinase (ASM), which is responsible for breaking down sphingomyelin into ceramide and phosphocholine. While ASMD type A is always inherited as an autosomal recessive disease, ASMD type B is not only autosomal recessive. In some cases, individuals with one normal copy of the gene and one mutated copy (carriers) can have mild symptoms. Takahashi et al. emphasized the connection between specific mutations in the SMPD1 gene and the resulting clinical manifestations in Niemann–Pick Disease [1].
In ASMD type B, although the typical mode of inheritance is autosomal recessive, there can be cases where individuals who are carriers (heterozygous for the mutation) may exhibit mild symptoms or have some manifestations of the disease. The severity of symptoms in carriers can vary, and this phenomenon is often referred to as “carrier or heterozygote manifestations”. It means that, in some genetic disorders, individuals with only one copy of the mutated gene may show milder forms of the condition or may have subtle symptoms [2].
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 accumulation of this substance is responsible for the severe neurovisceral symptoms observed in ASMD type A. ASMD type B is primarily caused by missense mutations that result in a defective enzyme with residual catalytic activity. Although the enzyme is defective, it still retains partial functionality, enabling the partial breakdown of sphingomyelin. This residual activity is associated with a milder non-neuronopathic type B phenotype, which typically presents with hepatosplenomegaly and lung involvement but lacks severe neurological symptoms seen in ASMD type A. Recent developments in molecular biology have identified more than 100 mutations in SMPD1 in patients with ASMD type A/B, which are listed in the Human Gene Mutation Database (HGMD). Most of these mutations are missense (65.4%) or frameshift (19%) mutations. A deletion mutation, NM_000543.4(SMPD1):c.1829_1831delGCC (p.Arg610del), was considered the most frequent mutation reported worldwide. This mutation was associated with an attenuated ASMD type B phenotype [3]. Forty mutations were studied in vitro, and their impact on ASM activity was assessed. Twelve of these mutations retained some enzymatic activity, with eleven of them found in patients with ASMD type B. One specific mutation, p.Phe572Leu, retained 30% activity and was identified in a patient with ASMD type A, along with another mutation, p.Gly247Ser [4][5]. The study also noted six mutations associated with type A disease, three of which were found in Jewish Ashkenazi patients, where the disease is relatively common [6][7][8][9]. Moreover, Gluck and colleagues investigated 12 Arab Israeli families with ASMD type A in the lower Galilee and the West Bank, Palestine. Through a molecular analysis, they discovered a novel genetic mutation, a single base pair deletion in the SMPD1 gene known as 677delT, which likely contributes to the development of ASMD type A in these patients.

3. Acid Sphingomyelinase Deficiencies: Clinical Aspects in Niemann–Pick Disease Type A and B

ASMD (NPD type A and B) are autosomal recessive lysosomal storage disorders caused by a deficiency in the activity of acid sphingomyelinase (ASM). This enzyme regulates the homeostasis of lysosomal sphingomyelin (SM), and its inactivation leads to the accumulation of SM, cholesterol, and other lipids in lysosomes [10]. ASM is encoded by the SMPD1 (sphingomyelin phosphodiesterase 1) gene, which is located on chromosome 11. More than 180 pathogenic mutations, including missense and nonsense mutations, deletions, and splicing abnormalities, have been described in the SMPD1 gene in patients with ASMD type A and B [11]. ASMD type B is a pan-ethnic disorder found worldwide. The majority of cases are located in the United States (USA), western Europe, Saudi Arabia, Turkey, and Tunisia. ASMD type A is more common in individuals of Ashkenazi Jewish descent than in the general population [12]. The difference between ASMD type A and B is based on the activity of ASM. In type A, there is a significant reduction in ASM activity (<5%), while in type B, there is a higher residual activity of the enzyme [10]. The accumulation of sphingomyelin and other lipids in cells such as hepatocytes, monocytes, and macrophages may lead to organ damage and dysfunction. At lung histology, the so-called vacuolated foamy macrophages, known as “Niemann–Pick cells”, can be found in the alveolar spaces, alveolar septa, and pleura. Niemann–Pick cells typically exhibit intense blue staining with the May Grunwald–Giemsa and the Schmorl reaction, and they are also referred to as “sea-blue histiocytes”. These foam cells accumulate in various organs, such as the liver, spleen, lungs, cerebral and cerebellar cortices, and bone marrow, and they can lead to organ failure. The severity of clinical symptoms is associated with the level of remaining acid sphingomyelinase activity [13]. Since foam cells can accumulate in the lungs, bronchoalveolar lavage (BAL) is a useful diagnostic tool in the work-up of ASMD. It is capable of detecting foam cells, although its use should be carefully considered due to the invasive nature of the procedure [14].

3.1. Niemann–Pick Disease Type A (ASMD Type A)

NPD type A is the most severe form. It is a neurodegenerative disease leading to death within the first years of life in most cases. NPD type A is characterized by progressive neuro- and psychomotor degeneration with gradual worsening of hypotonia, leading to a loss of language and mobility. The disease affects the cerebellum and cerebrum. A severe myelin deficiency and accumulation of foamy cells and lipid-laden glial cells can be retrieved in brain specimens from infants with NPD type A [11][13]. The first manifestation in NPD type A is organomegaly. A study conducted on ten patients affected by NPD type A showed hepatosplenomegaly was present by 4 months of age in association with abnormally elevated levels of liver enzymes, and total and direct bilirubin. Neurological symptoms more often begin by 9 months. Children have a sleep disorder with frequent arousals accompanied by periods of crying for hours. A growth delay and progressive hypotonia with a loss of the deep tendon reflexes subsequently arise accompanied by a progressive reduction in infant sucking with an insufficient intake of calories. In all the patients, the neurodegeneration causes frequent respiratory infections mostly related to aspiration [15]. In NPD type A, macular cherry-red spots are detectable in all infants by 12 months. This term describes the ophthalmoscopic appearance of the retina in neurometabolic disorders, like Niemann–Pick Disease. The red color of the fovea (in Caucasian patients) contrasts with the surrounding retina, which is pale for the accumulation of lipids and sphingolipids in the ganglionic cells of the retina at the macula [16][17].

3.2. Niemann–Pick Disease Type B (ASMD Type B)

NPD type B is a multisystemic disease with phenotypic heterogeneity and a variable severity and progression rate between patients. The most common clinical manifestations at onset are represented by splenomegaly and hepatomegaly. Splenomegaly is associated with recurrent bleedings, like recurrent epistaxis. However, there is no clear correlation between the rate and severity of bleeding and platelet counts, a characteristic manifestation of the disease [18]. Hepatomegaly is caused by the accumulation of the lipid-laden macrophages in the reticuloendothelial system of the liver. It can cause liver dysfunction, leading to cirrhosis and hepatic failure in some cases. Hepatic involvement, together with lung involvement, represents the most common cause of death in NPD type B [13][19]. The elevated levels of cholesterol, triglycerides, and LDL and very low levels of HDL cause, in children and adults, atherosclerosis with arteries’ calcification. Patients with ASMD type B may suffer from cardiac disease, and almost 10% have valve or coronary disease [13][19]. Skeletal involvement is also frequent in NPD type B. Delayed skeletal maturation with a growth restriction and short stature is typical. Osteopenia and osteoporosis with fractures may then occur. Moreover, Niemann–Pick cells can infiltrate the reticuloendothelial system of the bone marrow, causing leukopenia and thrombocytopenia [19][20].

3.3. Niemann–Pick Disease Type A/B (ASMD Type A/B)

An intermediate form of the disease, called ASMD or Niemann–Pick type A/B, has been described. Patients usually show all the symptoms of NPD type B but there is also neurological involvement, with extrapyramidal and cerebellar signs, nystagmus, mental retardation, and psychiatric disorders. The most common neurologic abnormalities are mild hypotonia and hyporeflexia. The onset of neurologic symptoms is later than in patients with NPD type A and are typically not characterized by a rapid progression. The precise mechanisms at the basis of the neurological involvement are not known yet. Indeed, in anatomopathological studies, the brain of patients affected by NPD type A/B with neurological involvement does not present evident abnormalities, due to a residual sphingomyelinase activity. Furthermore, one third of patients may have retinal involvement, although not always associated with the development of neurological deficits. It has also been reported that homozygotes and heterozygotes for the mutation ΔR608 seem to have a neuroprotective effect, and macular halos and cherry-red spots are less frequent in patients with this genotype [13][21][22][23].

4. The Genetic Basis of Niemann–Pick Disease Type C: Disease-Causing Mutations and Genotype–Phenotype Relationships

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 [24].
More in detail, NPC1 and NPC2 genes encode for proteins that play a crucial role in the intracellular transport of lipids, particularly cholesterol. Mutations in NPC1 or NPC2 genes lead to a shortage of functional protein, which impairs the movement of cholesterol and other lipids within cells. As a result, these lipids accumulate in cells, disrupting normal cellular functions that rely on lipids, such as the formation of cell membranes. The accumulation of lipids, along with impaired cellular functions, ultimately leads to cell death. This cell death results in the tissue and organ damage characteristic of Niemann–Pick Disease types C1 and C2. The accumulation of lipids in cells due to NPC mutations has broad implications for various organs and tissues, leading to the wide range of symptoms observed in individuals with Niemann–Pick Disease type C. These symptoms can include neurological problems, liver and spleen enlargement, and difficulties with movement and coordination, among others [25].
The NPC1 gene, in particular, exhibits significant genetic variability, with around 300 identified disease-causing mutations and over 60 polymorphisms described. Of interest, the G3097>T transversion in NPC1 is the basis for so-called Niemann–Pick D (Nova Scotian variant) [26]. In the past, early studies suggested that approximately 95% of affected families had mutations in the NPC1 gene. However, more recent research has identified a small number of families with mutations in the NPC2 gene, although these cases remain rare [27]. The NPC1 gene, located on chromosome 18q11-q12, consists of 25 exons and spans 56 kb. One of the prominent mutations in the NPC1 gene is the p.I1061T allele [28]. This mutation is particularly common, accounting for approximately 20–25% of alleles in patients diagnosed in France and the United Kingdom. It is also prevalent in a specific Spanish American isolate from the upper Rio Grande valley, but much less frequent in Portugal, Spain, or Italy. When present in the homoallelic state (meaning both alleles carry the mutation), it leads to significant abnormalities in cellular cholesterol trafficking in patient fibroblasts. Interestingly, it is associated with a juvenile neurologic onset form of the disease [29]. In the heteroallelic state (when paired with another mutation), it has not been found to be associated with the most severe infantile neurologic onset form of the disease. The p.I1061T mutant protein is functionally defective, leading to protein misfolding and its selection for degradation within the endoplasmic reticulum. This characteristic makes it a potential target for chaperone therapy, a promising approach for treating certain genetic disorders by assisting the correct folding of mutant proteins. The specific type and location of mutations in the NPC1 gene can significantly influence the severity of NPC1 in affected individuals. Mutations that disrupt critical functional domains or result in a complete loss of functional protein tend to be associated with more severe forms of the disease. In particular, patients with NPC1 who have nonsense or frameshift mutations generally experience a more severe neurological course. These types of mutations often result in a nonfunctional or truncated NPC1 protein, leading to a more severe phenotype. In patients with NPC1, missense mutations have highlighted the functional importance of specific domains within the NPC1 protein. Homozygous mutations in the sterol-sensing domain of the NPC1 protein are particularly harmful. These mutations lead to the absence of mature NPC1 protein. Patients with these mutations exhibit a very severe disease phenotype, both biochemically and clinically. The cysteine-rich luminal loop of the NPC1 protein seems to be a hotspot for genetic mutations associated with Niemann–Pick Disease type C1. This region contains about one-third of all described mutations in the NPC1 gene. Despite being a common site for mutations, the impact of these mutations can vary significantly both at the cellular and clinical levels [30][31].
Of particular note is that the cysteine-rich luminal loop contains the three most frequent mutations discussed earlier. Additionally, mutations found in this loop tend to result in a less severe impairment of cellular trafficking, leading to what is referred to as a “variant” phenotype. This means that mutations in this region may cause a milder form of the disease, affecting both the cellular processes and clinical manifestations to a lesser extent compared to mutations in other regions of the NPC1 gene [32][33].
Understanding the specific location and nature of mutations within the NPC1 gene, especially in regions like the cysteine-rich luminal loop, is crucial for predicting the clinical course of NPC1 in affected individuals. Variability in the impact of these mutations underscores the complexity of the disease and highlights the need for a detailed genetic analysis in diagnosing and understanding NPC1 and related disorders.
The NPC2 gene, also known as HE1 (Human Epididymis Protein 1), is mapped to the long arm of chromosome 14 at position 14q24.3 [34]. A specific mutation, denoted as E20X, is relatively frequent in individuals with NPD type C2 and results in a truncated NPC2 protein, which can lead to severe clinical phenotypes [27][35]. Many mutations in the NPC2 gene cause the resulting protein to be truncated, preventing it from functioning properly. These mutations are associated with very severe clinical phenotypes. Severe truncating mutations often result in early-onset, rapidly progressing forms of the disease. Unlike truncating mutations, missense mutations may not completely abolish protein function, allowing for a more varied range of phenotypes. Individuals with missense mutations may exhibit a spectrum of clinical manifestations, including juvenile and adult-onset forms of the disease.
In both NPD type C1 and C2, the study of a large number of families has demonstrated that mutations in these genes correlate with the neurological form of the disease, while the correlation with the systemic manifestations needs to be better clarified.

5. Niemann–Pick Disease Type C: Clinical Aspects

Niemann–Pick Disease type C (NPD type C) is a rare autosomal recessive lysosomal storage disorder caused by defects in cholesterol trafficking and its esterification. The prevalence of the disease ranges between 1 in 120,000 and 1 in 150,000 [36].
The clinical presentation of NPD type C is extremely diverse. Although once considered rare, it is now recognized that NPD type C is more prevalent than previously thought and should be more accurately considered as an under-recognized disease, particularly in adults [37]. Indeed, the lack of a defined phenotypic spectrum makes a clinical diagnosis challenging. The age of onset varies from the perinatal period to adulthood. Affected patients can live up to 70 years [37]. NPD type C is a neurovisceral condition. The heterogeneous organ involvement typically occurs at different times, follows an independent course, and usually precedes the onset of neurological symptoms. At the time of diagnosis, systemic involvement is not present in 15% of pediatric patients and in almost 50% of adult-onset patients. NPD type C is typically characterized by cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Most cases also exhibit a characteristic vertical supranuclear gaze palsy. Other common symptoms include seizures, cataplexy, narcolepsy, and dystonia. Furthermore, adult-onset NPD type C can be misdiagnosed because its clinical features overlap with those of more common hereditary ataxic disorders [38]. The majority of patients, including adults, die from progressive and fatal neurological diseases, while only a small subset of adult patients die from hepatic or respiratory failure. Except for the infantile forms, the systemic disease is usually not very severe, and fatal lung involvement has been reported in only a few patients with NPC2 mutations [37][39][40][41]. Thrombocytopenia and leukopenia may occur due to bone marrow infiltration by Niemann–Pick cells, while hepatosplenomegaly is a common manifestation of systemic involvement [42].
Four phenotypes of NPD type C have been described. All of these conditions are characterized by systemic involvement, followed by neurological symptoms.
Fetal and early infantile form: Fetal hydrops and fetal ascites are the most common clinical presentations of the disease during the perinatal period, which could rapidly lead to death. About 40% of patients present with prolonged neonatal cholestatic jaundice and progressive hepatosplenomegaly. It usually regresses spontaneously; in only 10% of cases, it worsens and leads to liver failure. In some cases, severe respiratory failure, including fatal cases, may occur. This phase could be followed by progressive neurodegeneration, ultimately leading to death within the first few years of life. In early childhood, the first neurological symptoms usually include central hypotonia and delayed developmental motor milestones, followed by the loss of acquired motor skills, mental regression, and spasticity with pyramidal tract involvement. An intention tremor is common, while seizures are typically absent. Brain imaging reveals indications of leukodystrophy and cerebral atrophy. The prognosis is rarely more than 5 years.
Late infantile form: This form presents with the development of seizures, a progressive language delay, gait problems, ataxia, hearing loss, vertical supranuclear gaze palsy, and eventually cataplexy and dementia. Death most commonly occurs between the ages of 7 and 12.
Juvenile form: This is the most common form, occurring in mid-to-late childhood. It is characterized by the emergence of school difficulties, ataxia, and a loss of motor abilities, followed by seizures and dementia. In children aged 5–12 years, moderate splenomegaly is common. The lifespan ranges from the late teens to 30 years old or beyond.
Adult-onset form: In adolescent and adult patients, the disease often manifests with a more gradual and subtle onset. In one-third of cases, patients exhibit only a psychiatric presentation (typically psychosis) with a normal neurological examination. Some patients exhibit a milder form of juvenile-onset ataxia, dystonia, and dysarthria with varying degrees of cognitive dysfunction. Movement disorders are very common (58%), while epilepsy is rare (15%). Dementia can often manifest [36].
The diagnosis of NPD type C is challenging. Biochemically, the diagnosis could be confirmed through filipin staining, which demonstrates free cholesterol storage in fibroblasts. However, nowadays, the diagnosis is primarily based on genetics, which involves identifying specific mutations in the NPC1 and NPC2 genes. NPC1 encodes NPC protein 1, a transmembrane protein, while NPC2 encodes NPC protein 2, a soluble lysosomal protein involved in intracellular cholesterol trafficking. In the event that NPC protein 1 or 2 is dysfunctional, cholesterol tends to accumulate in the intracellular lamellar bodies of alveolar macrophages and alveolar type 2 cells, compromising surfactant production and homeostasis [29].
Lung involvement has been reported, particularly in patients with NPC2 mutations, leading to clinical manifestations such as alveolar proteinosis [43].

References

  1. Takahashi, T.; Suchis, M.; Desnicks, R.J.; Takadag, G.; Schuchmanst, E.H. Identification and Expression of Five Mutations in the Human Acid Sphingomyelinase Gene Causing Types A and B Niemann-Pick Disease. Molecular Evidence for Genetic Heterogeneity in the Neuronopathic and Non-Neuronopathic Forms. J. Biol. Chem. Med. Mol. Genet. 1992, 267, 12552–12558.
  2. Wang, R.; Qin, Z.; Huang, L.; Luo, H.; Peng, H.; Zhou, X.; Zhao, Z.; Liu, M.; Yang, P.; Shi, T. SMPD1 expression profile and mutation landscape help decipher genotype–phenotype association and precision diagnosis for acid sphingomyelinase deficiency. Hereditas 2023, 160, 11.
  3. Zampieri, S.; Filocamo, M.; Pianta, A.; Lualdi, S.; Gort, L.; Coll, M.J.; Sinnott, R.; Geberhiwot, T.; Bembi, B.; Dardis, A. SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. Hum. Mutat. 2016, 37, 139–147.
  4. Dardis, A.; Zampieri, S.; Filocamo, M.; Burlina, A.; Bembi, B.; Pittis, M.G. Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann-Pick Type B disease. Hum. Mutat. 2005, 26, 164.
  5. Tóth, B.; Erdős, M.; Székely, A.; Ritli, L.; Bagossi, P.; Sümegi, J.; Maródi, L. Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing Niemann-Pick Disease. JIMD Rep. 2012, 3, 125–129.
  6. Levran, O.; Desnick, R.J.; Schuchman, E.H. Type A Niemann-Pick Disease: A frameshift mutation in the acid sphingomyelinase gene (fsP330) occurs in Ashkenazi Jewish patients. Hum. Mutat. 1993, 2, 317–319.
  7. Levran, O.; Desnick, R.J.; Schuchman, E.H. Identification and Expression of a Common Missense Mutation (L302P) in the Acid Sphingomyelinase Gene of Ashkenazi Jewish Type A Niemann-Pick Disease Patients. Blood 1992, 80, 2081–2087.
  8. Levran, O.; Desnick, R.J.; Schuchman, E.H. Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients. J. Clin. Investig. 1991, 88, 806–810.
  9. Levran, O.; Desnick, R.J.; Schuchman, E.H. Niemann-Pick Disease: A frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients. Proc. Natl. Acad. Sci. USA 1991, 88, 3748–3752.
  10. Torres, S.; Balboa, E.; Zanlungo, S.; Enrich, C.; Garcia-Ruiz, C.; Fernandez-Checa, J.C. Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease. Front. Physiol. 2017, 8, 982.
  11. Schuchman, E.H.; Desnick, R.J. Types A and B Niemann-Pick Disease. Mol. Genet. Metab. 2017, 120, 27–33.
  12. Simonaro, C.M.; Desnick, R.J.; McGovern, M.M.; Wasserstein, M.P.; Schuchman, E.H. The demographics and distribution of type B Niemann-Pick Disease: Novel mutations lead to new genotype/phenotype correlations. Am. J. Hum. Genet. 2002, 71, 1413–1419.
  13. McGovern, M.M.; Avetisyan, R.; Sanson, B.J.; Lidove, O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J. Rare Dis. 2017, 12, 41.
  14. Rossi, G.; Cavazza, A.; Spagnolo, P.; Bellafiore, S.; Kuhn, E.; Carassai, P.; Caramanico, L.; Montanari, G.; Cappiello, G.; Nannini, N.; et al. The role of macrophages in interstitial lung diseases: Number 3 in the Series ‘Pathology for the clinician’ Edited by Peter Dorfmüller and Alberto Cavazza. Eur. Respir. Rev. 2017, 26, 170009.
  15. McGovern, M.M.; Aron, A.; Brodie, S.E.; Desnick, R.J.; Wasserstein, M.P. Natural history of Type A Niemann-Pick Disease: Possible endpoints for therapeutic trials. Neurology 2006, 66, 228–232.
  16. Ospina, L.H.; Lyons, C.J.; McCormick, A.Q. ‘Cherry-red spot’ or ‘perifoveal white patch’? Can. J. Ophthalmol. 2005, 40, 609–610.
  17. Leavitt, J.A.; Kotagal, S. The ‘cherry red’ spot. Pediatr. Neurol. 2007, 37, 74–75.
  18. McGovern, M.M.; Wasserstein, M.P.; Giugliani, R.; Bembi, B.; Vanier, M.T.; Mengel, E.; Brodie, S.E.; Mendelson, D.; Skloot, G.; Cox, G.F.; et al. A prospective, cross-sectional survey study of the natural history of Niemann-Pick Disease type B. Pediatrics 2008, 122, e341–e349.
  19. Simpson, W.L.; Mendelson, D.; Wasserstein, M.P.; McGovern, M.M. Imaging manifestations of Niemann-Pick Disease type B. AJR. Am. J. Roentgenol. 2010, 194, W12–W19.
  20. Wasserstein, M.P.; Larkin, A.E.; Glass, R.B.; Schuchman, E.H.; Desnick, R.J.; McGovern, M.M. Growth restriction in children with type B Niemann-Pick Disease. J. Pediatr. 2003, 142, 424–428.
  21. Wasserstein, M.P.; Aron, A.; Brodie, S.E.; Simonaro, C.; Desnick, R.J.; McGovern, M.M. Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick Disease. J. Pediatr. 2006, 149, 554–559.
  22. McGovern, M.M.; Wasserstein, M.P.; Aron, A.; Desnick, R.J.; Schuchman, E.H.; Brodie, S.E. Ocular manifestations of Niemann-Pick Disease type B. Ophthalmology 2004, 111, 1424–1427.
  23. Gülhan, B.; Özçelik, U.; Gürakan, F.; Güçer, Ş.; Orhan, D.; Cinel, G.; Yalcin, E.; Ersoz, D.D.; Kiper, N.; Kale, G.; et al. Different features of lung involvement in Niemann-Pick Disease and Gaucher disease. Respir. Med. 2012, 106, 1278–1285.
  24. Vance, J.E. Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett. 2006, 580, 5518–5524.
  25. Vanier, M.T.; Rodriguez-Lafrasse, C.; Rousson, R.; Duthel, S.; Harzer, K.; Pentchev, P.G.; Revol, A.; Louisot, P. Type C Niemann-Pick Disease: Biochemical aspects and phenotypic heterogeneity. Dev. Neurosci. 1991, 13, 307–314.
  26. Greer, W.L.; Riddell, D.C.; Gillan, T.L.; Girouard, G.S.; Sparrow, S.M.; Byers, D.M.; Dobson, M.J.; Neumann, P.E. The Nova Scotia (type D) form of Niemann-Pick Disease is caused by a G3097-->T transversion in NPC1. Am. J. Hum. Genet. 1998, 63, 52–54.
  27. Verot, L.; Chikh, K.; Freydière, E.; Honoré, R.; Vanier, M.T.; Millat, G. Niemann-Pick C disease: Functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clin. Genet. 2007, 71, 320–330.
  28. Millat, G.; Marçais, C.; Rafi, M.A.; Yamamoto, T.; Morris, J.A.; Pentchev, P.G.; Ohno, K.; Wenger, D.A.; Vanier, M.T. Niemann-Pick C1 disease: The I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am. J. Hum. Genet. 1999, 65, 1321–1329.
  29. Ramirez, C.M.; Lopez, A.M.; Le, L.Q.; Posey, K.S.; Weinberg, A.G.; Turley, S.D. Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann-Pick type C disease. Biochim. Biophys. Acta 2014, 1841, 54–61.
  30. Millat, G.; Marçais, C.; Tomasetto, C.; Chikh, K.; Fensom, A.H.; Harzer, K.; Wenger, D.A.; Ohno, K.; Vanier, M.T. Niemann-Pick C1 disease: Correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am. J. Hum. Genet. 2001, 68, 1373–1385.
  31. Greer, W.L.; Dobson, M.J.; Girouard, G.S.; Byers, D.M.; Riddell, D.C.; Neumann, P.E. Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. Am. J. Hum. Genet. 1999, 65, 1252–1260.
  32. Sun, X.; Marks, D.L.; Park, W.D.; Wheatley, C.L.; Puri, V.; O’Brien, J.F.; Kraft, D.L.; Lundquist, P.A.; Patterson, M.C.; Snow, K.; et al. Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am. J. Hum. Genet. 2001, 68, 1361–1372.
  33. Park, W.D.; O’Brien, J.F.; Lundquist, P.A.; Kraft, D.L.; Vockley, C.W.; Karnes, P.S.; Patterson, M.C.; Snow, K. Identification of 58 novel mutations in Niemann-Pick Disease type C: Correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum. Mutat. 2003, 22, 313–325.
  34. Naureckiene, S.; Sleat, D.E.; Lackland, H.; Fensom, A.; Vanier, M.T.; Wattiaux, R.; Jadot, M.; Lobel, P. Identification of HE1 as the second gene of Niemann-Pick C disease. Science 2000, 290, 2298–2301.
  35. Millat, G.; Chikh, K.; Naureckiene, S.; Sleat, D.E.; Fensom, A.H.; Higaki, K.; Elleder, M.; Lobel, P.; Vanier, M.T. Niemann-Pick Disease type C: Spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am. J. Hum. Genet. 2001, 69, 1013–1021.
  36. Vanier, M.T. Niemann-Pick Disease type C. Orphanet J. Rare Dis. 2010, 5, 1.
  37. Geberhiwot, T.; Moro, A.; Dardis, A.; Ramaswami, U.; Sirrs, S.; Marfa, M.P.; Vanier, M.T.; Walterfang, M.; Bolton, S.; International Niemann-Pick Disease Registry (INPDR); et al. Consensus clinical management guidelines for Niemann-Pick Disease type C. Orphanet J. Rare Dis. 2018, 13, 50.
  38. Vo, M.L.; Levy, T.; Lakhani, S.; Wang, C.; Ross, M.E. Adult-onset Niemann-Pick Disease type C masquerading as spinocerebellar ataxia. Mol. Genet. Genom. Med. 2022, 10, 1906.
  39. Patterson, M.C. A riddle wrapped in a mystery: Understanding Niemann-Pick Disease, type C. Neurologist 2003, 9, 301–310.
  40. Vanier, M.T.; Millat, G. Niemann-Pick Disease type C. Clin. Genet. 2003, 64, 269–281.
  41. Wraith, J.E.; Baumgartner, M.R.; Bembi, B.; Covanis, A.; Levade, T.; Mengel, E.; Pineda, M.; Sedel, F.; Topcu, M.; Patterson, M.C.; et al. Recommendations on the diagnosis and management of Niemann-Pick Disease type C. Mol. Genet. Metab. 2009, 98, 152–165.
  42. Guillemot, N.; Troadec, C.; De Villemeur, T.B.; Clément, A.; Fauroux, B. Lung disease in Niemann-Pick Disease. Pediatr. Pulmonol. 2007, 42, 1207–1214.
  43. Griese, M.; Brasch, F.; Aldana, V.R.; Cabrera, M.M.; Goelnitz, U.; Ikonen, E.; Karam, B.J.; Liebisch, G.; Linder, M.D.; Lezana, F.J.; et al. Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis. Clin. Genet. 2010, 77, 119–130.
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Subjects: Genetics & Heredity
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Claudio Tirelli , Ornella Rondinone , Marta Italia ,
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