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Thierry Levade - One of the best experts on this subject based on the ideXlab platform.
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Spinal muscular atrophy and Farber Disease due to ASAH1 variants: A case report.
American Journal of Medical Genetics Part A, 2020Co-Authors: Bo Hoon Lee, Thierry Levade, Phillip C. Mongiovi, Bethany Marston, Joan Mountain, Emma CiafaloniAbstract:Genetic variations in the ASAH1 gene are associated with a spectrum of disorders ranging from Farber Disease (FD) to spinal muscular atrophy with or without progressive myoclonic epilepsy (SMA-PME). FD presents most commonly in infants with subcutaneous joint nodules, progressive arthritis and granulomas of the larynx and epiglottis leading to a hoarse cry. SMA-PME is characterized by childhood onset progressive weakness due to motor neuron Disease followed by progressive epilepsy, tremor, and sensorineural hearing loss. We present a case of a 4-year-old boy with phenotypic features of both FD and SMA who was found to have two previously unreported heterozygous variants in the ASAH1 gene.
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Allogeneic hematopoietic cell transplantation in Farber Disease.
Journal of Inherited Metabolic Disease, 2019Co-Authors: Karoline Ehlert, Thierry Levade, Andrea Jarisch, Maja Di Rocco, Edoardo Lanino, Michael H. Albert, Monika Führer, Tayfun Güngör, Francis Ayuk, Josef VormoorAbstract:BACKGROUND Farber Disease (FD) is a rare, lysosomal storage disorder caused by deficient acid ceramidase activity. FD has long been considered a fatal disorder with death in the first three decades of life resulting either from respiratory insufficiency as a consequence of airway involvement or from progressive neurodegeneration because of nervous system involvement. Peripheral symptoms associated with FD, including inflammatory joint Disease, have been described to improve relatively rapidly after hematopoietic cell transplantation (HCT). AIMS To evaluate the Disease-specific status and limitations in the long-term follow-up after HCT, investigate genotype/phenotype correlations and the benefit of allogeneic HCT in FD patients with nervous system involvement. PATIENTS AND METHODS Transplant- and Disease-related information of ten FD patients was obtained by using a questionnaire, physicians' letters and additional telephone surveys. ASAH1 gene mutations were identified to search for genotype/phenotype correlations. RESULTS After mainly busulfan-based preparative regimens, all patients engrafted with one late graft loss. The inflammatory symptoms resolved completely in all patients. Abnormal neurologic findings were present pre-transplant in 4/10 patients, post-transplant in 6/10 patients. Mutational analyses revealed new mutations in the ASAH1 gene and a broad diversity of phenotypes without a genotype/phenotype correlation. With a median follow-up of 10.4 years, overall survival was 80% with two transplant-related deaths. CONCLUSION Allogeneic HCT leads to complete and persistent resolution of the inflammatory aspects in FD patients. It appears to have no beneficial effect on progression of nervous system involvement. New mutations in the acid ceramidase gene were identified. A genotype/phenotype correlation could not be established.
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Acid ceramidase deficiency: Farber Disease and SMA-PME
Orphanet Journal of Rare Diseases, 2018Co-Authors: Samuel Amintas, Thierry Levade, Jeffrey A. MedinAbstract:Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber Disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using Disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.
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allogeneic hematopoietic cell transplantation in Farber Disease
Journal of Inherited Metabolic Disease, 2018Co-Authors: Karoline Ehlert, Thierry Levade, Andrea Jarisch, Maja Di Rocco, Edoardo Lanino, Michael H. Albert, Monika Führer, Tayfun Güngör, Francis Ayuk, Josef VormoorAbstract:Farber Disease (FD) is a rare, lysosomal storage disorder caused by deficient acid ceramidase activity. FD has long been considered a fatal disorder with death in the first three decades of life resulting either from respiratory insufficiency as a consequence of airway involvement or from progressive neurodegeneration because of nervous system involvement. Peripheral symptoms associated with FD, including inflammatory joint Disease, have been described to improve relatively rapidly after hematopoietic cell transplantation (HCT). To evaluate the Disease-specific status and limitations in the long-term follow-up after HCT, investigate genotype/phenotype correlations and the benefit of allogeneic HCT in FD patients with nervous system involvement. Transplant- and Disease-related information of ten FD patients was obtained by using a questionnaire, physicians’ letters and additional telephone surveys. ASAH1 gene mutations were identified to search for genotype/phenotype correlations. After mainly busulfan-based preparative regimens, all patients engrafted with one late graft loss. The inflammatory symptoms resolved completely in all patients. Abnormal neurologic findings were present pre-transplant in 4/10 patients, post-transplant in 6/10 patients. Mutational analyses revealed new mutations in the ASAH1 gene and a broad diversity of phenotypes without a genotype/phenotype correlation. With a median follow-up of 10.4 years, overall survival was 80% with two transplant-related deaths. Allogeneic HCT leads to complete and persistent resolution of the inflammatory aspects in FD patients. It appears to have no beneficial effect on progression of nervous system involvement. New mutations in the acid ceramidase gene were identified. A genotype/phenotype correlation could not be established.
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acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy
Neuromuscular Disorders, 2015Co-Authors: Joanna J Gan, Thierry Levade, Virginie Garcia, Jane Tian, Michele Tagliati, Joseph E Parisi, Jeffrey M Chung, Richard A Lewis, Robert H Baloh, Tyler Mark PiersonAbstract:Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an extremely rare disorder related to the lysosomal storage Disease, Farber lipogranulomatosis. Both disorders are autosomal recessive conditions caused by mutations in the ASAH1 gene encoding acid ceramidase. Farber Disease is associated with joint deformities, lipomatous skin nodules, and often is fatal by 2-3 years of age; while SMA-PME is characterized by childhood-onset motor neuron Disease and progressive myoclonic epilepsy. We report a case of SMA-PME with a novel mutation in the ASAH1 gene encoding acid ceramidase. The proband presented with childhood-onset of diffuse muscle atrophy and hypotonia. He also had diffuse weakness with greater proximal than distal involvement. Tongue fasciculations were present and his reflexes were either diminished or absent. He ambulated with an unsteady and hesitant gait. He subsequently developed myoclonic epilepsy along with other associated features including tremor, polymyoclonus, and sensorineural hearing loss. Neurophysiological studies revealed a motor neuron disorder and generalized epilepsy. Exome sequencing analysis identified compound heterozygous variants and biochemical analysis indicated acid ceramidase activity was approximately 12 percent of normal controls. Our proband was phenotypically similar to other cases of SMA-PME, albeit with somewhat lesser severity, slower progression, and greater longevity. As lysosomal disorders are sometimes amendable to early interventions, it is important to make early diagnoses in these cases. The combination of motor neuron Disease and progressive myoclonic epilepsy should prompt genetic evaluation of ASAH1.
Jeffrey A. Medin - One of the best experts on this subject based on the ideXlab platform.
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hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency
Laboratory Investigation, 2019Co-Authors: Salvatore Molino, Jakub Sikora, Shauna A Rasmussen, Jitka Rybova, Everett Tate, Aron M Geurts, Patricia V Turner, William M Mckillop, Jeffrey A. MedinAbstract:Farber Disease (FD) is a rare lysosomal storage disorder (LSD) characterized by systemic ceramide accumulation caused by a deficiency in acid ceramidase (ACDase). In its classic form, FD manifests with painful lipogranulomatous nodules in extremities and joints, respiratory complications, and neurological involvement. Hepatosplenomegaly is commonly reported, and severe cases of FD cite liver failure as a cause of early death. Mice homozygous for an orthologous patient mutation in the ACDase gene (Asah1P361R/P361R) recapitulate the classical form of human FD. In this study, we demonstrate impaired liver function and elevation of various liver injury markers in Asah1P361R/P361R mice as early as 5 weeks of age. Histopathology analyses demonstrated significant formation and recruitment of foamy macrophages, invasion of neutrophils, progressive tissue fibrosis, increased cell proliferation and death, and significant storage pathology within various liver cell types. Lipidomic analyses revealed alterations to various lipid concentrations in both serum and liver tissue. A significant accumulation of ceramide and other sphingolipids in both liver and hepatocytes was noted. Sphingolipid acyl chains were also altered, with an increase in long acyl chain sphingolipids coinciding with a decrease in ultra-long acyl chains. Hepatocyte transcriptome analyses revealed significantly altered gene transcription. Molecular pathways related to inflammation were found activated, and molecular pathways involved in lipid metabolism were found deactivated. Altered gene transcription within the sphingolipid pathway itself was also observed. The data presented herein demonstrates that deficiency in ACDase results in liver pathology as well as sphingolipid and gene transcription profile changes that lead to impaired liver function.
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acid ceramidase deficiency in mice leads to severe ocular pathology and visual impairment
American Journal of Pathology, 2019Co-Authors: Benjamin S Sajdak, Jakub Sikora, Murtaza S Nagree, Alexander E Salmon, Jiři Gurka, Iris S Kassem, Daniel M Lipinski, Joseph Carroll, Jeffrey A. MedinAbstract:Farber Disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.
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Acid ceramidase deficiency: Farber Disease and SMA-PME
Orphanet Journal of Rare Diseases, 2018Co-Authors: Samuel Amintas, Thierry Levade, Jeffrey A. MedinAbstract:Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber Disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using Disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.
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Deletion of MCP-1 Impedes Pathogenesis of Acid Ceramidase Deficiency
Nature Publishing Group, 2018Co-Authors: Shaalee Dworski, Jeffrey A. MedinAbstract:Abstract Farber Disease (FD) is an ultra-rare Lysosomal Storage Disorder caused by deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency manifest a spectrum of symptoms including formation of nodules, painful joints, and a hoarse voice. Classic FD patients will develop histiocytes in organs and die in childhood. Monocyte chemotactic protein (MCP-1; CCL2) is significantly elevated in both FD patients and a mouse model we previously generated. Here, to further study MCP-1 in FD, we created an ACDase;MCP-1 double mutant mouse. We show that deletion of MCP-1 reduced leukocytosis, delayed weight loss, and improved lifespan. Reduced inflammation and fibrosis were observed in livers from double mutant animals. Bronchial alveolar lavage fluid analyses revealed a reduction in cellular infiltrates and protein accumulation. Furthermore, reduced sphingolipid accumulation was observed in the lung and liver but not in the brain. The neurological and hematopoietic defects observed in FD mice were maintained. A compensatory cytokine response was found in the double mutants, however, that may contribute to continued signs of inflammation and injury. Taken together, targeting a reduction of MCP-1 opens the door to a better understanding of the mechanistic consequences of ceramide accumulation and may even delay the progression of FD in some organ systems
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Enzyme replacement therapy for Farber Disease: Proof-of-concept studies in cells and mice
BBA Clinical, 2017Co-Authors: Shaalee Dworski, Calogera M. Simonaro, Alex Solyom, Changzhi Zhu, Victor Deangelis, Jeffrey A. Medin, Edward H. SchuchmanAbstract:A series of studies were carried out in Farber Disease (OMIM #228000) cells and mice to evaluate the feasibility of enzyme replacement therapy (ERT) for this disorder. Media from Chinese hamster ovary (CHO) cells overexpressing human recombinant acid ceramidase (rhAC) was used to treat fibroblasts from a Farber Disease patient, leading to significantly reduced ceramide. We also found that chondrocytes from Farber Disease mice had a markedly abnormal chondrogenic phenotype, and this was corrected by rhAC as well. Acute dosing of rhAC in Farber mice confirmed the enzyme's bioactivity in vivo, and showed that it could be safely administered at doses up to 50 mg/kg. These studies also revealed little or no re-accumulation of ceramide in tissues for at least 7 days after enzyme administration. Once weekly administration of rhAC moderately improved survival of the mice, which could be enhanced by starting enzyme administration at an earlier age (3 days vs. 3 weeks). Repeat administration of the enzyme also led to normalization of spleen size, significantly reduced plasma levels of monocyte chemoattractant protein 1 (MCP-1), reduced infiltration of macrophages into liver and spleen, and significantly reduced ceramide and sphingosine in tissues. Overall, we conclude that ERT should be further developed for this debilitating and life-threatening disorder.
Edward H. Schuchman - One of the best experts on this subject based on the ideXlab platform.
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Loss of acid ceramidase activity in a murine model of Farber Disease leads to an early and profound immuno-phenotype that reflects alterations in both the innate and adaptive immune cell populations
Journal of Immunology, 2018Co-Authors: Christine M. Coquery, Edward H. Schuchman, Alexander Sólyom, Changzhi Zhu, Victor Deangelis, Brante Sampey, Eric J. Gaukel, Stephen A. WringAbstract:Farber Disease is an ultra-rare lysosomal storage disorder where a deficiency of acid ceramidase activity leads to the accumulation of ceramide and the formation of granulomas which, in conjunction with a chronic inflammatory state, likely results in tissue damage. A rapidly progressive murine knock-in Asah1 P361R/P361R model of Farber Disease recapitulates many aspects of the human Disease, including an increase in ceramide and pronounced tissue inflammation. The focus of this study was to describe the aberrant immune cells in this Disease model. Blood, livers, lungs, and spleens were collected from 4- to 8-week old litter-matched Farber and wild-type mice for characterization by flow cytometry. Characterization of the monocyte population revealed a marked increase in the frequency of MHCII − CD11b hi Ly6C + cells (3–6 fold vs WT). These cells were highly activated as evidenced by CD86 expression, and skewed toward a pro-inflammatory M1 phenotype, based on CD38 expression. A concurrent decrease in CD206 + anti-inflammatory M2 macrophages was identified. In addition to the macrophage compartment, a profound increase in neutrophils in the spleen, liver, and lung was evident by 4 weeks of age (2–7 fold vs. wild-type). Marked differences in the adaptive immune compartment also were noted, with a clear increase in the frequency of plasmablasts (precursors to immunoglobulin-producing plasma cells), likely secondary to the increase in pro-inflammatory monocytes. Importantly, the alterations observed in the tissues were reflected in the blood of Farber mice. In summary, these data expand the characterization of the murine Farber Disease model and provide insight into the immuno-phenotype of Farber Disease.
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Morbidity and mortality associated with Farber Disease and prospects for therapy
Expert Opinion on Orphan Drugs, 2017Co-Authors: Edward H. Schuchman, John J. Mitchell, Alex SolyomAbstract:ABSTRACTIntroduction: Farber Disease is the lysosomal storage disorder due to the deficiency of acid ceramidase activity. Although it was described over six decades ago, it remains poorly described due to its unusual clinical presentation and rarity. No targeted therapies currently exist.Areas covered: The history of Farber Disease, acid ceramidase and research leading to the development of therapy will be summarized, along with current knowledge regarding the clinical presentation and patient management.Expert opinion: Farber Disease is often misdiagnosed as idiopathic juvenile arthritis. The clinical presentation is broad, with onset and survival ranging from early childhood to adults. Multiple organ systems, including the central nervous system, may be involved, but the most consistent finding in all patients is subcutaneous nodules that form mostly around joints. The nodules consist of lipid-filled macrophages, and inflammation is a major driver of the pathobiology. Pain, dysphonia and limitation of m...
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Enzyme replacement therapy for Farber Disease: Proof-of-concept studies in cells and mice
BBA Clinical, 2017Co-Authors: Shaalee Dworski, Calogera M. Simonaro, Alex Solyom, Changzhi Zhu, Victor Deangelis, Jeffrey A. Medin, Edward H. SchuchmanAbstract:A series of studies were carried out in Farber Disease (OMIM #228000) cells and mice to evaluate the feasibility of enzyme replacement therapy (ERT) for this disorder. Media from Chinese hamster ovary (CHO) cells overexpressing human recombinant acid ceramidase (rhAC) was used to treat fibroblasts from a Farber Disease patient, leading to significantly reduced ceramide. We also found that chondrocytes from Farber Disease mice had a markedly abnormal chondrogenic phenotype, and this was corrected by rhAC as well. Acute dosing of rhAC in Farber mice confirmed the enzyme's bioactivity in vivo, and showed that it could be safely administered at doses up to 50 mg/kg. These studies also revealed little or no re-accumulation of ceramide in tissues for at least 7 days after enzyme administration. Once weekly administration of rhAC moderately improved survival of the mice, which could be enhanced by starting enzyme administration at an earlier age (3 days vs. 3 weeks). Repeat administration of the enzyme also led to normalization of spleen size, significantly reduced plasma levels of monocyte chemoattractant protein 1 (MCP-1), reduced infiltration of macrophages into liver and spleen, and significantly reduced ceramide and sphingosine in tissues. Overall, we conclude that ERT should be further developed for this debilitating and life-threatening disorder.
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Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency.
PEDIATRICS, 2016Co-Authors: Hooi Ling Teoh, Edward H. Schuchman, Alexander Sólyom, David Mowat, Tony Roscioli, Michelle A. Farrar, Hugo SampaioAbstract:Survival of motor neuron 1–negative spinal muscular atrophy (SMA) is heterogeneous and remains a diagnostic challenge. The clinical spectrum continues to expand and ∼33 genes have been identified to date. The present report describes a 9-year-old girl with novel clinical phenotype of a patient with polyarticular arthritis followed by symptoms of SMA due to acid ceramidase deficiency. Whole exome sequencing identified compound heterozygous pathogenic mutation in the N-acylsphingosine amidohydrolase 1 gene. Functional assay with leukocyte acid ceramidase activity showed a decreased level in the proband confirming pathogenicity of the mutations. Mutations of N-acylsphingosine amidohydrolase 1 are known to separately cause Farber Disease (arthritis, subcutaneous nodules, and dysphonia) or SMA with progressive myoclonic epilepsy. The present combined phenotype is novel, bringing together SMA with progressive myoclonic epilepsy and Farber Disease and establishing a phenotypic spectrum. Acid ceramidase deficiency is an important consideration in patients presenting with polyarticular arthritis and motor neuron Disease.
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Polyarticular arthritis as presenting feature of Farber Disease: a lysosomal storage Disease involving inflammation
Pediatric Rheumatology, 2014Co-Authors: Alexander Sólyom, Nesrin Karabul, Calogera M. Simonaro, Boris Hügle, Edward H. SchuchmanAbstract:Farber lipogranulomatosis (Farber Disease; FD) is an ultra-rare lysosomal storage disorder resulting from the inherited deficiency of the enzyme acid ceramidase, and the accumulation of the lipid substrate, ceramide. Ceramide is a pro-inflammatory and pro-apoptotic lipid that has been implicated in the pathogenesis of cartilage disorders. Farber Disease has a heterogeneous presentation ranging from a severe phenotype with respiratory and CNS involvement with an average life expectancy of 1.3 years, to a moderate phenotype, which generally includes joint swelling, contractures and pain. The clinical similarity between the moderate Farber phenotype and the more severe forms of Juvenile Idiopathic Arthritis (JIA) suggests that moderate Farber Disease cases may be diagnosed as JIA in some cases.
Klaus Harzer - One of the best experts on this subject based on the ideXlab platform.
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Molecular basis of acid ceramidase deficiency in a neonatal form of Farber Disease: identification of the first large deletion in ASAH1 gene.
Molecular Genetics and Metabolism, 2013Co-Authors: Mariana Q. Alves, Klaus Harzer, Thierry Levade, Stéphane Carpentier, Emmanuelle Le Trionnaire, Isaura Ribeiro, M. Gil RibeiroAbstract:Abstract Farber Disease, also known as Farber's lipogranulomatosis, is a clinically heterogeneous autosomal recessive Disease caused by mutations in the ASAH1 gene. This gene codes for acid ceramidase, a lysosomal heterodimeric enzyme that hydrolyzes ceramide into sphingosine and fatty acid. To date, less than 25 distinct mutations have been identified in Farber patients, but no large deletions have yet been reported. In this work, cultured fibroblasts from a Farber patient with the rare neonatal form of Farber Disease were studied to elucidate the molecular basis of this extremely severe phenotype. Direct sequencing of ASAH1 genomic DNA revealed the causative heterozygous mutation in the donor splice site consensus sequence of intron 11, g.24491A>G (c.917+4A>G), that resulted in the absence of detectable mRNA. Subsequent analysis of ASAH1 mRNA showed total skipping of exons 3 to 5. Long-range PCR and sequencing led to the identification of a gross deletion of ASAH1 gene, g.8728_18197del (c.126-3941_382+1358del) predicting the synthesis of a truncated polypeptide, p.Tyr42_Leu127delinsArgfs*10. Accordingly, no molecular forms corresponding to precursor or proteolytically processed mature protein were observed. These findings indicate that any functionally active acid ceramidase is absent in patient cells, underscoring the severity of the clinical phenotype. Molecular findings in the non-consanguineous parents confirmed the compound heterozygous ASAH1 genotype identified in this Farber case. This work unravels for the first time the mutations underlying the neonatal form of Farber Disease and represents the first report of a large deletion identified in the ASAH1 gene. Screening for gross deletions in other patients in whom the mutation present in the second allele had not yet been identified is required to elucidate further its overall contribution for the molecular pathogenesis of this devastating Disease.
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The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber Disease cells
Oncogene, 2001Co-Authors: Christof Burek, Klaus Harzer, Hans Georg Koch, Johannes Roth, Klaus Schulze-osthoffAbstract:The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber Disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber Disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and γ-irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber Disease and control fibroblasts. Interestingly, Farber Disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis.
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natural ceramide is unable to escape the lysosome in contrast to a fluorescent analogue
FEBS Letters, 1998Co-Authors: Martine Chatelut, Klaus Harzer, Robert Salvayre, Michele Leruth, Arie Dagan, Sergio Marchesini, Shimon Gatt, Pierre J Courtoy, Thierry LevadeAbstract:Since the generation upon cell stimulation of the second messenger ceramide has been reported to occur in an endosomal/lysosomal compartment, we investigated whether ceramide formed in the lysosomes can escape this compartment. The metabolic fate of radiolabelled ceramide produced by intralysosomal hydrolysis of LDL-associated [ceramide-3H]sphingomyelin or [stearoyl-1-(14)C]sulfatide was examined in fibroblasts from control individuals and a patient with inborn lysosomal ceramidase deficiency (Farber Disease). The behavior of this radioactive ceramide was compared to that of a fluorescent (lissamine-rhodaminyl) ceramide analogue deriving from sulfatide degradation. While in Farber cells the natural, radiolabelled ceramide remained completely undegraded and accumulated in the lysosomes, the fluorescent derivative was rapidly converted to sphingomyelin. These findings strongly suggest that, in contrast to fluorescent derivatives, endogenous long-chain ceramide is unable to exit from lysosomes, therefore making the lysosomal ceramide unlikely to be a biomodulatory molecule.
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Model SV40-transformed fibroblast lines for metabolic studies of human prosaposin and acid ceramidase deficiencies.
Clinica chimica acta; international journal of clinical chemistry, 1997Co-Authors: Martine Chatelut, Barbara C. Paton, Klaus Harzer, Jean Feunteun, Jean-pierre Basile, Yasuo Kishimoto, John S. O'brien, Helen Christomanou, Marie-thérèse Pieraggi, Jean-claude ThiersAbstract:Abstract Skin fibroblasts from patients with Farber Disease (acid ceramidase deficiency) and from two siblings of the only known family affected with prosaposin deficiency were transformed by transfection with a plasmid carrying the SV40 large T antigen. The prosaposin-deficient transformed cell lines conserved their original metabolic defects, and in particular they were free of detectable immunoreactivity when using anti-saposin B and anti-saposin C antisera. Ultrastructurally, the cells contained heterogeneous lysosomal storage products. As found for their parental cell lines, the SV40-transformed fibroblasts exhibited deficient in vitro activities of lysosomal ceramidase and β-galactosylceramidase, but a normal activity of acid sphingomyelinase. As observed for SV40-transformed fibroblasts from Farber Disease, degradation of radioactive glucosylceramide or low density lipoprotein-associated radiolabelled sphingomyelin by the prosaposin-deficient cells in situ showed a clear impairment in the turnover of lysosomal ceramide. Ceramide storage in prosaposin-deficient cells was also demonstrated by ceramide mass determination. In contrast to acid ceramidase deficient cells, both the accumulation of ceramide and the reduced in vitro activity of acid ceramidase in cells from prosaposin deficiency could be corrected by addition of purified saposin D. The data confirm that prosaposin is required for lysosomal ceramide degradation, but not for sphingomyelin turnover. The SV40-transformed fibroblasts will be useful for pathophysiological studies on human prosaposin deficiency.
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A simple method for screening for Farber Disease on cultured skin fibroblasts
Clinica Chimica Acta, 1996Co-Authors: Martine Chatelut, Klaus Harzer, Jean Feunteun, Anthony H. Fensom, Jean-pierre Basile, Robert Salvayre, Thierry LevadeAbstract:Farber Disease is an inborn lysosomal storage disorder characterized by accumulation of ceramide in the patient's tissues due to the deficient activity of acid ceramidase. Currently, confirmation of the diagnosis is performed in an extremely limited number of laboratories. We therefore developed a procedure which does not require any particular sphingolipid substrate and is based on the quantitation of ceramide levels in cultured skin fibroblasts. In the method we devised, the ceramide present in cellular lipid extracts subjected to mild alkaline hydrolysis was quantified using the commercially available diacylglycerol kinase kit. We show that both primary cultures of skin fibroblasts and SV40-transformed fibroblasts derived from a series of patients with Farber Disease exhibit ceramide excess as compared to their normal counterparts (2345-17 153 pmol/mg cell protein in Farber cells vs. 432-1298 pmol/mg cell protein in controls). Use of this simple method should greatly facilitate the biochemical diagnosis of Farber Disease.
Alexander Sólyom - One of the best experts on this subject based on the ideXlab platform.
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ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber Disease and spinal muscular atrophy with progressive myoclonic epilepsy.
Human Mutation, 2020Co-Authors: Sarah H. Elsea, John J. Mitchell, Alexander Sólyom, Kirt Martin, Paul Harmatz, Christina Lampe, Christina Grant, Laila Selim, Neslihan Oneli Mungan, Norberto GuelbertAbstract:Farber Disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber Disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber Disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of Disease-causing variants.
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Loss of acid ceramidase activity in a murine model of Farber Disease leads to an early and profound immuno-phenotype that reflects alterations in both the innate and adaptive immune cell populations
Journal of Immunology, 2018Co-Authors: Christine M. Coquery, Edward H. Schuchman, Alexander Sólyom, Changzhi Zhu, Victor Deangelis, Brante Sampey, Eric J. Gaukel, Stephen A. WringAbstract:Farber Disease is an ultra-rare lysosomal storage disorder where a deficiency of acid ceramidase activity leads to the accumulation of ceramide and the formation of granulomas which, in conjunction with a chronic inflammatory state, likely results in tissue damage. A rapidly progressive murine knock-in Asah1 P361R/P361R model of Farber Disease recapitulates many aspects of the human Disease, including an increase in ceramide and pronounced tissue inflammation. The focus of this study was to describe the aberrant immune cells in this Disease model. Blood, livers, lungs, and spleens were collected from 4- to 8-week old litter-matched Farber and wild-type mice for characterization by flow cytometry. Characterization of the monocyte population revealed a marked increase in the frequency of MHCII − CD11b hi Ly6C + cells (3–6 fold vs WT). These cells were highly activated as evidenced by CD86 expression, and skewed toward a pro-inflammatory M1 phenotype, based on CD38 expression. A concurrent decrease in CD206 + anti-inflammatory M2 macrophages was identified. In addition to the macrophage compartment, a profound increase in neutrophils in the spleen, liver, and lung was evident by 4 weeks of age (2–7 fold vs. wild-type). Marked differences in the adaptive immune compartment also were noted, with a clear increase in the frequency of plasmablasts (precursors to immunoglobulin-producing plasma cells), likely secondary to the increase in pro-inflammatory monocytes. Importantly, the alterations observed in the tissues were reflected in the blood of Farber mice. In summary, these data expand the characterization of the murine Farber Disease model and provide insight into the immuno-phenotype of Farber Disease.
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Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency.
PEDIATRICS, 2016Co-Authors: Hooi Ling Teoh, Edward H. Schuchman, Alexander Sólyom, David Mowat, Tony Roscioli, Michelle A. Farrar, Hugo SampaioAbstract:Survival of motor neuron 1–negative spinal muscular atrophy (SMA) is heterogeneous and remains a diagnostic challenge. The clinical spectrum continues to expand and ∼33 genes have been identified to date. The present report describes a 9-year-old girl with novel clinical phenotype of a patient with polyarticular arthritis followed by symptoms of SMA due to acid ceramidase deficiency. Whole exome sequencing identified compound heterozygous pathogenic mutation in the N-acylsphingosine amidohydrolase 1 gene. Functional assay with leukocyte acid ceramidase activity showed a decreased level in the proband confirming pathogenicity of the mutations. Mutations of N-acylsphingosine amidohydrolase 1 are known to separately cause Farber Disease (arthritis, subcutaneous nodules, and dysphonia) or SMA with progressive myoclonic epilepsy. The present combined phenotype is novel, bringing together SMA with progressive myoclonic epilepsy and Farber Disease and establishing a phenotypic spectrum. Acid ceramidase deficiency is an important consideration in patients presenting with polyarticular arthritis and motor neuron Disease.
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SAT0493 Farber Disease: First Natural History Cohort Demonstrates a Broad Clinical Spectrum with Implications for Juvenile Idiopathic Arthritis Patients
Annals of the Rheumatic Diseases, 2015Co-Authors: Alexander Sólyom, Boris Hügle, Norberto Guelbert, K. Ehlert, Bo Magnusson, Giedre Grigelioniene, Janet Gardner-medwin, Pranoot Tanpaiboon, Lawrence Jung, R. PuriAbstract:Background Farber Disease (Farber lipogranulomatosis; acid ceramidase deficiency) is a rare lysosomal storage disorder resulting from the inherited deficiency of the enzyme acid ceramidase, and the accumulation of the lipid substrate, ceramide. Ceramide is a potent pro-inflammatory and pro-apoptotic lipid. The moderate phenotype generally includes joint swelling, contractures and pain. The clinical similarity of the moderate Farber phenotype to polyarticular juvenile idiopathic arthritis (JIA) can lead to misdiagnosis. Differential diagnosis can be made by accounting for the comparatively early onset, progressive symmetric arthritis, presence of subcutaneous nodules, and an unusual, hoarse voice (due to nodule formation on the larynx) in Farber Disease patients. Objectives The analysis of clinical information from a cohort of Farber Disease patients to better define the overlap with juvenile idiopathic arthritis. Methods A cohort of 25 living Farber Disease patients has been established to provide insight into the phenotypic spectrum of the Disease, as well as the clinical history, diagnostic evaluations, and treatments the patients have undergone. Retrospectively, whenever possible, the presenting symptoms, clinical history, biochemical, and genetic diagnostic evaluations were recorded. Treatment modalities and response to treatment were registered. Results Patients in the cohort vary in age from 5 months to 33 years of age. Phenotypes range from infantile onset with systemic inflammation, to late childhood onset and very mild Disease. Most patients demonstrated the three typical symptoms of Farber Disease (arthritis, subcutaneous nodules, dysphonia). However, in several cases years passed between appearance of the individual symptoms. Treatment varied from haematopoietic stem cell transplantation, to biologics (incl. anti-TNFa and anti-IL-6) and intensive pain relief, to no treatment at all. Conclusions This study represents the largest collection of clinical data on Farber Disease to date. It is clear that the spectrum of phenotypes includes mild presentations not previously associated with Farber, and that in most cases a pediatric rheumatologist is involved in patient care. The fact that 25 patients could be collected over 6 months implies that the Disease is not as rare as earlier supposed. These results also suggest that acid ceramidase deficiency may likely account for a larger number of polyarticular JIA patients than previously thought. It is therefore important to increase awareness of Farber Disease among rheumatologists. The screening process will be greatly simplified with the use of dried blood spot assays. Enzyme replacement therapy for Farber is currently under development. Disclosure of Interest A. Solyom Grant/research support from: Plexcera Therapeutics LLC, Consultant for: Plexcera Therapeutics LLC, K. Ehlert: None declared, B. Hugle: None declared, B. Magnusson: None declared, G. Grigelioniene: None declared, N. Guelbert: None declared, J. Gardner-Medwin: None declared, P. Tanpaiboon: None declared, L. Jung: None declared, R. Puri: None declared, M. DiRocco: None declared, J. Mitchell: None declared, M. Beck: None declared, C. Simonaro: None declared, E. Schuchman Shareholder of: Plexcera Therapeutics LLC
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Polyarticular arthritis as presenting feature of Farber Disease: a lysosomal storage Disease involving inflammation
Pediatric Rheumatology, 2014Co-Authors: Alexander Sólyom, Nesrin Karabul, Calogera M. Simonaro, Boris Hügle, Edward H. SchuchmanAbstract:Farber lipogranulomatosis (Farber Disease; FD) is an ultra-rare lysosomal storage disorder resulting from the inherited deficiency of the enzyme acid ceramidase, and the accumulation of the lipid substrate, ceramide. Ceramide is a pro-inflammatory and pro-apoptotic lipid that has been implicated in the pathogenesis of cartilage disorders. Farber Disease has a heterogeneous presentation ranging from a severe phenotype with respiratory and CNS involvement with an average life expectancy of 1.3 years, to a moderate phenotype, which generally includes joint swelling, contractures and pain. The clinical similarity between the moderate Farber phenotype and the more severe forms of Juvenile Idiopathic Arthritis (JIA) suggests that moderate Farber Disease cases may be diagnosed as JIA in some cases.
