Niemann-Pick type C disease – the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment

Evans, Will; Hendriksz, Christian J.

doi:10.1192/pb.bp.116.054072

Cited by 49 publications

(43 citation statements)

References 36 publications

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“…Of note, our data reveal an increased synaptic pruning in Npc1 -/brains that could compromise neuronal connectivity as described in AD, schizophrenia and Grn -/models (Filipello, Morini et al, 2018, Hong, Beja-Glasser et al, 2016, Lui, Zhang et al, 2016, Sellgren, Gracias et al, 2019. Psychiatric symptoms have been described in NPC patients, including mental retardation, behavioral problems, schizophrenia-like psychosis, bipolar disorder, and attention deficit hyperactivity disorder (Bonnot et al, 2019b, Evans & Hendriksz, 2017. Further work is needed to clarify whether excessive microglial activity and synaptic pruning contribute to psychiatric manifestations reported in NPC patients.…”

Section: Discussionsupporting

confidence: 56%

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo

Dinkel

Müller

et al. 2019

Preprint

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Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in Npc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1 -/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking in Npc1 -/microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies of Npc1 -/microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novel ex vivo assays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murine Npc1 -/microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.

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Section: Discussionsupporting

confidence: 56%

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo

Dinkel

Müller

et al. 2019

Preprint

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“…Future studies could investigate the utility of eye tracking data to screen for NP-C in populations of patients that present with symptoms that are associated NP-C, for example, in patients with early-onset ataxia and / or frontotemporal dementia. It is thought that NP-C may be undiagnosed in some patient groups that display symptoms associated with NP-C, but where the symptoms are not diagnostic on their own [26][27][28] . Eye-tracking measures could contribute to identify those patients that warrant further follow-up investigation.…”

Section: Resultsmentioning

confidence: 99%

Oculomotor abnormalities in children with Niemann-Pick type C

Blundell

Frisson

Chakrapani

et al. 2018

Molecular Genetics and Metabolism

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Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye tracking to record monocular vertical and horizontal eye movements in 2 neurological NP-C patients (children with clinically observable oculomotor abnormalities) and 3 pre-neurological NP-C patients (children without clinically observable oculomotor abnormalities). Saccade onset latency, saccade peak velocity and saccade curvature were compared to healthy controls (N=77). NP-C patients had selective impairments of vertical saccade peak velocity and vertical saccade curvature, with slower peak velocities and greater curvature. Changes were more pronounced in neurological than pre-neurological patients, showing that these measures are sensitive to disease progress, but abnormal curvature and slowed downward saccades were present in both groups, showing that eye-tracking can register disease-related changes before these are evident in a clinical exam. Both slowing, curvature and the detailed characteristics of the curvature we observed are predicted by the detailed characteristics of RIMLF population codes. Onset latencies were not different from healthy controls. High-resolution video-based eye tracking is a promising sensitive and objective method to measure NP-C disease severity and neurological onset. It may also help evaluate responses to therapeutic interventions.

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“…Niemann-Pick type C (NPC) is a rare (∼1:150,000), pan-ethnic, globally occurring, inherited progressive neurodegenerative disorder characterized by an intracellular accumulation of cholesterol and other lipids like glycosphingolipids, sphingomyelin and sphingosine in the lysosomes and late endosomes [37,76]. Alan Crocker and Sydney Farber ∼1958 defined Niemann-Pick disease (the first case study of this disease was on Niemann-Pick family) based on an overview of tissue pathology; however, it was not until 1966 that the first molecular understanding of the disease came from Roscoe Brady's discovery of acid sphingomyelinase deficiency (later classified as Niemann-Pick types A and B) in these patients [16,123].…”

Section: Niemann-pick C Diseasementioning

confidence: 99%

Cholesterol: Revisiting its fluorescent journey on 200th anniversary of Chevruel’s “cholesterine”

Chaudhuri

Anand

2017

BSI

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The legacy of Micheal Chevruel's discovery of "cholesterine" as a non-saponifiable lipid from gall stones has ignited the imagination and research of countless minds for over two centuries now. In this review, we have provided a brief chronicle of the early history of cholesterol research which paved the way to present day understanding of membrane biology. We have discussed the properties and functionality of various fluorescent analogs of cholesterol in view of the ultra-high sensitivity, rapid response and spatial resolution obtained using fluorescence spectroscopic, microscopic and flow cytometric techniques. The repertoire of fluorescent analogs discussed for cholesterol research include the naturally occurring analogs (dehydroergosterol and cholestatrienol); polarity sensitive probes (NBD-and dansyl-cholesterol); bright and photostable probe (BODIPY-cholesterol); clickable alkyne cholesterol and cholesterol binding macromolecules (fluorescently labeled non-toxic subunits of perfringolysin O and filipin) in monitoring cholesterol content in live and fixed cells. We have elaborated on the applications of the fluorescent analogs of cholesterol in clinical research, taking atherosclerosis, Niemann-Pick C and Alzheimer's disease as representative examples. The applicability of fluorescent probes of cholesterol has become more relevant with the advent of various super-resolution microscopic techniques today and holds the promise of shedding light into the molecular orchestra of lipid-protein interaction with nanometer-scale resolution.

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Niemann-Pick type C disease – the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment

Cited by 49 publications

References 36 publications

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Oculomotor abnormalities in children with Niemann-Pick type C

Cholesterol: Revisiting its fluorescent journey on 200th anniversary of Chevruel’s “cholesterine”

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