A5023079379- Lysosomal Storage Disorders Research
- Autoimmune and Inflammatory Disorders Research
- Child Nutrition and Feeding Issues
- Cerebral Palsy and Movement Disorders
- Family and Disability Support Research
- Carbohydrate Chemistry and Synthesis
- Cytomegalovirus and herpesvirus research
- Neonatal and fetal brain pathology
- Infant Nutrition and Health
- Calcium signaling and nucleotide metabolism
- Iron Metabolism and Disorders
- HIV Research and Treatment
- Hemoglobinopathies and Related Disorders
- Metabolism and Genetic Disorders
- Cardiovascular Syncope and Autonomic Disorders
- Intracerebral and Subarachnoid Hemorrhage Research
- Neonatal Health and Biochemistry
- Folate and B Vitamins Research
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- Anesthesia and Pain Management
- Receptor Mechanisms and Signaling
- Cholesterol and Lipid Metabolism
- Cellular transport and secretion
- Dysphagia Assessment and Management
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2015-2024
National Institutes of Health
2015-2024
Eunice Kennedy Shriver Center
2017-2021
Hopital Universitaire Habib Bourguiba
2019
National Heart Lung and Blood Institute
2016
University of Pennsylvania
2016
Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling identify potential markers discovered three unknown bile acids that were increased plasma from NPC but not control subjects. The most elevated the subjects identified as 3β,5α,6β-trihydroxycholanic acid its glycine conjugate, which shown be metabolites of...
24(S)-hydroxycholesterol [24(S)-HC] is a cholesterol metabolite that formed almost exclusively in the brain. The concentrations of 24(S)-HC cerebrospinal fluid (CSF) and/or plasma might be sensitive marker altered metabolism CNS. A highly 2D-LC-MS/MS assay was developed for quantification human and CSF. In development an CSF, significant nonspecific binding observed resolved with addition 2.5% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) into CSF samples. sample preparation consists...
Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 associated neuroinflammation; however, attempts to therapeutically target neuroinflammation in have had mixed success. We show here that characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- demonstrated altered morphology, reduced levels of lineage markers and shift toward glycolytic metabolism. Treatment 2-hydroxypropyl-β-cyclodextrin (HPβCD), drug...
Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype heterogeneous with variable age of onset, classical a pediatric disorder. Currently there are no therapies approved FDA therapeutics trials for complicated rarity, heterogeneity, relatively slow rate neurological decline. Thus, identification relevant biomarkers necessary to provide tools that can...
Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment. Marked heterogeneity has been observed in individuals with same NPC1 genotype, thus suggesting significant effect modifier genes. Prior work demonstrated that decreased SOAT1 activity severity an mouse model. Thus, we hypothesized polymorphism associated expression might influence phenotype. Phenotyping and genomic sequencing 117 was performed...
Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy 2-hydroxypropyl-<i>β</i>-cyclodextrin (HP<i>β</i>CD) in animal models resulted initiation phase I/IIa clinical trial 2013 and IIb/III 2015. With trials ongoing, validation biomarker to track progression serve as supporting outcome measure has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations...
Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, drug used off-label in the United States for treatment of NPC1, appears to stabilize neurologic progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia aspiration risk has not been demonstrated instrumentally.To determine if therapy associated stabilized...
Abstract To understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing covariance (SCV) relationships that link genetic diversity to fitness individual in response histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants NPC1 gene disrupt cholesterol...
Niemann-Pick type C1 (NPC1) disease is a rare autosomal recessive, neurodegenerative lysosomal storage disorder, which presents with range of clinical phenotypes and hence diagnosis remains challenge. In view these difficulties, the search for novel, NPC1-specific biomarker (or set biomarkers) topic much interest. Here we employed high-resolution 1H nuclear magnetic resonance spectroscopy coupled advanced multivariate analysis techniques in order to explore seek differences between blood...
The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes hepatosplenomegaly, neurological degeneration premature death. timing severity NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data 42 patient-derived, primary fibroblast cell lines determine transcriptional changes induced by treatment with...
Aim To describe the neurocognitive and adaptive behavior profile of children adolescents with Niemann–Pick Disease type C1 ( NPC 1), a rare genetic disease that frequently presents in childhood, variable onset symptom complex involving neurodegeneration. Method Thirty‐eight participants (20 males, 18 females; mean age 8y 10mo, SD 4y 8mo, range 1–18y) 1 were evaluated through natural history protocol. Results severity was mild to moderate for most participants. Cognitive scores n =32) ranged...
The folding and trafficking of transmembrane glycoproteins are essential for cellular homeostasis compromised in many diseases. In Niemann-Pick type C disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, the glycoprotein NPC1 misfolds due to disease-causing missense mutations. While mutant has emerged as robust target proteostasis modulators, drug development efforts have been unsuccessful mouse models. Here, we demonstrated unexpected differences...
Abstract Background Several scales have been developed in the past two decades to evaluate Niemann–Pick disease Type C (NPC) severity clinical practice and trials. However, a lack of clarity concerning which scale use each setting is preventing standardised assessments across world, resulting incomparable data sets trial outcome measures. This study aimed establish agreed approaches for NPC research. Methods A Delphi method consensus development was used, comprising three survey rounds. In...
<ns4:p><ns4:bold>Background</ns4:bold>: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal storage disorder characterized by the accumulation of multiple lipids in late endosome/lysosomal system and reduced acidic store calcium. The regulates key aspects iron homeostasis, which prompted us to investigate whether there are hematological abnormalities metabolism defects NPC1.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold>: Iron-related parameters, systemic tissue metal ion...
Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists prognostication management. Cerebellar volume deficits are found to correlate with disease severity diffusion tensor (DTI) of the corpus callosum brainstem, has shown that microstructural disorganization associated NPC1 severity. This study investigates utility cerebellar DTI in...
ABSTRACT: Objective: Niemann-Pick disease type C1 (NPC1) is a lysosomal storage characterized by progressive neurodegeneration, with the age of diagnosis ranging from prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt in early years. Few prospective data are available to describe onset, including neurodevelopmental delays, children NPC1. This dearth information hinders planning and implementation adequate...
ABSTRACT Niemann‐Pick disease type C (NPC) is a rare and fatal lysosomal storage disorder characterized by neurodegeneration hepatic involvement. Mutations in either NPC1 or NPC2 , two genes encoding proteins, lead to an intracellular accumulation of unesterified cholesterol sphingolipids late endosomes/lysosomes. Early cholestatic considered hallmark patients with early onset. This can potentially result liver failure shortly after birth subclinical inflammation. Previous reports suggest...