Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States

Burton, Barbara K.; Ellis, Alexandra G.; Orr, Blair; Chatlani, Shilpa; Yoon, Kwangchae; Shoaff, Jessica R.; Gallo, Dan

doi:10.1016/j.ymgme.2021.06.011

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…The disease is highly heterogeneous and may present from the perinatal period to the seventh decade of life, although most subjects develop symptoms in childhood and die between 10 and 25 years of age [1,[4][5][6]12,13]. The diagnosis of NPC is often delayed in part due to the wide spectrum of clinical phenotypes, which are likely related to underlying genotypes (515 estimated pathogenic mutations) and epigenetic modifiers [5,6,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial

Hastings

Liu

Hurst

et al. 2022

Molecular Genetics and Metabolism

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Section: Introductionmentioning

confidence: 99%

Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial

Hastings

Liu

Hurst

et al. 2022

Molecular Genetics and Metabolism

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“…Albeit the NPC1 and NPC2 complementation groups are indistinguishable biochemically and clinically, it is commonly called NPC1 and NPC2 disease in the literature [58]. However, the high heterogeneity in the clinical manifestations of NPC disease hinders the diagnosis [59]. For these reasons, the diagnosis of NPC disease can take a very long time, even years, and must be assisted by specialists in various disciplines [60][61][62].…”

Section: Niemann Pick Type C Diseasementioning

confidence: 99%

The Antifungal Antibiotic Filipin as a Diagnostic Tool of Cholesterol Alterations in Lysosomal Storage Diseases and Neurodegenerative Disorders

et al. 2023

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Cholesterol is the most considerable member of a family of polycyclic compounds understood as sterols, and represents an amphipathic molecule, such as phospholipids, with the polar hydroxyl group located in position 3 and the rest of the molecule is completely hydrophobic. In cells, it is usually present as free, unesterified cholesterol, or as esterified cholesterol, in which the hydroxyl group binds to a carboxylic acid and thus generates an apolar molecule. Filipin is a naturally fluorescent antibiotic that exerts a primary antifungal effect with low antibacterial activity, interfering with the sterol stabilization of the phospholipid layers and favoring membrane leakage. This polyene macrolide antibiotic does not bind to esterified sterols, but only to non-esterified cholesterol, and it is commonly used as a marker to label and quantify free cholesterol in cells and tissues. Several lines of evidence have indicated that filipin staining could be a good diagnostic tool for the cholesterol alterations present in neurodegenerative (e.g., Alzheimer’s Disease and Huntington Disease) and lysosomal storage diseases (e.g., Niemann Pick type C Disease and GM1 gangliosidosis). Here, we have discussed the uses and applications of this fluorescent molecule in lipid storage diseases and neurodegenerative disorders, exploring not only the diagnostic strength of filipin staining, but also its limitations, which over the years have led to the development of new diagnostic tools to combine with filipin approach.

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“…NPC1 is a rare disease but the number of patients suffering from NPC may be underestimated or misdiagnosed due to challenges in detecting the disease. 42 Current diagnostic methods such as filipin staining of cholesterol in fibroblasts and mass spectrometry detection of oxysterols are rather unspecific since these lipids may be increased due to other lysosomal storage disorders. 43 Thus, we were curious if our fluorogenic probe 12 identifies cells with a buildup of sphingosine and potentially offer a complementary diagnostic approach.…”

Section: ■ Development Of a Fluorogenic Probe For The Direct Detectio...mentioning

confidence: 99%

“…We next explored if we could detect elevated endogenous sphingosine levels in diseased cell lines. NPC1 is a rare disease but the number of patients suffering from NPC may be underestimated or misdiagnosed due to challenges in detecting the disease . Current diagnostic methods such as filipin staining of cholesterol in fibroblasts and mass spectrometry detection of oxysterols are rather unspecific since these lipids may be increased due to other lysosomal storage disorders .…”

Section: Development Of a Fluorogenic Probe For The Direct Detection ...mentioning

confidence: 99%

Bioconjugation Strategies for Revealing the Roles of Lipids in Living Cells

Knittel

Devaraj

2022

Acc. Chem. Res.

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Conspectus The structural boundaries of living cells are composed of numerous membrane-forming lipids. Lipids not only are crucial for the cellular compartmentalization but also are involved in cell signaling as well as energy storage. Abnormal lipid levels have been linked to severe human diseases such as cancer, multiple sclerosis, neurodegenerative diseases, as well as lysosomal storage disorders. Given their biological significance, there is immense interest in studying lipids and their effect on cells. However, limiting factors include the low solubility of lipids, their structural complexity, and the challenge of using genetic techniques to directly manipulate lipid structure. Current methods to study lipids rely mostly on lipidomics, which analyzes the composition of lipid extracts using mass spectrometry. Although, these efforts have successfully catalogued and profiled a great number of lipids in cells, many aspects about their exact functional role and subcellular distribution remain enigmatic. In this Account, we outline how our laboratory developed and applied different bioconjugation strategies to study the role of lipids and lipid modifications in cells. Inspired by our ongoing work on developing lipid bioconjugation strategies to generate artificial cell membranes, we developed a ceramide synthesis method in live cells using a salicylaldehyde ester that readily reacts with sphingosine in form of a traceless ceramide ligation. Our study not only confirmed existing knowledge about the association of ceramides with cell death, but also gave interesting new findings about the structure–function relationship of ceramides in apoptosis. Our initial efforts led us to investigate probes that detect endogenous sphingolipids using live cell imaging. We describe the development of a fluorogenic probe that reacts chemoselectively with sphingosine in living cells, enabling the detection of elevated endogenous levels of this biomarker in human disease. Building on our interest in the fluorescence labeling of lipids, we have also explored the use of bioorthogonal reactions to label chemically synthesized lipid probes. We discuss the development of photocaged dihydrotetrazine lipids, where the initiation of the bioorthogonal reaction can be triggered by visible light, allowing for live cell modification of membranes with spatiotemporal control. Finally, proteins are often post-translationally modified by lipids, which have important effects on protein subcellular localization and function. Controlling lipid modifications with small molecule probes could help reveal the function of lipid post-translational modifications and could potentially inspire novel therapeutic strategies. We describe how our previous studies on synthetic membrane formation inspired us to develop an amphiphilic cysteine derivative that depalmitoylates membrane-bound S-acylated proteins in live cells. Ultimately, we applied this amphiphile mediated depalmitoylation (AMD) in studies investigating the palmitoylation of cancer relevant palmitoylat...

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Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States

Cited by 13 publications

References 17 publications

Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial

Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial

The Antifungal Antibiotic Filipin as a Diagnostic Tool of Cholesterol Alterations in Lysosomal Storage Diseases and Neurodegenerative Disorders

Bioconjugation Strategies for Revealing the Roles of Lipids in Living Cells

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