pick disease
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2022 ◽  
Vol 12 ◽  
Author(s):  
Jiang Du ◽  
Xinlei Liu ◽  
Yan Zhang ◽  
Xiaojing Han ◽  
Chunya Ma ◽  
...  

Niemann–Pick disease type C1 (NPC1) is a neurodegenerative disorder characterized by lysosomal storage of free cholesterol. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a cyclic oligosaccharide derivative that is being developed to treat NPC1. Recently, metformin was reported to be beneficial in various neurodegenerative diseases, such as Alzheimer’s and Huntington’s diseases. In this study, we examined the effects of combined treatment with HPβCD and metformin on Npc1−/− mice. Unfortunately, body weight and survival rates showed that cotreatment with metformin did not extend survival time and increase the body weight of HPβCD-treated Npc1−/− mice. However, cotreatment with metformin reduced inflammatory response and inhibited the proinflammatory cytokine release in the brain, liver and spleen of HPβCD-treated Npc1−/− mice. Furthermore, metformin did not reduce the free cholesterol levels in Npc1−/− brain tissue or fibroblasts. In conclusion, our results demonstrate that metformin does not show beneficial effects on body weight or survival time but reduced the inflammatory response in a mouse model of NPC1 when combined with HPβCD.


2022 ◽  
Vol 7 ◽  
pp. 11
Author(s):  
Isabelle Williams ◽  
Sumeet Pandey ◽  
Wolfram Haller ◽  
Hein Q. Huynh ◽  
Alicia Chan ◽  
...  

Background:  Blockade of tumour necrosis factor (anti-TNF) is effective in patients with Crohn’s Disease but has been associated with infection risk and neurological complications such as demyelination. Niemann-Pick disease Type C1 (NPC1) is a lysosomal storage disorder presenting in childhood with neurological deterioration, liver damage and respiratory infections. Some NPC1 patients develop severe Crohn’s disease. Our objective was to investigate the safety and effectiveness of anti-TNF in NPC1 patients with Crohn’s disease. Methods: Retrospective data on phenotype and therapy response were collected in 2019-2020 for the time period 2014 to 2020 from patients in the UK, France, Germany and Canada with genetically confirmed NPC1 defects and intestinal inflammation. We investigated TNF secretion in peripheral blood mononuclear cells treated with NPC1 inhibitor in response to bacterial stimuli. Results: NPC1 inhibitor treated peripheral blood mononuclear cells (PBMCs) show significantly increased TNF production after lipopolysaccharide or bacterial challenge providing a rationale for anti-TNF therapy. We identified 4 NPC1 patients with Crohn’s disease (CD)-like intestinal inflammation treated using anti-TNF therapy (mean age of onset 8.1 years, mean treatment length 27.75 months, overall treatment period 9.25 patient years). Anti-TNF therapy was associated with reduced gastrointestinal symptoms with no apparent adverse neurological events. Therapy improved intestinal inflammation in 4 patients. Conclusions: Anti-TNF therapy appears safe in patients with NPC1 and is an effective treatment strategy for the management of intestinal inflammation in these patients.


2022 ◽  
Vol 11 (1) ◽  
pp. 247
Author(s):  
Moein Mobini ◽  
Shabnam Radbakhsh ◽  
Francyne Kubaski ◽  
Peyman Eshraghi ◽  
Saba Vakili ◽  
...  

Background and Aims: Niemann–Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients. Methods: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial. Trehalose was administrated intravenously (IV) (15 g/week) for three months. The efficacy of trehalose in the management of clinical symptoms was evaluated in patients by assessing the quality of life, serum biomarkers, and high-resolution computed tomography (HRCT) of the lungs at the baseline and end of the interventional trial (day 0 and week 12). Results: The mean of TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients after intervention at W12 compared to the baseline W0, although the difference was not statistically significant. The serum levels of lyso-SM-509 and lyso-SM were decreased in three and four patients out of five, respectively, compared with baseline. Elevated ALT and AST levels were decreased in all patients after 12 weeks of treatment; however, changes were not statistically significant. Pro-oxidant antioxidant balance (PAB) was also decreased and glutathione peroxidase (GPX) activity was increased in serum of patients at the end of the study. Imaging studies of spleen and lung HRCT showed improvement of symptoms in two patients. Conclusions: Positive trends in health-related quality of life (HRQoL), serum biomarkers, and organomegaly were observed after 3 months of treatment with trehalose in patients with NPA and NPB. Although not statistically significant, due to the small number of patients enrolled, these results are encouraging and should be further explored.


2021 ◽  
Vol 4 (2) ◽  
pp. 131-132
Author(s):  
Zara Arshad ◽  
Nimra Rana ◽  
Wajahat Sultan Baig

We hereby report a rare case of a young child with Niemann-Pick disease who had multiple hospital admissions due to repeated gastrointestinal and respiratory tract infections. The disease is overall quite rare in our population however, our case highlights the fact that in any young child with repeated infections of unknown etiology, this condition should be considered and evaluated.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
William Evans ◽  
Marc Patterson ◽  
Frances Platt ◽  
Christina Guldberg ◽  
Toni Mathieson ◽  
...  

Abstract Background Several scales have been developed in the past two decades to evaluate Niemann–Pick disease Type C (NPC) severity in clinical practice and trials. However, a lack of clarity concerning which scale to use in each setting is preventing the use of standardised assessments across the world, resulting in incomparable data sets and clinical trial outcome measures. This study aimed to establish agreed approaches for the use of NPC severity scales in clinical practice and research. Methods A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked nine multiple-choice and open-ended questions to gather opinions on the six severity scales and domains. In Rounds 2 and 3, questions aimed to gain consensus on the opinions revealed in Round 1 using a typical Likert scale. Results Nineteen experts, active in NPC paediatric and adult research and treatment, participated in this study. Of these, 16/19 completed Rounds 1 and 2 and 19/19 completed Round 3. Consensus (defined as ≥ 70% agreement or neutrality, given the study aim to identify the severity scales that the clinical community would accept for international consistency) was achieved for 66.7% of the multiple-choice questions in Round 2 and 83% of the multiple-choice questions in Round 3. Consensus was almost reached (68%) on the use of the 5-domain NPCCSS scale as the first choice in clinical practice. Consensus was reached (74%) for the 17-domain NPCCSS scale as the first choice in clinical trial settings, but the domains measured in the 5-domain scale should be prioritised as the primary endpoints. Experts called for educational and training materials on how to apply the NPCCSS (17- and 5-domains) for clinicians working in NPC. Conclusions In achieving a consensus on the use of the 17-domain NPCCSS scale as the first choice for assessing clinical severity of NPC in clinical trial settings but prioritising the domains in the 5-domain NPCCSS scale for routine clinical practice, this study can help to inform future discussion around the use of the existing NPC clinical severity scales. For routine clinical practice, the study helps provide clarity on which scale is favoured by a significant proportion of a representative body of experts, in this case, the 5-domain NPCCSS scale.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2991-2991
Author(s):  
Guillaume Denis ◽  
Louis Terriou ◽  
Thomas Séné ◽  
Regis Costello ◽  
Martin Michaud ◽  
...  

Abstract The most prevalent etiologies of splenomegaly (SM) are easily detected in routine clinical practice. However, after these first-line diagnoses have been ruled out, many cases remain unexplained. Frequently, signs and symptoms are non-specific hiding rare etiologies such as Lysosomal Storage Diseases (LSD) (e.g., Gaucher disease (GD), Niemann-Pick disease type B). SplenoMegaly Study (SMS) aims to estimate the prevalence of different etiologies in unexplained SM and to describe their diagnostic work-up. We present here the final results of the study. SMS is a prospective, observational, multi-center, longitudinal study performed in France. All patients with unexplained SM, aged ≥15 years, consulting to the French hematology or internal medicine departments were invited to take part of the study. SM was confirmed by echography or CT-scan with a craniocaudal length ≥13 cm; unexplained was defined as negative clinical and biological routine workup. All conducted exams and tests for diagnosis purpose were under each physician's responsibility. For each patient, last visit took place when an etiology was identified or up to 12 months after inclusion. From Sept-2015 to Apr-2020, 505 patients were enrolled by 87 centers (secondary centers [71.3%] and tertiary centers [28.7%]). Physicians were mainly internists (52.9%) or hematologists (46.0%). Patients characteristics at inclusion were as follows: male gender, 61.2%; median age, 51.0 years old (16-94 years old); median spleen length, 15.0 cm (13-30 cm); heterogeneous spleen structure, 11.1%. A total of 501 patients completed the study. After a median duration of 6.6 months, 232 patients (46.3%) received a diagnosis. When compared to patients without diagnosis, patients with diagnosis were older (median age 59.5 vs 45.0; p<0.001), had more often a massive SM (≥18 cm) (25.2% vs 10.7%; p<0.001) and heterogeneous spleen structure (15.9% vs 6.6%; p=0.002). Their biological test results (hemoglobin, leucocytes, CRP, albumin) were also significantly altered and they showed more constitutional (48.3% vs 37.3%) and digestive symptoms (41.9% vs 28.4%) compared to patients without diagnosis. The proportion of diagnosed patients was higher in tertiary than secondary centers (55.2% vs 32.6%). Hematological (lymphoid and myeloid) malignancies represented only 38.7% (n=87) of established diagnoses (Figure 1). Non-malignant diseases, accounted for 61.3% of diagnosis, were: autoimmune disorders (20.0%, n=45), portal hypertension (12.0%, n=27), infectious diseases (11.6%, n=26), LSD (4.4% [n=10], including type 1 Gaucher Disease (GD1) [n=4]; Niemann-Pick disease type B [n=3] and type C [n=2]; and Fabry disease [n=1]), other disorders (13.3%, n=30) and non-specified (3%, n=7). Hematological malignancies were more common in elderly patients (median age 66.0, p<0.001) with massive SM (p<0.001). Compared to other diagnoses, a large proportion of patients diagnosed with portal hypertension were obese (51.9%) and had ongoing metabolism or nutrition disorders (40.7%). Patients with autoimmune disorders had higher CRP levels (median value, 11.5 mg/L) and showed more osteoarticular symptoms (34.8%). All 4 GD1 patients had thrombocytopenia (≤100G/L platelets). Among the tests contributing to diagnosis, biopsies were performed in 34.3% (n=172) of patients, mainly bone marrow trephine biopsy (BMTB) (20.8%, n=104). Half of patients with BMTB received a diagnosis. Splenectomy was performed in 19 patients (4.0%) and was conclusive in 14 of them. β-Glucocerebrosidase activity assay to test for GD was performed in 79.8% of patients. Among patients without diagnosis, 22.7% of them were not tested for GD. In SMS, patients at inclusion had unexplained SM despite routine clinical and biologic analysis. The diagnostic yield improved after further medical evaluations reaching an etiologic diagnosis in 46% of patients. Patients with an established diagnosis were older, had a larger spleen and altered biological parameters compared to patients without diagnosis. Interestingly, non-malignant diseases accounted for 61.3% of diagnoses. It is noteworthy the diversity of LSD etiologies obtained: 10 patients (4%) were diagnosed with LSD, including 4 GD1 patients. This study provides useful new information to optimize the diagnostic strategy of splenomegaly poorly explained by routine workup. SMS is sponsored by Sanofi-Genzyme. Figure 1 Figure 1. Disclosures Denis: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Séné: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Costello: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Michaud: Sanofi: Honoraria, Research Funding. Hellé: Sanofi: Current Employment. Lagadec: Sanofi: Current Employment. Bauduer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Urbanski: Sanofi: Honoraria, Research Funding. Berger: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.


Cureus ◽  
2021 ◽  
Author(s):  
Hira Qadir ◽  
Mahad M Baig ◽  
Anas Adil ◽  
Maria Aisha ◽  
Izzan Raees

Author(s):  
Antony Cougnoux ◽  
Julia C. Yerger ◽  
Mason Fellmeth ◽  
Jenny Serra-Vinardell ◽  
Fatemeh Navid ◽  
...  

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