The Experts below are selected from a list of 240 Experts worldwide ranked by ideXlab platform
Rudolf Jaenisch - One of the best experts on this subject based on the ideXlab platform.
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restarting stalled autophagy a potential therapeutic approach for the Lipid Storage Disorder niemann pick type c1 disease
Autophagy, 2014Co-Authors: Sovan Sarkar, Dorothea Maetzel, Viktor I Korolchuk, Rudolf JaenischAbstract:Autophagy is essential for cellular homeostasis and its dysfunction in human diseases has been implicated in the accumulation of misfolded protein and in cellular toxicity. We have recently shown impairment in autophagic flux in the Lipid Storage Disorder, Niemann-Pick type C1 (NPC1) disease associated with abnormal cholesterol sequestration, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery. Abrogation of autophagy also causes cholesterol accumulation, suggesting that defective autophagic flux in NPC1 disease may act as a primary causative factor not only by imparting its deleterious effects, but also by increasing cholesterol load. However, cholesterol depletion treatment with HP-β-cyclodextrin impedes autophagy, whereas pharmacologically stimulating autophagy restores its function independent of amphisome formation. Of potential therapeutic relevance is that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may rescue both the cholesterol and autophagy defects in NPC1 disease.
Agostino Colli - One of the best experts on this subject based on the ideXlab platform.
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Severe steatohepatitis in a patient with a rare neutral Lipid Storage Disorder due to ABDH5 mutation
Journal of hepatology, 2008Co-Authors: Anna Ronchetti, Daniela Tavian, Daniele Prati, Roberto Colombo, Maria Grazia Pezzotta, Francesco Callea, Agostino ColliAbstract:Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dysLipidemia and impaired glucose tolerance, but inherited Disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin–Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral Lipid Storage Disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible.
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Case report Severe steatohepatitis in a patient with a rare neutral Lipid Storage Disorder due to ABDH5 mutation q
2008Co-Authors: Anna Ronchetti, Daniela Tavian, Daniele Prati, Roberto Colombo, Maria Grazia Pezzotta, Francesco Callea, Agostino ColliAbstract:Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dysLipidemia and impaired glucose tolerance, but inherited Disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin–Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral Lipid Storage Disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible. 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Kate Strong - One of the best experts on this subject based on the ideXlab platform.
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observational cohort study of the natural history of niemann pick disease type c in the uk a 5 year update from the uk clinical database
BMC Neurology, 2015Co-Authors: Jackie Imrie, Lesley Heptinstall, Stephen Knight, Kate StrongAbstract:Niemann-Pick disease type C (NP-C) is a rare neurovisceral Lipid Storage Disorder characterised by progressive, disabling neurological symptoms and premature death in most patients. During the last decade, national cohort studies have accrued a great deal of data on the symptomatology and natural history of NP-C. In an observational cohort study, we present a substantial update based on the clinical presentation and follow-up of all known UK-based patients with a confirmed diagnosis of NP-C who have been tracked on an electronic database at the Department of Genetic Medicine, University of Manchester, UK. Patients were stratified according to accepted age-at-neurological-onset categories. Data on patients’ clinical signs and symptoms, medical history and genetic studies are summarised using descriptive methods. A total of 146 patients with NP-C were included, representing the full known UK NP-C cohort, as observed from database information between 1999 and the end of 2011: 72 patients (49 %) were alive at the end of the observation period. Among a total of 116 patients (79 %) who possessed at least one identified, disease-causing NP-C gene mutation, 114 (98 %) had NPC1 and two (2 %) had NPC2 mutations. Overall, 53/194 (27 %) identified mutations were novel. Six patients (4 %) had an early, non-neurological neonatal onset form of NP-C. The numbers (%) of patients with accepted age-at-neurological onset forms were: 8 (5 %) early-infantile onset, 51 (35 %) late-infantile onset, 42 (29 %) juvenile onset, and 25 (17 %) adolescent/adult onset. Fourteen patients diagnosed based on visceral symptoms and/or sibling history, confirmed in most cases by genetic analysis, did not have any neurological manifestations at last follow up (11 patients with mean [SD] age at last follow up 2.5 [1.8] years: 3 with mean [SD] age at death 20.8 [15.9] years). A total of 51 patients (35 %) received miglustat therapy. The mean (SD) overall treatment duration up to the end of the observation period was 2.6 (2.3) years. This UK cohort is the largest national NP-C cohort reported to date, and confirms the wide phenotypic variability of the disease, as reported in other countries. Further analyses are required to assess the impact of miglustat therapy on neurological disease progression.
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observational cohort study of the natural history of niemann pick disease type c in the uk a 5 year update from the uk clinical database
BMC Neurology, 2015Co-Authors: John Imrie, Lesley Heptinstall, Stephen Knight, Kate StrongAbstract:Background Niemann-Pick disease type C (NP-C) is a rare neurovisceral Lipid Storage Disorder characterised by progressive, disabling neurological symptoms and premature death in most patients. During the last decade, national cohort studies have accrued a great deal of data on the symptomatology and natural history of NP-C.
Stefan A Kolb - One of the best experts on this subject based on the ideXlab platform.
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disease characteristics prognosis and miglustat treatment effects on disease progression in patients with niemann pick disease type c an international multicenter retrospective chart review
Orphanet Journal of Rare Diseases, 2019Co-Authors: Mercedes Pineda, Katarina Jurickova, Parvaneh Karimzadeh, Miriam Kolnikova, Vera Malinova, Jose Luis Insua, Christian Velten, Stefan A KolbAbstract:Niemann-Pick disease Type C (NP-C) is a lysosomal Lipid Storage Disorder characterized by progressive neurodegenerative symptomatology. The signs and symptoms of NP-C vary with age at disease onset, and available therapies are directed at alleviating symptoms and stabilizing disease progression. We report the characteristics and factors related to disease progression, and analyze the effect of miglustat treatment on disease progression and patient survival using NP-C disability scales. This retrospective, observational chart review included patients with NP-C from five expert NP-C centers. Patient disability scores were recorded using three published NP-C disability scales, and a unified disability scale was developed to allow comparison of data from each scale. Disease progression was represented by scores on the unified NP-C disability scale. Patients were stratified as infantile (< 4 years), juvenile (≥ 4 − < 16 years), and adult (≥ 16 years) based on age at diagnosis, and treated ≥1 year and non-treated/treated < 1 year based on the duration of miglustat treatment. The analysis included 63 patients; the majority (61.9%) were on miglustat therapy for ≥1 year. Ataxia and clumsiness/frequent fall were the most common neurologic symptoms across age groups, whereas, hypotonia and delayed developmental milestones were specific to infantile patients. In both infantile and juvenile patients, visceral signs preceded diagnosis and neurologic signs were noted at or shortly after diagnosis. Adult patients presented with a range of visceral, neurologic, and psychiatric signs in years preceding diagnosis. Patients on miglustat therapy for ≥1 year had a lower mean annual disease progression compared with those untreated/treated < 1 year (1.32 vs 3.54 points/year). A significant reduction in annual disease progression in infantile patients, and a trend towards reduced disease progression in juvenile patients after ≥1 year of miglustat treatment, translated into higher age at last contact or death in these groups. The type and onset of symptoms varied across age groups and were consistent with descriptions of NP-C within the literature. Miglustat treatment was associated with a reduced rate of disability score worsening in infantile and juvenile patients, both in agreement with increased age at last contact.
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Disease characteristics, prognosis and miglustat treatment effects on disease progression in patients with Niemann-Pick disease Type C: an international, multicenter, retrospective chart review
BMC, 2019Co-Authors: Mercedes Pineda, Katarina Jurickova, Parvaneh Karimzadeh, Miriam Kolnikova, Vera Malinova, Jose Luis Insua, Christian Velten, Stefan A KolbAbstract:Abstract Background Niemann-Pick disease Type C (NP-C) is a lysosomal Lipid Storage Disorder characterized by progressive neurodegenerative symptomatology. The signs and symptoms of NP-C vary with age at disease onset, and available therapies are directed at alleviating symptoms and stabilizing disease progression. We report the characteristics and factors related to disease progression, and analyze the effect of miglustat treatment on disease progression and patient survival using NP-C disability scales. Methods This retrospective, observational chart review included patients with NP-C from five expert NP-C centers. Patient disability scores were recorded using three published NP-C disability scales, and a unified disability scale was developed to allow comparison of data from each scale. Disease progression was represented by scores on the unified NP-C disability scale. Patients were stratified as infantile (
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development of a suspicion index to aid diagnosis of niemann pick disease type c
Neurology, 2012Co-Authors: Frits A Wijburg, Frederic Sedel, M Pineda, Christian J Hendriksz, Michael C Fahey, Mark Walterfang, Marc Patterson, J E Wraith, Stefan A KolbAbstract:Objectives: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive lysosomal Lipid Storage Disorder that is invariably fatal. NP-C diagnosis can be delayed for years due to heterogeneous presentation; adult-onset NP-C can be particularly difficult to diagnose. We developed a Suspicion Index tool, ranking specific symptoms within and across domains, including family members who have NP-C, to provide a risk prediction score to identify patients who should undergo testing for NP-C. Methods: A retrospective chart review was performed in 5 centers in Europe and 2 in Australia (n = 216). Three patient types were selected: classic or variant filipin staining NP-C cases (n = 71), NP-C noncases (confirmed negative by filipin staining; n = 64), or controls with at least 1 characteristic symptom of NP-C (n = 81). NP-C signs and symptoms were categorized into visceral, neurologic, or psychiatric domains. Logistic regression was performed on individual signs and symptoms within and across domains, and regression coefficients were used to develop prediction scores for NP-C. Internal validation was performed with the bootstrap resampling method. Results: The Suspicion Index tool has good discriminatory performance with cutpoints for grading suspicion of NP-C. Neonatal jaundice/cholestasis, splenomegaly, vertical supranuclear gaze palsy, cataplexy, and cognitive decline/dementia were strong predictors of NP-C, as well as symptoms occurring in multiple domains in individual patients, and also parents/siblings or cousins with NP-C. Conclusions: The Suspicion Index tool is a screening tool that can help identify patients who may warrant further investigation for NP-C. A score ≥70 indicates that patients should be referred for testing for NP-C.
Sovan Sarkar - One of the best experts on this subject based on the ideXlab platform.
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restarting stalled autophagy a potential therapeutic approach for the Lipid Storage Disorder niemann pick type c1 disease
Autophagy, 2014Co-Authors: Sovan Sarkar, Dorothea Maetzel, Viktor I Korolchuk, Rudolf JaenischAbstract:Autophagy is essential for cellular homeostasis and its dysfunction in human diseases has been implicated in the accumulation of misfolded protein and in cellular toxicity. We have recently shown impairment in autophagic flux in the Lipid Storage Disorder, Niemann-Pick type C1 (NPC1) disease associated with abnormal cholesterol sequestration, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery. Abrogation of autophagy also causes cholesterol accumulation, suggesting that defective autophagic flux in NPC1 disease may act as a primary causative factor not only by imparting its deleterious effects, but also by increasing cholesterol load. However, cholesterol depletion treatment with HP-β-cyclodextrin impedes autophagy, whereas pharmacologically stimulating autophagy restores its function independent of amphisome formation. Of potential therapeutic relevance is that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may rescue both the cholesterol and autophagy defects in NPC1 disease.
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impaired autophagy in the Lipid Storage Disorder niemann pick type c1 disease
Elsevier, 2013Co-Authors: Sovan Sarkar, Dorothea Maetzel, Bernadette Carroll, Yosef Buganim, John P Cassady, Malkiel A Cohen, Souvik Chakraborty, Haoyi Wang, Eric Spooner, Hidde L PloeghAbstract:SUMMARY Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of Lipid-Storage Disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-b-cyclodextrin, which is used for cholesteroldepletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-b-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.