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William Krivit - One of the best experts on this subject based on the ideXlab platform.
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allogeneic mesenchymal stem cell infusion for treatment of metachromatic Leukodystrophy mld and hurler syndrome mps ih
Bone Marrow Transplantation, 2002Co-Authors: Omer N Koc, J Day, M Nieder, Stanton L Gerson, Hillard M Lazarus, William KrivitAbstract:Allogeneic mesenchymal stem cell infusion for treatment of metachromatic Leukodystrophy (MLD) and Hurler syndrome (MPS-IH)
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measurements from normal umbilical cord blood of four lysosomal enzymatic activities α l iduronidase hurler galactocerebrosidase globoid cell Leukodystrophy arylsulfatase a metachromatic Leukodystrophy arylsulfatase b maroteaux lamy
Bone Marrow Transplantation, 2000Co-Authors: Rita Degasperi, S S Raghavan, C Carrier, P Rubenstein, Magama Sosa, Joanne Kurtzberg, Charles Peters, John E Wagner, Edwin H. Kolodny, William KrivitAbstract:Measurements from normal umbilical cord blood of four lysosomal enzymatic activities: α- L -iduronidase (Hurler), galactocerebrosidase (globoid cell Leukodystrophy), arylsulfatase A (metachromatic Leukodystrophy), arylsulfatase B (Maroteaux-Lamy)
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bone marrow transplantation for globoid cell Leukodystrophy adrenoLeukodystrophy metachromatic Leukodystrophy and hurler syndrome
Current Opinion in Hematology, 1999Co-Authors: William Krivit, Elsa Shapiro, Patrick Aubourg, Charles PetersAbstract:Bone marrow transplantation protocols for inherited metabolic storage diseases are unique for each disorder treated. Differences depend also upon how old the patient was when onset occurred and rate of progression of disease. Treatment is directed to prevent or ameliorate the inexorable neurological
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hematopoietic stem cell transplantation in globoid cell Leukodystrophy
The New England Journal of Medicine, 1998Co-Authors: William Krivit, Joanne Kurtzberg, Charles Peters, John E Wagner, Edwin H. Kolodny, D. A. Wenger, Elsa Shapiro, Guy Cornu, Marie T Vanier, Daniel J LoesAbstract:BACKGROUND: Globoid-cell Leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell Leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell Leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.
Geneviève Bernard - One of the best experts on this subject based on the ideXlab platform.
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de novo variants in polr3b cause ataxia spasticity and demyelinating neuropathy
American Journal of Human Genetics, 2021Co-Authors: Djurdja Djordjevic, Nicole I. Wolf, Maxime Pinard, Marie Gauthier, Constance Smithhicks, Trevor L Hoffman, Renske Oegema, Ellen Van Binsbergen, Berivan Baskin, Geneviève BernardAbstract:POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating Leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related Leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.
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Dystonia in RNA Polymerase III-Related Leukodystrophy.
Movement Disorders Clinical Practice, 2019Co-Authors: Ghalia Al Yazidi, Luan T. Tran, Kether Guerrero, Adeline Vanderver, Raphael Schiffmann, Nicole I. Wolf, Sylvain Chouinard, Geneviève BernardAbstract:Objectives To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-related Leukodystrophy patient cohort and to further characterize their dystonic features. Background POLR3-related Leukodystrophy is a hypomyelinating Leukodystrophy characterized by neurological and non-neurological features. Dystonia remains a challenging and under-recognized feature. Methods A retrospective chart review was performed in a cohort of 20 patients for whom videos of a standardized neurological examination were available. Patients were recruited at the Montreal Children's Hospital of the McGill University Health Center and the Myelin Disorders Bioregistry Project. Families were consented at the initial assessment and the following data was recorded: age and symptoms at clinical presentation, investigations, causal gene and mutation(s), type and severity of dystonia, and treatment response when needed. Standardized examination videos were reviewed by three independent reviewers and scored using the Global Dystonia Scale. Results 10 males and 10 females were included in this study; 12/20 had POLR3A mutations, while 8/20 had POLR3B mutations; 19/20 patients had documented dystonia, with 3/19 requiring therapy. There was a good response in two patients to a single agent, and a poor response in one patient to three agents; the majority had mild-to-moderate multifocal dystonia without a functional impact. Conclusions Dystonia is a common, yet underdiagnosed, slowly progressive manifestation of POLR3-related Leukodystrophy, and in most cases has limited-to-no functional impact. When treatment is needed, good response to typically used medication may occur. Further studies are needed to assess evolution of dystonia over time, patients' functional outcome, and response to therapy (when needed).
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disease specific therapies in leukodystrophies and leukoencephalopathies
Molecular Genetics and Metabolism, 2015Co-Authors: Guy Helman, Geneviève Bernard, Joshua L Bonkowsky, Keith Van Haren, Amy Pizzino, Nancy Braverman, Dean Suhr, Marc C Patterson, Ali S Fatemi, Jeff LeonardAbstract:Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of Leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of Leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, Leukodystrophy patients are in need of advanced therapies and if possible, a cure.
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4h syndrome with late onset growth hormone deficiency caused by polr3a mutations
JAMA Neurology, 2012Co-Authors: Ana Potic, Raphael Schiffmann, Bernard Brais, Karine Choquet, Geneviève BernardAbstract:Objective To report a novel clinical and genetic presentation of a patient with 4H syndrome, which is a recently described Leukodystrophy syndrome characterized by ataxia, hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Design Case report. Setting University teaching hospital. Patient A 20-year-old male patient with 4H syndrome. Results The patient was found to have delayed tooth eruption and a late-onset growth hormone deficiency without overt growth failure. He was a compound heterozygote for the novel missense mutations R1005H and A1331T of POLR3A, which codes for the largest subunit of RNA polymerase III. Conclusion This is the first report of this type of Leukodystrophy from southeastern Europe, which suggests that POLR3A mutations should be suspected in patients with hypomyelination and various central nervous system–based endocrine abnormalities.
Edwin H. Kolodny - One of the best experts on this subject based on the ideXlab platform.
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measurements from normal umbilical cord blood of four lysosomal enzymatic activities α l iduronidase hurler galactocerebrosidase globoid cell Leukodystrophy arylsulfatase a metachromatic Leukodystrophy arylsulfatase b maroteaux lamy
Bone Marrow Transplantation, 2000Co-Authors: Rita Degasperi, S S Raghavan, C Carrier, P Rubenstein, Magama Sosa, Joanne Kurtzberg, Charles Peters, John E Wagner, Edwin H. Kolodny, William KrivitAbstract:Measurements from normal umbilical cord blood of four lysosomal enzymatic activities: α- L -iduronidase (Hurler), galactocerebrosidase (globoid cell Leukodystrophy), arylsulfatase A (metachromatic Leukodystrophy), arylsulfatase B (Maroteaux-Lamy)
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hematopoietic stem cell transplantation in globoid cell Leukodystrophy
The New England Journal of Medicine, 1998Co-Authors: William Krivit, Joanne Kurtzberg, Charles Peters, John E Wagner, Edwin H. Kolodny, D. A. Wenger, Elsa Shapiro, Guy Cornu, Marie T Vanier, Daniel J LoesAbstract:BACKGROUND: Globoid-cell Leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell Leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell Leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.
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correction of the galactocerebrosidase deficiency in globoid cell Leukodystrophy cultured cells by sl3 3 retroviral mediated gene transfer
Biochemical and Biophysical Research Communications, 1996Co-Authors: Miguel Gama A Sosa, Rita De Gasperi, Samir D Undevia, Joseph Yeretsian, Strutha C Rouse, Timothy A Lyerla, Edwin H. KolodnyAbstract:Globoid cell Leukodystrophy (GCL) or Krabbe disease is an autosomal recessive inherited disease caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of galactocerebroside, a major component of myelin. An animal model homologue of GCL is the twitcher mouse. In the present work, using novel recombinant retroviruses harboring the SL3-3 LTR, we have been able to stably correct the galactocerebrosidase deficiency in twitcher mouse TM-2 cells and in primary human fibroblasts from a patient with globoid cell Leukodystrophy. These results show the possibility of retroviral-mediated gene therapy for the treatment of GCL.
Charles Peters - One of the best experts on this subject based on the ideXlab platform.
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measurements from normal umbilical cord blood of four lysosomal enzymatic activities α l iduronidase hurler galactocerebrosidase globoid cell Leukodystrophy arylsulfatase a metachromatic Leukodystrophy arylsulfatase b maroteaux lamy
Bone Marrow Transplantation, 2000Co-Authors: Rita Degasperi, S S Raghavan, C Carrier, P Rubenstein, Magama Sosa, Joanne Kurtzberg, Charles Peters, John E Wagner, Edwin H. Kolodny, William KrivitAbstract:Measurements from normal umbilical cord blood of four lysosomal enzymatic activities: α- L -iduronidase (Hurler), galactocerebrosidase (globoid cell Leukodystrophy), arylsulfatase A (metachromatic Leukodystrophy), arylsulfatase B (Maroteaux-Lamy)
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bone marrow transplantation for globoid cell Leukodystrophy adrenoLeukodystrophy metachromatic Leukodystrophy and hurler syndrome
Current Opinion in Hematology, 1999Co-Authors: William Krivit, Elsa Shapiro, Patrick Aubourg, Charles PetersAbstract:Bone marrow transplantation protocols for inherited metabolic storage diseases are unique for each disorder treated. Differences depend also upon how old the patient was when onset occurred and rate of progression of disease. Treatment is directed to prevent or ameliorate the inexorable neurological
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hematopoietic stem cell transplantation in globoid cell Leukodystrophy
The New England Journal of Medicine, 1998Co-Authors: William Krivit, Joanne Kurtzberg, Charles Peters, John E Wagner, Edwin H. Kolodny, D. A. Wenger, Elsa Shapiro, Guy Cornu, Marie T Vanier, Daniel J LoesAbstract:BACKGROUND: Globoid-cell Leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell Leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell Leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.
Chiren Tsai - One of the best experts on this subject based on the ideXlab platform.
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late infantile metachromatic Leukodystrophy clinical manifestations of five taiwanese patients and genetic features in asia
Orphanet Journal of Rare Diseases, 2015Co-Authors: Hsiangru Liaw, Hsiufen Lee, Chingshiang Chi, Chiren TsaiAbstract:Background This study was conducted to describe the clinical and genetic features of patients with late infantile metachromatic Leukodystrophy.