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Edward H Schuchman - One of the best experts on this subject based on the ideXlab platform.
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types a and b niemann pick Disease
Molecular Genetics and Metabolism, 2017Co-Authors: Edward H Schuchman, Robert J DesnickAbstract:The eponym Niemann-Pick Disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of Disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the Disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this Disease. We will also discuss the current status of therapy for this disorder.
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types a and b niemann pick Disease
Best Practice & Research Clinical Endocrinology & Metabolism, 2015Co-Authors: Edward H Schuchman, Melissa P WassersteinAbstract:Two distinct metabolic abnormalities are encompassed under the eponym Niemann-Pick Disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick Disease (NPD). Type A NPD patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of Disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene ( SMPD1 ). Patients in the second NPD category are designated as having types C and D NPD. These patients may have mild hepatosplenomegaly, but the central nervous system is profoundly affected. Impaired intracellular trafficking of cholesterol causes types C and D NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed.
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morbidity and mortality in type b niemann pick Disease
Genetics in Medicine, 2013Co-Authors: Margaret M Mcgovern, Natalie Lippa, Emilia Bagiella, Edward H Schuchman, Robert J Desnick, Melissa P WassersteinAbstract:The purpose of this study was to perform a systematic evaluation of morbidity and mortality in type B Niemann–Pick Disease. A total of 103 patients with Niemann–Pick Disease (49 males, 54 females, age range: 1–72 years) participated in natural history studies through Mount Sinai’s International Center for Types A and B Niemann–Pick Disease between 1992 and 2012. Serious morbidities included significant neurological, hepatic, and cardiac Disease. Thirteen patients had some degree of neurological impairment. Nine patients had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart Disease were present in nine patients. Of note, only four patients were oxygen dependent, although progressive pulmonary Disease is a well-described feature of Niemann–Pick Disease. During the follow-up period, 18 deaths occurred. The median age of death was 15.5 years (range 1–72). Causes of death included pneumonia, liver failure, and hemorrhage. The majority of deaths (12 of 18) occurred in patients <21 years, yielding a mortality rate of 19% in the pediatric population. This study demonstrates that Niemann–Pick Disease is a life-threatening disorder with significant morbidity and mortality, especially in the pediatric population. The information collected in this series highlights the need for safe, effective therapy for Niemann–Pick Disease. Genet Med 2013:15(8):618–623
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brain pathology in niemann pick Disease type a insights from the acid sphingomyelinase knockout mice
Journal of Neurochemistry, 2011Co-Authors: Maria Dolores Ledesma, Alessandro Prinetti, Sandro Sonnino, Edward H SchuchmanAbstract:Severe neurological involvement characterizes Niemann Pick Disease (NPD) type A, an inherited disorder caused by loss of function mutations in the gene encoding acid sphingomyelinase (ASM). Mice lacking ASM, which mimic NPD type A, have provided important insights into the aberrant brain phenotypes induced by ASM deficiency. For example, lipid alterations, including the accumulation of sphingolipids, affect the membranes of different subcellular compartments of neurons and glial cells, leading to anomalies in signalling pathways, neuronal polarization, calcium homeostasis, synaptic plasticity, myelin production or immune response. These findings contribute to our understanding of the overall role of sphingolipids and their metabolic enzymes in brain physiology, and pave the way to design and test new therapeutic strategies for type A NPD and other neurodegenerative disorders. Some of these have already been tested in mice lacking ASM with promising results.
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acid sphingomyelinase cell membranes and human Disease lessons from niemann pick Disease
FEBS Letters, 2010Co-Authors: Edward H SchuchmanAbstract:Acid sphingomyelinase (ASM) plays an important role in normal membrane turnover through the hydrolysis of sphingomyelin, and is one of the key enzymes responsible for the production of ceramide. ASM activity is deficient in the genetic disorder Types A and B Niemann–Pick Disease (NPD). ASM knockout (ASMKO) mice were originally constructed to study this disorder, and numerous defects in ceramide-related signaling have been shown. Studies in these mice have further suggested that ASM may be involved in the pathogenesis of several common Diseases through the reorganization of membrane microdomains. This review will focus on the role of ASM in membrane biology, with a specific emphasis on what a rare genetic disorder (NPD) has taught us about more common events.
Margaret M Mcgovern - One of the best experts on this subject based on the ideXlab platform.
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morbidity and mortality in type b niemann pick Disease
Genetics in Medicine, 2013Co-Authors: Margaret M Mcgovern, Natalie Lippa, Emilia Bagiella, Edward H Schuchman, Robert J Desnick, Melissa P WassersteinAbstract:The purpose of this study was to perform a systematic evaluation of morbidity and mortality in type B Niemann–Pick Disease. A total of 103 patients with Niemann–Pick Disease (49 males, 54 females, age range: 1–72 years) participated in natural history studies through Mount Sinai’s International Center for Types A and B Niemann–Pick Disease between 1992 and 2012. Serious morbidities included significant neurological, hepatic, and cardiac Disease. Thirteen patients had some degree of neurological impairment. Nine patients had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart Disease were present in nine patients. Of note, only four patients were oxygen dependent, although progressive pulmonary Disease is a well-described feature of Niemann–Pick Disease. During the follow-up period, 18 deaths occurred. The median age of death was 15.5 years (range 1–72). Causes of death included pneumonia, liver failure, and hemorrhage. The majority of deaths (12 of 18) occurred in patients <21 years, yielding a mortality rate of 19% in the pediatric population. This study demonstrates that Niemann–Pick Disease is a life-threatening disorder with significant morbidity and mortality, especially in the pediatric population. The information collected in this series highlights the need for safe, effective therapy for Niemann–Pick Disease. Genet Med 2013:15(8):618–623
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liver and skin histopathology in adults with acid sphingomyelinase deficiency niemann pick Disease type b
The American Journal of Surgical Pathology, 2012Co-Authors: Beth L Thurberg, Melissa P Wasserstein, Thomas D Schiano, Fanny Obrien, Susan M Richards, Gerald F Cox, Margaret M McgovernAbstract:Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin (SM) in multiple cell types, and occurs most prominently within the liver, spleen, and lungs, leading to significant clinical Disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick Disease type B. Eleven of the 17 were enrolled in the trial and each received a single dose of rhASM and underwent a repeat liver biopsy on day 14. Biopsies were evaluated for fibrosis, SM accumulation, and macrophage infiltration by light and electron microscopy. When present, fibrosis was periportal and pericellular, predominantly surrounding affected Kupffer cells. Two baseline biopsies exhibited frank cirrhosis. SM was localized to isolated Kupffer cells in mildly affected biopsies and was present in both Kupffer cells and hepatocytes in more severely affected cases. Morphometric quantification of SM storage in liver biopsies ranged from 4% to 44% of the microscopic field. Skin biopsies were also performed at baseline and day 14 to compare the SM distribution in a peripheral tissue with that of liver. SM storage was present at lower levels in multiple cell types of the skin, including dermal fibroblasts, macrophages, vascular endothelial cells, vascular smooth muscle cells, and Schwann cells. This phase 1 trial of rhASM in adults with ASMD provided a unique opportunity for a prospective assessment of hepatic and skin pathology in this rare Disease and their potential usage as pharmacodynamic biomarkers.
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a prospective cross sectional survey study of the natural history of niemann pick Disease type b
Pediatrics, 2008Co-Authors: Margaret M Mcgovern, Marie T Vanier, Eugen Mengel, Melissa P Wasserstein, David S Mendelson, Gwen Skloot, Bruno Bembi, Roberto Giugliani, Scott E Brodie, Robert J DesnickAbstract:OBJECTIVE. The objective of this study was to characterize the clinical features of patients with Niemann-Pick Disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy. METHODS. Fifty-nine patients who had Niemann-Pick Disease type B, were at least 6 years of age, and manifested at least 2 Disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period. RESULTS. Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all Disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung Disease. Patients commonly showed restrictive lung Disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of Disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. CONCLUSIONS. This study documents the multisystem involvement and clinical variability of Niemann-Pick B Disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with Disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.
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acid sphingomyelinase deficiency prevalence and characterization of an intermediate phenotype of niemann pick Disease
The Journal of Pediatrics, 2006Co-Authors: Melissa P Wasserstein, Robert J Desnick, Scott E Brodie, Alan M Aron, Calogera M Simonaro, Margaret M McgovernAbstract:Objective To document the prevalence of neurologic Disease in Niemann-Pick Disease (NPD) NPD-B. Study design Sixty-four patients with NPD-B had detailed neurologic and ophthalmologic evaluations. The presence of neurologic abnormalities was compared with genotype. Results Nineteen of 64 patients (30%) had neurologic abnormalities, which were minor and nonprogressive in 14 (22%), and global and progressive in 5 (8%). In these five patients, the onset of neurologic difficulties occurred between 2 and 7 years of age and was associated with peripheral neuropathy, retinal abnormalities, and the Q292K mutation. No patients with at least one copy of ΔR608 had neurologic involvement. Conclusions The majority of patients with NPD-B have no neurologic abnormalities. In patients with neurologic abnormalities, the findings can be minor and static or severe and progressive. The latter phenotype follows a course distinct from that of classic NPD-A and is associated with the Q292K mutation and characteristic retinal findings. Thus, similar to other lysosomal storage disorders, there is a broad spectrum of neurologic abnormalities in acid sphingomyelinase deficiency, which makes the current classification scheme inaccurate.
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natural history of type a niemann pick Disease possible endpoints for therapeutic trials
Neurology, 2006Co-Authors: Margaret M Mcgovern, Robert J Desnick, Adam R Aron, Scott E Brodie, Melissa P WassersteinAbstract:Objective: To describe the Disease course and natural history of Type A Niemann-Pick Disease (NPD). Methods: Ten patients with NPD-A (six male, four female; age range at entry: 3 to 6 months) were serially evaluated including clinical neurologic, ophthalmologic, and physical examinations, and assessment of development. Laboratory analyses, abdominal and brain ultrasounds, and chest radiographs also were obtained and information on intercurrent illnesses and cause of mortality was collected. Results: All affected infants had a normal neonatal course and early development. The first symptom detected in all patients was hepatosplenomegaly. Developmental age did not progress beyond 10 months for adaptive behavior, 12 months for expressive language, 9 months for gross motor skills, and 10 months for fine motor skills. Non-neurologic symptoms included frequent vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbance. Neurologic examination at the time of presentation was normal in most patients. Later neurologic examinations revealed progressive hypotonia with loss of the deep tendon reflexes. All patients had cherry red spots by 12 months. The median time from diagnosis to death was 21 months. The cause of death was respiratory failure in nine patients and complications from bleeding in the tenth. Conclusions: The clinical course in Type A Niemann-Pick Disease is similar among affected patients and is characterized by a relentless neurodegenerative course that leads to death, usually within 3 years.
Melissa P Wasserstein - One of the best experts on this subject based on the ideXlab platform.
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types a and b niemann pick Disease
Best Practice & Research Clinical Endocrinology & Metabolism, 2015Co-Authors: Edward H Schuchman, Melissa P WassersteinAbstract:Two distinct metabolic abnormalities are encompassed under the eponym Niemann-Pick Disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick Disease (NPD). Type A NPD patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of Disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene ( SMPD1 ). Patients in the second NPD category are designated as having types C and D NPD. These patients may have mild hepatosplenomegaly, but the central nervous system is profoundly affected. Impaired intracellular trafficking of cholesterol causes types C and D NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed.
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morbidity and mortality in type b niemann pick Disease
Genetics in Medicine, 2013Co-Authors: Margaret M Mcgovern, Natalie Lippa, Emilia Bagiella, Edward H Schuchman, Robert J Desnick, Melissa P WassersteinAbstract:The purpose of this study was to perform a systematic evaluation of morbidity and mortality in type B Niemann–Pick Disease. A total of 103 patients with Niemann–Pick Disease (49 males, 54 females, age range: 1–72 years) participated in natural history studies through Mount Sinai’s International Center for Types A and B Niemann–Pick Disease between 1992 and 2012. Serious morbidities included significant neurological, hepatic, and cardiac Disease. Thirteen patients had some degree of neurological impairment. Nine patients had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart Disease were present in nine patients. Of note, only four patients were oxygen dependent, although progressive pulmonary Disease is a well-described feature of Niemann–Pick Disease. During the follow-up period, 18 deaths occurred. The median age of death was 15.5 years (range 1–72). Causes of death included pneumonia, liver failure, and hemorrhage. The majority of deaths (12 of 18) occurred in patients <21 years, yielding a mortality rate of 19% in the pediatric population. This study demonstrates that Niemann–Pick Disease is a life-threatening disorder with significant morbidity and mortality, especially in the pediatric population. The information collected in this series highlights the need for safe, effective therapy for Niemann–Pick Disease. Genet Med 2013:15(8):618–623
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liver and skin histopathology in adults with acid sphingomyelinase deficiency niemann pick Disease type b
The American Journal of Surgical Pathology, 2012Co-Authors: Beth L Thurberg, Melissa P Wasserstein, Thomas D Schiano, Fanny Obrien, Susan M Richards, Gerald F Cox, Margaret M McgovernAbstract:Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin (SM) in multiple cell types, and occurs most prominently within the liver, spleen, and lungs, leading to significant clinical Disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick Disease type B. Eleven of the 17 were enrolled in the trial and each received a single dose of rhASM and underwent a repeat liver biopsy on day 14. Biopsies were evaluated for fibrosis, SM accumulation, and macrophage infiltration by light and electron microscopy. When present, fibrosis was periportal and pericellular, predominantly surrounding affected Kupffer cells. Two baseline biopsies exhibited frank cirrhosis. SM was localized to isolated Kupffer cells in mildly affected biopsies and was present in both Kupffer cells and hepatocytes in more severely affected cases. Morphometric quantification of SM storage in liver biopsies ranged from 4% to 44% of the microscopic field. Skin biopsies were also performed at baseline and day 14 to compare the SM distribution in a peripheral tissue with that of liver. SM storage was present at lower levels in multiple cell types of the skin, including dermal fibroblasts, macrophages, vascular endothelial cells, vascular smooth muscle cells, and Schwann cells. This phase 1 trial of rhASM in adults with ASMD provided a unique opportunity for a prospective assessment of hepatic and skin pathology in this rare Disease and their potential usage as pharmacodynamic biomarkers.
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a prospective cross sectional survey study of the natural history of niemann pick Disease type b
Pediatrics, 2008Co-Authors: Margaret M Mcgovern, Marie T Vanier, Eugen Mengel, Melissa P Wasserstein, David S Mendelson, Gwen Skloot, Bruno Bembi, Roberto Giugliani, Scott E Brodie, Robert J DesnickAbstract:OBJECTIVE. The objective of this study was to characterize the clinical features of patients with Niemann-Pick Disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy. METHODS. Fifty-nine patients who had Niemann-Pick Disease type B, were at least 6 years of age, and manifested at least 2 Disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period. RESULTS. Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all Disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung Disease. Patients commonly showed restrictive lung Disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of Disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. CONCLUSIONS. This study documents the multisystem involvement and clinical variability of Niemann-Pick B Disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with Disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.
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acid sphingomyelinase deficiency prevalence and characterization of an intermediate phenotype of niemann pick Disease
The Journal of Pediatrics, 2006Co-Authors: Melissa P Wasserstein, Robert J Desnick, Scott E Brodie, Alan M Aron, Calogera M Simonaro, Margaret M McgovernAbstract:Objective To document the prevalence of neurologic Disease in Niemann-Pick Disease (NPD) NPD-B. Study design Sixty-four patients with NPD-B had detailed neurologic and ophthalmologic evaluations. The presence of neurologic abnormalities was compared with genotype. Results Nineteen of 64 patients (30%) had neurologic abnormalities, which were minor and nonprogressive in 14 (22%), and global and progressive in 5 (8%). In these five patients, the onset of neurologic difficulties occurred between 2 and 7 years of age and was associated with peripheral neuropathy, retinal abnormalities, and the Q292K mutation. No patients with at least one copy of ΔR608 had neurologic involvement. Conclusions The majority of patients with NPD-B have no neurologic abnormalities. In patients with neurologic abnormalities, the findings can be minor and static or severe and progressive. The latter phenotype follows a course distinct from that of classic NPD-A and is associated with the Q292K mutation and characteristic retinal findings. Thus, similar to other lysosomal storage disorders, there is a broad spectrum of neurologic abnormalities in acid sphingomyelinase deficiency, which makes the current classification scheme inaccurate.
Marie T Vanier - One of the best experts on this subject based on the ideXlab platform.
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Diagnostic tests for Niemann-Pick Disease type C (NP-C): A critical review.
Molecular Genetics and Metabolism, 2016Co-Authors: Marie T Vanier, Philippe Latour, Peter Bauer, Christian J Hendriksz, Paul Gissen, Maria Josep Coll, Alberto Burlina, Cyril Goizet, Richard W. D. Welford, Thorsten MarquardtAbstract:Niemann-Pick Disease type C (NP-C) is a neurovisceral lysosomal cholesterol trafficking and lipid storage disorder caused by mutations in one of the two genes, NPC1 or NPC2. Diagnosis has often been a difficult task, due to the wide range in age of onset of NP-C and clinical presentation of the Disease, combined with the complexity of the cell biology (filipin) laboratory testing, even in combination with genetic testing. This has led to substantial delays in diagnosis, largely depending on the access to specialist centres and the level of knowledge about NP-C of the physician in the area. In recent years, advances in mass spectrometry has allowed identification of several sensitive plasma biomarkers elevated in NP-C (e.g. cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and bile acid metabolites), which, together with the concomitant progress in molecular genetic technology, have greatly impacted the strategy of laboratory testing. Specificity of the biomarkers is currently under investigation and other pathologies are being found to also result in elevations. Molecular genetic testing also has its limitations, notably with unidentified mutations and the classification of new variants. This review is intended to increase awareness on the currently available approaches to laboratory diagnosis of NP-C, to provide an up to date, comprehensive and critical evaluation of the various techniques (cell biology, biochemical biomarkers and molecular genetics), and to briefly discuss ongoing/future developments. The use of current tests in proper combination enables a rapid and correct diagnosis in a large majority of cases. However, even with recent progress, definitive diagnosis remains challenging in some patients, for whom combined genetic/biochemical/cytochemical markers do not provide a clear answer. Expertise and reference laboratories thus remain essential, and further work is still required to fulfill unmet needs.
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stable or improved neurological manifestations during miglustat therapy in patients from the international Disease registry for niemann pick Disease type c an observational cohort study
Orphanet Journal of Rare Diseases, 2015Co-Authors: Marc C. Patterson, Marie T Vanier, Eugen Mengel, B Schwierin, Audrey Muller, Peter Cornelisse, Mercè PinedaAbstract:Background Niemann-Pick Disease type C (NP-C) is a rare neurovisceral Disease characterised by progressive neurological degeneration, where the rate of neurological Disease progression varies depending on age at neurological onset. We report longitudinal data on functional Disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat.
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Complex lipid trafficking in Niemann-Pick Disease type C
Journal of Inherited Metabolic Disease, 2015Co-Authors: Marie T VanierAbstract:Niemann-Pick Disease type C (NPC) is an atypical lysosomal storage Disease resulting from mutations in one of two genes, either NPC1 or NPC2 . Although a neurovisceral disorder, it is above all a neurodegenerative Disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of Diseases affecting other genes that were very recently shown to impact the "NPC pathway".
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recommendations for the diagnosis and management of niemann pick Disease type c an update
Molecular Genetics and Metabolism, 2012Co-Authors: Marc C. Patterson, Mark Walterfang, Marie T Vanier, Frédéric Sedel, Christian J Hendriksz, Frits A WijburgAbstract:Niemann-Pick Disease type C (NP-C) is a rare inherited neurovisceral Disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues. Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy. Epileptic seizures are also common in affected patients. Typically, neurological Disease onset occurs during childhood, although an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations. Categorization of patients according to age at onset of neurological manifestations (i.e. early-infantile, late-infantile, juvenile and adolescent/adult-onset) can be useful for the evaluation of Disease course and treatment responses. The first international guidelines for the clinical management of NP-C in children and adults were published in 2009. Since that time a significant amount of data regarding the epidemiology, detection/diagnosis, and treatment of NP-C has been published. Here, we report points of consensus among experts in the diagnosis and treatment of NP-C based on a follow-up meeting in Paris, France in September 2011. This article serves as an update to the original guidelines providing, among other things, further information on detection/diagnostic methods, potential new methods of monitoring Disease progression, and therapy. Treatment goals and the application of Disease-specific therapy with miglustat are also re-evaluated.
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recommendations on the diagnosis and management of niemann pick Disease type c
Molecular Genetics and Metabolism, 2009Co-Authors: J E Wraith, Mercè Pineda, Thierry Levade, Eugen Mengel, Frédéric Sedel, Bruno Bembi, Matthias R Baumgartner, Athanasios Covanis, Meral Topcu, Marie T VanierAbstract:Niemann-Pick Disease type C (NP-C) is a lysosomal storage Disease in which impaired intracellular lipid trafficking leads to excess storage of cholesterol and glycosphingolipids in the brain and other tissues. It is characterized clinically by a variety of progressive, disabling neurological symptoms including clumsiness, limb and gait ataxia, dysarthria, dysphagia and cognitive deterioration (dementia). Until recently, there has been no Disease-modifying therapy available for NP-C, with treatment limited to supportive measures. In most countries, NP-C is managed through specialist centers, with non-specialist support provided locally. However, effective patient support is hampered by the absence of national or international clinical management guidelines. In this paper, we seek to address this important gap in the current literature. An expert panel was convened in Paris, France in January 2009 to discuss best care practices for NP-C. This commentary reviews current literature on key aspects of the clinical management of NP-C in children, juveniles and adults, and provides recommendations based on consensus between the experts at the meeting.
Forbes D. Porter - One of the best experts on this subject based on the ideXlab platform.
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single cell transcriptome analysis of niemann pick Disease type c1 cerebella
International Journal of Molecular Sciences, 2020Co-Authors: Antony Cougnoux, Niamh X. Cawley, Christopher A. Wassif, James R Iben, Julia C Yerger, Mason Fellmeth, Jenny Serravinardell, Kyle Martin, Fatemeh Navid, Forbes D. PorterAbstract:Niemann-Pick Disease, type C1 (NPC1) is a lysosomal Disease characterized by endolysosomal storage of unesterified cholesterol and decreased cellular cholesterol bioavailability. A cardinal symptom of NPC1 is cerebellar ataxia due to Purkinje neuron loss. To gain an understanding of the cerebellar neuropathology we obtained single cell transcriptome data from control (Npc1+/+) and both three-week-old presymptomatic and seven-week-old symptomatic mutant (Npc1-/-) mice. In seven-week-old Npc1-/- mice, differential expression data was obtained for neuronal, glial, vascular, and myeloid cells. As anticipated, we observed microglial activation and increased expression of innate immunity genes. We also observed increased expression of innate immunity genes by other cerebellar cell types, including Purkinje neurons. Whereas neuroinflammation mediated by microglia may have both neuroprotective and neurotoxic components, the contribution of increased expression of these genes by non-immune cells to NPC1 pathology is not known. It is possible that dysregulated expression of innate immunity genes by non-immune cells is neurotoxic. We did not anticipate a general lack of transcriptomic changes in cells other than microglia from presymptomatic three-week-old Npc1-/- mice. This observation suggests that microglia activation precedes neuronal dysfunction. The data presented in this paper will be useful for generating testable hypotheses related to Disease progression and Purkinje neurons loss as well as providing insight into potential novel therapeutic interventions.
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mechanistic convergence and shared therapeutic targets in niemann pick Disease
Journal of Inherited Metabolic Disease, 2020Co-Authors: Alexandria Colaco, Forbes D. Porter, Ecem Kaya, Elias Adriaenssens, Lianne C Davis, Stefania Zampieri, Maria E Fernandezsuarez, Chong Y Tan, Patrick Deegan, Antony GalioneAbstract:Niemann-Pick Disease type C (NPC) and Tangier Disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier Disease is caused by a defect in ABCA1. Tangier Disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the Disease. When a Tangier Disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic Diseases. In this study, we found that when ABCA1 is defective (Tangier Disease) there is secondary inhibition of the NPC Disease pathway, linking these two Diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier Disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.
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An induced pluripotent stem cell line (TRNDi001-D) from a Niemann-Pick Disease type C1 (NPC1) patient carrying a homozygous p. I1061T (c. 3182T>C) mutation in the NPC1 gene.
Stem cell research, 2020Co-Authors: Manisha Pradhan, Amanda Roeder, Jeanette Beers, Jizhong Zou, Chengyu Liu, Forbes D. Porter, Wei ZhengAbstract:Abstract Niemann-Pick Disease, type C (NPC) is a rare autosomal recessive genetic Disease caused by mutations in either NPC1 or NPC2, which encodes an intracellular cholesterol-binding protein in lysosome. Deficiency of either NPC1 or NPC2 protein results in malfunction of intracellular cholesterol trafficking and lysosomal accumulation of unesterified cholesterols. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a male patient that has a homozygous p.I1061T missense mutation in NPC1 using a non-integrating Sendai virus technique. This NPC1 iPSC line offers a useful resource for Disease modeling and drug development.
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maternal immune activation modifies the course of niemann pick Disease type c1 in a gender specific manner
Molecular Genetics and Metabolism, 2020Co-Authors: Antony Cougnoux, William J Pavan, Mason Fellmeth, Alana L Gibson, Cristin D Davidson, Forbes D. PorterAbstract:Abstract Niemann-Pick Disease, type C1 (NPC1) is a rare neurodegenerative lysosomal storage Disease with a wide spectrum of clinical manifestation. Multiple genetic factors influence the NPC1 mouse phenotype, but very little attention has been given to prenatal environmental factors that might have long-term effects on the neuroinflammatory component of NPC1 pathology. Studies in other mouse models of cerebellar ataxia have shown that developmental exposures lead to Purkinje neuron degeneration later in life, suggesting that environmental exposures during development can impact cerebellar biology. Thus, we evaluated the potential effect of maternal immune activation (MIA) on Disease progression in an Npc1 mouse model. The MIA paradigm used mimics viral infection using the toll like receptor 3 agonist polyinosinic-polycytidilic acid during gestation. Through phenotypic and pathologic tests, we measured motor and behavioral changes as well as cerebellar neuroinflammation and neurodegeneration. We observed a gender and genotype dependent effect of MIA on the cerebellum. While the effects of MIA have been previously shown to primarily affect male progeny, we observed increased sensitivity of female mutant progeny to prenatal exposure to treatment with polyinosinic-polycytidilic acid. Specifically, prenatal MIA resulted in female NPC1 mutant progeny with greater motor deficits and a corresponding decrease in cerebellar Purkinje neurons. Our data suggest that prenatal environmental exposures may be one factor contributing to the phenotypic variability observed in individuals with NPC1.
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Abnormal LAMP1 glycosylation may play a role in Niemann-Pick Disease, type C pathology.
PloS one, 2020Co-Authors: Niamh X. Cawley, Caitlin Sojka, Antony Cougnoux, Anna T. Lyons, Elena-raluca Nicoli, Christopher A. Wassif, Forbes D. PorterAbstract:A hallmark of Niemann-Pick Disease, type C (NPC) is the progressive degeneration of Purkinje neurons in the cerebellum caused by the accumulation of free cholesterol and glycosphingolipids in the lysosome. Recent studies suggest that the state of glycosylation of lysosomal membrane proteins may play a role in Disease progression. Our study has identified the presence of a highly glycosylated form of Lysosome Associated Membrane Protein 1 (LAMP1) that correlated spatiotemporally with Purkinje neuron loss. This form of LAMP1 was predominantly localized to activated microglia; showing a ~5-fold increase in surface labeling by FACS analysis. This suggests a potential role for LAMP1 in the neuro-inflammatory process in these mice during Disease progression. Analysis of other mouse models of neurodegeneration that exhibit neuro-inflammation showed little or no presence of this glycosylated form of LAMP1, suggesting this observation for LAMP1 is specific to NPC Disease. Furthermore, early treatment of Npc1-/- mice with 2-hydroxypropyl-β-cyclodextrin (HPβCD), significantly prevented the appearance of the glycosylated LAMP1 in the cerebellum of Npc1-/- mice at 7 weeks, consistent with the prevention of neuro-inflammation in mice treated with this drug. Treatment of Npc1-/- mice with HPβCD at 7 weeks, after Disease onset, did not reverse or prevent further appearance of the hyperglycosylated LAMP1, demonstrating that once this aspect of neuro-inflammation began, it continued despite the HPβCD treatment. Analysis of LAMP1 in cerebellar tissue of NPC1 patients showed a small level of hyperglycosylated LAMP1 in the tissue, however, this was not seen in the CSF of patients.