scholarly journals Exome sequence analysis of siblings affected with Niemann-Pick type C disease

2021 ◽  
Author(s):  
◽  
Shaun Carswell
Keyword(s):  
Disease Severity ◽  
Age Of Onset ◽  
Monogenic Disease ◽  
Chromosome 11 ◽  
Unesterified Cholesterol ◽  
Pulmonary Tissue ◽  
Sibling Pairs ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene

<p>Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease.</p>

scholarly journals Exome sequence analysis of siblings affected with Niemann-Pick type C disease

2021 ◽  
Author(s):  
◽  
Shaun Carswell
Keyword(s):  
Disease Severity ◽  
Age Of Onset ◽  
Monogenic Disease ◽  
Chromosome 11 ◽  
Unesterified Cholesterol ◽  
Pulmonary Tissue ◽  
Sibling Pairs ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene

<p>Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease.</p>

scholarly journals Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model

2021 ◽  
Author(s):  
◽  
Natalie Hammond
Keyword(s):  
Clinical Trial ◽  
Liver Disease ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Therapeutic Efficacy ◽  
Premature Death ◽  
Unesterified Cholesterol ◽  
Deacetylase Inhibitor ◽  
Type C ◽  
Niemann Pick

<p>Niemann-Pick type C (NPC) disease is a rare neuro-visceral, lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late endosomal/lysosomal cholesterol transport genes NPC1 (95%) or NPC2 (5%) are the causative factors which leads to an accumulation of unesterified cholesterol and sphingolipids in the late endosome/lysosome. It is a build-up of these lipids that, in the majority of cases, ultimately leads to premature death prior to adolescence. In recent years, an imbalance of histone acetylation in a yeast model of NPC disease and subsequently an increased expression of histone deacetylase genes in NPC patient fibroblasts relative to healthy controls was discovered. This led to the finding that Vorinostat (suberoylanilide hydroxamic acid (SAHA); Zolinza®) a histone deacetylase inhibitor (HDACi) drug, rescued unesterified cholesterol accumulation in NPC patient fibroblasts. From these findings in NPC patient fibroblasts, a Phase I clinical trial testing the efficacy of orally-administered Vorinostat in adult NPC disease patients commenced in 2014; however, the therapeutic efficacy of Vorinostat in a whole animal model of NPC disease has not been investigated and is thus unknown. In this thesis, the therapeutic efficacy of intra-peritoneal administered 150 mg/kg Vorinostat in the Npc1nmf164 mouse was explored. This internationally approved HDACi reduced liver disease by decreasing lipid accumulation without increasing expression of NPC1; however, the treatment did not delay weight loss, onset of ataxia and premature death, possibly due to insufficient concentrations penetrating through the blood brain barrier. Transcriptome analysis suggested Vorinostat improved liver disease in a pleiotropic manner, not surprising given the epigenetic nature of HDACi at the gene expression level. Overall, the results herein are of particular importance to the current clinical trial where the therapeutic efficacy is being investigated without any knowledge of efficacy in an animal of NPC disease.</p>

scholarly journals Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

2021 ◽  
Vol 22 (16) ◽  
pp. 8858
Author(s):  
Antonietta Bernardo ◽  
Chiara De Nuccio ◽  
Sergio Visentin ◽  
Alberto Martire ◽  
Luisa Minghetti ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Autophagic Flux ◽  
Unesterified Cholesterol ◽  
A2a Adenosine Receptor ◽  
Disease Mechanisms ◽  
Mitochondrial Functions ◽  
Type C ◽  
Niemann Pick ◽  
Cellular Compartments ◽  
The Brain

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.

Impacts and Burden of Niemann Pick Type-C: A Patient and Caregiver Perspective

2021 ◽  
Author(s):  
Eugen Mengel ◽  
Marc C Patterson ◽  
Michael Chladek ◽  
Christina Guldberg ◽  
Christine íDali ◽  
...  
Keyword(s):  
Lived Experience ◽  
Motor Skills ◽  
Age Of Onset ◽  
Fine Motor ◽  
Fine Motor Skills ◽  
Increased Risk ◽  
Wide Range ◽  
Type C ◽  
Niemann Pick ◽  
The Impact

Abstract Background Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients’ and caregivers’ quality of life (QOL) and reduces the patient’s life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients’ and caregivers’ daily lives to understand the burden of disease.Results A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months – 65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients’ and caregivers’ activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL.Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients’ and caregivers’ HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers).ConclusionsAmbulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.Trial registrationNCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129

scholarly journals Synthesis of multi-lactose-appended β-cyclodextrin and its cholesterol-lowering effects in Niemann–Pick type C disease-like HepG2 cells

2017 ◽  
Vol 13 ◽  
pp. 10-18 ◽  
Author(s):  
Keiichi Motoyama ◽  
Rena Nishiyama ◽  
Yuki Maeda ◽  
Taishi Higashi ◽  
Yoichi Ishitsuka ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
High Dose ◽  
Unesterified Cholesterol ◽  
Peanut Lectin ◽  
Cholesterol Lowering ◽  
Cholesterol Levels ◽  
Type C ◽  
Intracellular Cholesterol ◽  
Niemann Pick ◽  
Very High

Niemann–Pick type C (NPC) disease, characterized by intracellular accumulation of unesterified cholesterol and other lipids owing to defects in two proteins NPC1 and NPC2, causes neurodegeneration and other fatal neurovisceral symptoms. Currently, treatment of NPC involves the use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD is effective in the treatment of hepatosplenomegaly in NPC disease, albeit at a very high dose. One of the methods to reduce the required dose of HP-β-CD for treatment of NPC is to actively targeting hepatocytes with β-cyclodextrin (β-CD). The aim of the present study was to synthesize a novel multi-lactose-appended β-CD (multi-Lac-β-CD) and to evaluate its cholesterol-lowering effect in U18666A-treated HepG2 (NPC-like HepG2) cells. Further, the study aimed at delivering β-CD to hepatocytes via cholesterol-accumulated HepG2 cells, and indicated that the newly synthesized multi-Lac-β-CD had an average degree of substitution of lactose (DSL) of 5.6. This newly synthesized multi-Lac-β-CD was found to significantly decrease the concentration of intracellular cholesterol with negligible cytotoxicity as compared to HP-β-CD. An increased internalization of TRITC-multi-Lac-β-CD (DSL 5.6) as compared to TRITC-HP-β-CD was observed in NPC-like HepG2 cells. Further, the dissociation constant of peanut lectin with multi-Lac-β-CD (DSL5.6) was found to be extremely low (2.5 × 10−8 M). These results indicate that multi-Lac-β-CD (DSL5.6) diminished intracellular cholesterol levels in NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis.

scholarly journals Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
G. D’Arcangelo ◽  
D. Grossi ◽  
M. Racaniello ◽  
A. Cardinale ◽  
A. Zaratti ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Autosomal Recessive ◽  
Neurological Deficits ◽  
Synaptic Potentiation ◽  
Unesterified Cholesterol ◽  
Severe Dementia ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found thatin vivoMiglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

scholarly journals Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C

2009 ◽  
Vol 9999B ◽  
pp. n/a-n/a ◽  
Author(s):  
Nicole M. Yanjanin ◽  
Jorge I. Vélez ◽  
Andrea Gropman ◽  
Kelly King ◽  
Simona E. Bianconi ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Disease Type ◽  
Clinical Progression ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Characterization of a Spontaneous Novel Mutation in the NPC2 Gene in a Cat Affected by Niemann Pick Type C Disease

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112503 ◽  
Author(s):  
Stefania Zampieri ◽  
Ezio Bianchi ◽  
Carlo Cantile ◽  
Roberta Saleri ◽  
Bruno Bembi ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene

scholarly journals Clinical Disease Progression and Biomarkers in Niemann–Pick Disease Type C: A Prospective Cohort Study

2020 ◽  
Author(s):  
Eugen Mengel ◽  
Bruno Bembi ◽  
Mireia del Toro ◽  
Federica Deodato ◽  
Matthias Gautschi ◽  
...  
Keyword(s):  
Disease Progression ◽  
Clinical Care ◽  
Healthy Individuals ◽  
Unesterified Cholesterol ◽  
Rater Reliability ◽  
Routine Clinical Care ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Abstract BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937).ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.Trial Registration: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030; EudraCT 2014-005194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE. OR-REL-NPC-01: Unregistered.

Sign in / Sign up

Export Citation Format

Share Document