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Monica Nizzardo - One of the best experts on this subject based on the ideXlab platform.
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current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 smard1
Cellular and Molecular Life Sciences, 2020Co-Authors: Martina G L Perego, Noemi Galli, Alessandra Govoni, Michela Taiana, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Stefania CortiAbstract:Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.
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Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights.
Journal of cellular and molecular medicine, 2019Co-Authors: Matteo Saladini, Alessandra Govoni, Michela Taiana, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.
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AAV9-mediated gene therapy in a SMARD1 mouse model (PL1.003)
Neurology, 2015Co-Authors: Monica Nizzardo, Paola Rinchetti, Chiara Simone, Federica Rizzo, Sabrina Salani, Sara Dametti, Roberto Del Bo, Brian K. Kaspar, Gianna Ulzi, Kevin D. FoustAbstract:OBJECTIVE: The aim of this study is to demonstrate the efficacy of the adeno-associated virus serotype 9 (AAV9)-mediated gene therapy to ameliorate the disease phenotype of a Spinal muscular atrophy with respiratory distress type 1 (SMARD1) in vivo model. BACKGROUND:SMARD1 is an autosomal recessive motor neuron disease affecting children, caused by mutations in the IGHMBP2 gene. No effective therapy is currently available for SMARD1. It has been recently demonstrated that AAV9-mediated gene therapy can rescue the phenotype of animal models of another motor neuron disorder, Spinal Muscular Atrophy 5q (SMA), and a clinical trial with this strategy is ongoing. DESIGN/METHODS: In this study, we performed systemic injection of AAV9 encoding the wild-type IGHMBP2 in order to replace the defective gene in the SMARD1 mouse model. To test this strategy also in an in vitro model, we transferred wild-type IGHMBP2 into human SMARD1 induced pluripotent stem cells (iPSC)-derived motor neurons analysing any modifications of the pathological phenotype. RESULTS:We demonstrated that the AAV9-IGHMBP2 administration, rescued not only the level of the protein, but also the motor function, neuromuscular physiology and lifespan of SMARD1 mice. Moreover we observed an amelioration of the pathological aspects of the central nervous system, heart and muscle. When we administrated the wild-type IGHMBP2 into the iPSC-derived motor neurons, we detected an increase of their survival and axonal length in long-term culture. CONCLUSIONS:Our data support the translational potential of AAV mediated gene therapies for SMARD1, opening the path for AAV9-mediated therapy in human clinical trials. Study Supported by: Italian Ministry of Health GR-2010-2309229 to M.N. Disclosure: Dr. Nizzardo has nothing to disclose. Dr. Simone has nothing to disclose. Dr. Rizzo has nothing to disclose. Dr. Salani has nothing to disclose. Dr. Ulzi has nothing to disclose. Dr. Dametti has nothing to disclose. Dr. Rinchetti has nothing to disclose. Dr. Del Bo has nothing to disclose. Dr. Kaspar stands to receive license fee payments from Milo Biotechnology Corporation. Dr. Foust has nothing to disclose. Dr. Bresolin has nothing to disclose. Dr. Comi has nothing to disclose. Dr. Corti has nothing to disclose.
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Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model
Science advances, 2015Co-Authors: Monica Nizzardo, Paola Rinchetti, Chiara Simone, Federica Rizzo, Sabrina Salani, Sara Dametti, Roberto Del Bo, Kevin D. Foust, Brian K. Kaspar, Nereo BresolinAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)–mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-type IGHMBP2 to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell–derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials.
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Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model
2015Co-Authors: Monica Nizzardo, Paola Rinchetti, Federica Rizzo, Sabrina Salani, Sara Dametti, Roberto Del Bo, C. Simone, K. Foust, B. Kaspar, Nereo BresolinAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children that is caused by mutations in the IGHMBP2 gene (11q13) and lacks a cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy rescued the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. In this study, we report rescue of the disease phenotype in a SMARD1 mouse model following therapeutic delivery of an AAV9 construct encoding the wild-type IGHMBP2 via systemic injection to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and lifespan (450% increase), ameliorating pathological features in the CNS, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1 induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials
Stefania Corti - One of the best experts on this subject based on the ideXlab platform.
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current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 smard1
Cellular and Molecular Life Sciences, 2020Co-Authors: Martina G L Perego, Noemi Galli, Alessandra Govoni, Michela Taiana, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Stefania CortiAbstract:Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.
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Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights.
Journal of cellular and molecular medicine, 2019Co-Authors: Matteo Saladini, Alessandra Govoni, Michela Taiana, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.
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Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1.
Journal of cellular and molecular medicine, 2015Co-Authors: Fiammetta Vanoli, Paola Rinchetti, Francesca Porro, Valeria Parente, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans.
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iPSC-Derived Neural Stem Cells Act via Kinase Inhibition to Exert Neuroprotective Effects in Spinal Muscular Atrophy with Respiratory Distress Type 1
Stem cell reports, 2014Co-Authors: Chiara Simone, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Giulietta Riboldi, Federica Rizzo, Sabrina Salani, Margherita Ruggieri, Monica Bucchia, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders.
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The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: a systematic review.
Journal of the Neurological Sciences, 2014Co-Authors: Francesca Porro, Monica Nizzardo, Paola Rinchetti, Francesca Magri, Giulietta Riboldi, Chiara Simone, Chiara Zanetta, Irene Faravelli, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as distal spinal-muscular atrophy 1 (DSMA10), is an autosomal recessive type of spinal muscular atrophy that is related to mutations in the IGHMBP2 gene, which encodes for the immunoglobulin μ-binding protein. SMARD1 patients usually present low birth weight, diaphragmatic palsy and distal muscular atrophy. Clinical features are still the most important factor that leads to the diagnosis of SMARD1, due to the fact that IGHMBP2 gene mutations are characterized by significant phenotypic heterogeneity. In the present review, we will systematically discuss the genetic, clinical and neuropathological features of SMARD1 in order to provide a complete overview of SMARD1 variable clinical presentations and of the most important diagnostic tools which can be used to identify and properly manage affected individuals. This background is crucial also in the perspective of the development of novel therapeutic strategies for this still orphan disorder.
Christoph Hübner - One of the best experts on this subject based on the ideXlab platform.
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The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory Distress Type 1 (SMARD1)
Pediatrics, 2011Co-Authors: M. Eckart, Raymonda Varon, Christoph Hübner, Markus Schuelke, U-peter. Guenther, Jan Idkowiak, B. Grolle, P Boffi, L. Van Maldergem, K. Von AuAbstract:Only scarce information is available on the long-term outcome and the natural course of children with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene. To describe the natural disease course, to systematically quantify the residual capacities of children with SMARD1 who survive on permanent mechanical respiration, and to identify markers predicting the disease outcome at the time of manifestation. We conducted a longitudinal study of 11 infantile SMARD1 patients over a mean observational period of 7.8 (SD 3.2) years. Disease-specific features were continuously assessed by using a semiquantitative scoring system. Additionally, we analyzed the residual enzymatic activity of 6 IGHMBP2 mutants in our patients. After an initial rapid decline of the clinical score until the age of 2 years, residual capabilities reached a plateau or even improved. The overall clinical outcome was markedly heterogeneous, but clinical scores at the age of 3 months showed a positive linear correlation with the clinical outcome at 1 year and at 4 years of age. If expressed in an in vitro recombinant system, mutations of patients with more favorable outcomes retained residual enzymatic activity. Despite their severe disabilities and symptoms, most SMARD1 patients are well integrated into their home environment and two thirds of them are able to attend kindergarten or school. This information will help to counsel parents at the time of disease manifestation.
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The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory Distress Type 1 (SMARD1)
Pediatrics, 2011Co-Authors: M. Eckart, Raymonda Varon, Christoph Hübner, Markus Schuelke, U-peter. Guenther, Jan Idkowiak, B. Grolle, P Boffi, L. Van Maldergem, K. Von AuAbstract:Background: Only scarce information is available on the long-term outcome and the natural course of children with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene. Objective: To describe the natural disease course, to systematically quantify the residual capacities of children with SMARD1 who survive on permanent mechanical respiration, and to identify markers predicting the disease outcome at the time of manifestation. Methods: We conducted a longitudinal study of 11 infantile SMARD1 patients over a mean observational period of 7.8 (SD 3.2) years. Disease-specific features were continuously assessed by using a semiquantitative scoring system. Additionally, we analyzed the residual enzymatic activity of 6 IGHMBP2 mutants in our patients. Results: After an initial rapid decline of the clinical score until the age of 2 years, residual capabilities reached a plateau or even improved. The overall clinical outcome was markedly heterogeneous, but clinical scores at the age of 3 months showed a positive linear correlation with the clinical outcome at 1 year and at 4 years of age. If expressed in an in vitro recombinant system, mutations of patients with more favorable outcomes retained residual enzymatic activity. Conclusions: Despite their severe disabilities and symptoms, most SMARD1 patients are well integrated into their home environment and two thirds of them are able to attend kindergarten or school. This information will help to counsel parents at the time of disease manifestation. * Abbreviations: DSMA — : distal spinal muscular atrophy DSMA1 — : distal spinal muscular atrophy type 1 IGHMBP2 — : immunoglobulin μ-binding protein 2 OMIM — : Online Mendelian Inheritance of Man SMA — : spinal muscular atrophy SMARD1 — : spinal muscular atrophy with respiratory distress type 1
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Distress Type 1 (SMARD1) The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory
2011Co-Authors: P Boffi, Raymonda Varon, Christoph Hübner, Ulf-peter Guenther, Markus Schuelke, M. Eckart, Jan Idkowiak, L. Van Maldergem, B. GrolleAbstract:abstract BACKGROUND: Only scarce information is available on the long-termoutcome and the natural course of children with infantile spinalmuscular atrophy with respiratory distress type 1 (SMARD1) due tomutations in the IGHMBP2 gene.OBJECTIVE: To describe the natural disease course, to systematicallyquantify the residual capacities of children with SMARD1 who surviveonpermanentmechanicalrespiration,andtoidentifymarkerspredict-ing the disease outcome at the time of manifestation.METHODS: We conducted a longitudinal study of 11 infantile SMARD1patients over a mean observational period of 7.8 (SD 3.2) years.Disease-specific features were continuously assessed by using asemiquantitative scoring system. Additionally, we analyzed the residualenzymatic activity of 6 IGHMBP2 mutants in our patients.RESULTS:Afteraninitialrapiddeclineoftheclinicalscoreuntiltheageof 2 years, residual capabilities reached a plateau or even improved.The overall clinical outcome was markedly heterogeneous, but clinicalscoresattheageof3monthsshowedapositivelinearcorrelationwiththe clinical outcome at 1 year and at 4 years of age. If expressed in anin vitro recombinant system, mutations of patients with more favor-able outcomes retained residual enzymatic activity.CONCLUSIONS: Despite their severe disabilities and symptoms, mostSMARD1 patients are well integrated into their home environment andtwo thirds of them are able to attend kindergarten or school. This in-formation will help to counsel parents at the time of disease manifes-tation. Pediatrics 2012;129:1–9
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Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease
Journal of Molecular Medicine, 2009Co-Authors: Ulf-peter Guenther, Raymonda Varon, Christoph Hübner, Lusy Handoko, Sibylle Jablonka, Ulrich Stephani, Chang-yong Tsao, Jerry R. Mendell, Susanne Lützkendorf, Gunnar DittmarAbstract:Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin μ-binding protein 2 ( IGHMBP2 ) gene. Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy. Contrary to this “classic” infantile disease, we have previously described a DSMA1 patient with juvenile disease onset. In this paper, we present (1) a second juvenile case and (2) the first study of DSMA1 on protein level in patients with infantile ( n = 3) as well as juvenile ( n = 2) disease onset observing elevated residual steady-state IGHMBP2 protein levels in the patients with late onset DSMA1 as compared to those with classic DSMA1. Mutation screening in IGHMBP2 revealed two patients compound heterozygous for a novel missense mutation (c.1478C→T; p.T493I) and another previously described mutation. In lymphoblastoid cells of both patients, steady-state IGHMBP2 protein levels were reduced. In comparison to wild-type IGHMBP2, the p.T493I variant protein had an increased tendency to aggregate and spontaneously degrade in vitro. We verified a change in the physicochemical properties of the p.T493I variant which may explain the pathogenicity of this mutation. Our data further suggest that the age of onset of DSMA1 is variable, and we discuss the effect of residual IGHMBP2 protein levels on the clinical course and the severity of the disease.
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Spinal muscular atrophy with respiratory distress type 1 (SMARD1).
Journal of Child Neurology, 2007Co-Authors: Angela M. Kaindl, Raymonda Varon, Ulf-peter Guenther, Klaus Zerres, Sabine Rudnik-schoneborn, Markus Schuelke, Christoph HübnerAbstract:Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin µ-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.
Markus Schuelke - One of the best experts on this subject based on the ideXlab platform.
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The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory Distress Type 1 (SMARD1)
Pediatrics, 2011Co-Authors: M. Eckart, Raymonda Varon, Christoph Hübner, Markus Schuelke, U-peter. Guenther, Jan Idkowiak, B. Grolle, P Boffi, L. Van Maldergem, K. Von AuAbstract:Only scarce information is available on the long-term outcome and the natural course of children with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene. To describe the natural disease course, to systematically quantify the residual capacities of children with SMARD1 who survive on permanent mechanical respiration, and to identify markers predicting the disease outcome at the time of manifestation. We conducted a longitudinal study of 11 infantile SMARD1 patients over a mean observational period of 7.8 (SD 3.2) years. Disease-specific features were continuously assessed by using a semiquantitative scoring system. Additionally, we analyzed the residual enzymatic activity of 6 IGHMBP2 mutants in our patients. After an initial rapid decline of the clinical score until the age of 2 years, residual capabilities reached a plateau or even improved. The overall clinical outcome was markedly heterogeneous, but clinical scores at the age of 3 months showed a positive linear correlation with the clinical outcome at 1 year and at 4 years of age. If expressed in an in vitro recombinant system, mutations of patients with more favorable outcomes retained residual enzymatic activity. Despite their severe disabilities and symptoms, most SMARD1 patients are well integrated into their home environment and two thirds of them are able to attend kindergarten or school. This information will help to counsel parents at the time of disease manifestation.
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The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory Distress Type 1 (SMARD1)
Pediatrics, 2011Co-Authors: M. Eckart, Raymonda Varon, Christoph Hübner, Markus Schuelke, U-peter. Guenther, Jan Idkowiak, B. Grolle, P Boffi, L. Van Maldergem, K. Von AuAbstract:Background: Only scarce information is available on the long-term outcome and the natural course of children with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene. Objective: To describe the natural disease course, to systematically quantify the residual capacities of children with SMARD1 who survive on permanent mechanical respiration, and to identify markers predicting the disease outcome at the time of manifestation. Methods: We conducted a longitudinal study of 11 infantile SMARD1 patients over a mean observational period of 7.8 (SD 3.2) years. Disease-specific features were continuously assessed by using a semiquantitative scoring system. Additionally, we analyzed the residual enzymatic activity of 6 IGHMBP2 mutants in our patients. Results: After an initial rapid decline of the clinical score until the age of 2 years, residual capabilities reached a plateau or even improved. The overall clinical outcome was markedly heterogeneous, but clinical scores at the age of 3 months showed a positive linear correlation with the clinical outcome at 1 year and at 4 years of age. If expressed in an in vitro recombinant system, mutations of patients with more favorable outcomes retained residual enzymatic activity. Conclusions: Despite their severe disabilities and symptoms, most SMARD1 patients are well integrated into their home environment and two thirds of them are able to attend kindergarten or school. This information will help to counsel parents at the time of disease manifestation. * Abbreviations: DSMA — : distal spinal muscular atrophy DSMA1 — : distal spinal muscular atrophy type 1 IGHMBP2 — : immunoglobulin μ-binding protein 2 OMIM — : Online Mendelian Inheritance of Man SMA — : spinal muscular atrophy SMARD1 — : spinal muscular atrophy with respiratory distress type 1
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Distress Type 1 (SMARD1) The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory
2011Co-Authors: P Boffi, Raymonda Varon, Christoph Hübner, Ulf-peter Guenther, Markus Schuelke, M. Eckart, Jan Idkowiak, L. Van Maldergem, B. GrolleAbstract:abstract BACKGROUND: Only scarce information is available on the long-termoutcome and the natural course of children with infantile spinalmuscular atrophy with respiratory distress type 1 (SMARD1) due tomutations in the IGHMBP2 gene.OBJECTIVE: To describe the natural disease course, to systematicallyquantify the residual capacities of children with SMARD1 who surviveonpermanentmechanicalrespiration,andtoidentifymarkerspredict-ing the disease outcome at the time of manifestation.METHODS: We conducted a longitudinal study of 11 infantile SMARD1patients over a mean observational period of 7.8 (SD 3.2) years.Disease-specific features were continuously assessed by using asemiquantitative scoring system. Additionally, we analyzed the residualenzymatic activity of 6 IGHMBP2 mutants in our patients.RESULTS:Afteraninitialrapiddeclineoftheclinicalscoreuntiltheageof 2 years, residual capabilities reached a plateau or even improved.The overall clinical outcome was markedly heterogeneous, but clinicalscoresattheageof3monthsshowedapositivelinearcorrelationwiththe clinical outcome at 1 year and at 4 years of age. If expressed in anin vitro recombinant system, mutations of patients with more favor-able outcomes retained residual enzymatic activity.CONCLUSIONS: Despite their severe disabilities and symptoms, mostSMARD1 patients are well integrated into their home environment andtwo thirds of them are able to attend kindergarten or school. This in-formation will help to counsel parents at the time of disease manifes-tation. Pediatrics 2012;129:1–9
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Spinal muscular atrophy with respiratory distress type 1 (SMARD1).
Journal of Child Neurology, 2007Co-Authors: Angela M. Kaindl, Raymonda Varon, Ulf-peter Guenther, Klaus Zerres, Sabine Rudnik-schoneborn, Markus Schuelke, Christoph HübnerAbstract:Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin µ-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.
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Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis.
Human mutation, 2007Co-Authors: Ulf-peter Guenther, Raymonda Varon, Christoph Hübner, Maria Schlicke, Véronique Dutrannoy, Alexander E Volk, Katja Von Au, Markus SchuelkeAbstract:Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient.
Nereo Bresolin - One of the best experts on this subject based on the ideXlab platform.
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current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 smard1
Cellular and Molecular Life Sciences, 2020Co-Authors: Martina G L Perego, Noemi Galli, Alessandra Govoni, Michela Taiana, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Stefania CortiAbstract:Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.
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Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights.
Journal of cellular and molecular medicine, 2019Co-Authors: Matteo Saladini, Alessandra Govoni, Michela Taiana, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.
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Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model
Science advances, 2015Co-Authors: Monica Nizzardo, Paola Rinchetti, Chiara Simone, Federica Rizzo, Sabrina Salani, Sara Dametti, Roberto Del Bo, Kevin D. Foust, Brian K. Kaspar, Nereo BresolinAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)–mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-type IGHMBP2 to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell–derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials.
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Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model
2015Co-Authors: Monica Nizzardo, Paola Rinchetti, Federica Rizzo, Sabrina Salani, Sara Dametti, Roberto Del Bo, C. Simone, K. Foust, B. Kaspar, Nereo BresolinAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children that is caused by mutations in the IGHMBP2 gene (11q13) and lacks a cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy rescued the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. In this study, we report rescue of the disease phenotype in a SMARD1 mouse model following therapeutic delivery of an AAV9 construct encoding the wild-type IGHMBP2 via systemic injection to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and lifespan (450% increase), ameliorating pathological features in the CNS, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1 induced pluripotent stem cell-derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials
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iPSC-Derived Neural Stem Cells Act via Kinase Inhibition to Exert Neuroprotective Effects in Spinal Muscular Atrophy with Respiratory Distress Type 1
Stem cell reports, 2014Co-Authors: Chiara Simone, Monica Nizzardo, Giacomo P Comi, Nereo Bresolin, Giulietta Riboldi, Federica Rizzo, Sabrina Salani, Margherita Ruggieri, Monica Bucchia, Stefania CortiAbstract:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders.
