The Experts below are selected from a list of 25770 Experts worldwide ranked by ideXlab platform
Anders Oldfors - One of the best experts on this subject based on the ideXlab platform.
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new morphologic and genetic findings in cap disease associated with β tropomyosin TPM2 mutations
Neurology, 2008Co-Authors: Monica Ohlsson, Susana Quijanoroy, Anders Oldfors, Niklas Darin, G Brochier, E Lacene, D Avilasmirnow, M Fardeau, Homa TajsharghiAbstract:OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndro ...
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congenital myopathy with nemaline rods and cap structures caused by a mutation in the β tropomyosin gene TPM2
JAMA Neurology, 2007Co-Authors: Homa Tajsharghi, Monica Ohlsson, Christopher Lindberg, Anders OldforsAbstract:Objective To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. Patients A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. Results Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the β-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. Conclusions The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.
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congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta tropomyosin gene TPM2
JAMA Neurology, 2007Co-Authors: Homa Tajsharghi, Monica Ohlsson, Christopher Lindberg, Anders OldforsAbstract:Objective To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. Patients A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. Results Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the β-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. Conclusions The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.
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distal arthrogryposis and muscle weakness associated with a beta tropomyosin mutation
Neurology, 2007Co-Authors: Homa Tajsharghi, Eva Kimber, Daniel Holmgren, M Tulinius, Anders OldforsAbstract:Tropomyosin (TM), a sarcomeric thin-filament protein, plays an essential part in muscle contraction by regulating actin-myosin interaction. We describe two patients, a woman and her daughter, with muscle weakness and distal arthrogryposis (DA) type 2B, caused by a heterozygous missense mutation, R133W, in TPM2, the gene encoding beta-TM. Our results demonstrate the involvement of muscle dysfunction in the pathogenesis of DA and the fact that DA2B may be caused by mutations in TPM2.
Homa Tajsharghi - One of the best experts on this subject based on the ideXlab platform.
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new morphologic and genetic findings in cap disease associated with β tropomyosin TPM2 mutations
Neurology, 2008Co-Authors: Monica Ohlsson, Susana Quijanoroy, Anders Oldfors, Niklas Darin, G Brochier, E Lacene, D Avilasmirnow, M Fardeau, Homa TajsharghiAbstract:OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndro ...
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congenital myopathy with nemaline rods and cap structures caused by a mutation in the β tropomyosin gene TPM2
JAMA Neurology, 2007Co-Authors: Homa Tajsharghi, Monica Ohlsson, Christopher Lindberg, Anders OldforsAbstract:Objective To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. Patients A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. Results Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the β-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. Conclusions The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.
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congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta tropomyosin gene TPM2
JAMA Neurology, 2007Co-Authors: Homa Tajsharghi, Monica Ohlsson, Christopher Lindberg, Anders OldforsAbstract:Objective To describe the clinical, morphologic, and genetic findings in a family in which one woman had nemaline myopathy, whereas her daughter showed features of cap disease. Patients A 66-year-old woman and her 35-year-old daughter had congenital, slowly progressive muscle weakness. They had weakness in both proximal and distal muscles and facial diplegia with bilateral ptosis, a long narrow face, a high arched palate, and micrognathia. Results Muscle biopsy specimens in the mother at age 57 years had shown nemaline myopathy, whereas a biopsy specimen at age 32 years had demonstrated no rods. Muscle biopsy specimens in the daughter at age 26 years had shown features of cap disease and no apparent nemaline rods. A missense mutation, Glu41Lys, in the β-tropomyosin gene TPM2 was identified in both patients but was absent in their healthy relatives. Conclusions The results indicate that mutations in TPM2 may cause nemaline myopathy as well as cap disease with a dominant mode of inheritance. These disorders may thus be phenotypic variants of the same genetic defect.
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distal arthrogryposis and muscle weakness associated with a beta tropomyosin mutation
Neurology, 2007Co-Authors: Homa Tajsharghi, Eva Kimber, Daniel Holmgren, M Tulinius, Anders OldforsAbstract:Tropomyosin (TM), a sarcomeric thin-filament protein, plays an essential part in muscle contraction by regulating actin-myosin interaction. We describe two patients, a woman and her daughter, with muscle weakness and distal arthrogryposis (DA) type 2B, caused by a heterozygous missense mutation, R133W, in TPM2, the gene encoding beta-TM. Our results demonstrate the involvement of muscle dysfunction in the pathogenesis of DA and the fact that DA2B may be caused by mutations in TPM2.
Susana Quijanoroy - One of the best experts on this subject based on the ideXlab platform.
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congenital myopathy causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms
Human Molecular Genetics, 2012Co-Authors: Julien Ochala, David S. Gokhin, I Penissonbesnier, Susana Quijanoroy, Nicole Monnier, Joel Lunardi, N Romero, Velia M FowlerAbstract:In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.
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whole body muscle mri in a series of patients with congenital myopathy related to TPM2 gene mutations
Neuromuscular Disorders, 2012Co-Authors: Mohamed Jarraya, Susana Quijanoroy, Nicole Monnier, N Romero, Anthony Behin, Daniela Avilasmirnov, Valerie Allamand, P Richard, A BaroisAbstract:Abstract Beta-tropomyosin 2 ( TPM2 ) gene mutations are a rare cause of congenital myopathy with variable clinical and histological features. We describe muscle involvement using Whole-Body muscle Magnetic Resonance Imaging (WBMRI) in 8 individuals with genetically proven TPM2 mutations and different clinical and histological features (nemaline myopathy, ‘cap disease', Bethlem-like phenotype, arthrogryposis). Most patients shared a recognizable MRI pattern with the involvement of masticatory and distal lower leg muscles. The lower leg showed constant soleus muscle involvement, and often also involvement of peroneus, tibialis anterior, and toe flexor muscles. Pelvic and shoulder girdles, and upper limbs muscles were quite spared. Two adult subjects (a patient and a paucisymptomatic parent) had a more diffuse involvement with striking fat infiltration of the rectus femoris muscle. Two children showed variant findings: one presented with masseter involvement associated with severe axial fat infiltration, the second had masticatory and distal leg muscle involvement (soleus and gastrocnemius muscles). Our study suggests that, independently of the clinical and histological presentation, most patients with TPM2 mutations show a predominant involvement of masticatory and distal leg muscles with the other regions relatively spared. More spread involvement may be observed. This cephalic-distal MRI pattern is not frequent in other known myopathies.
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whole body muscle mri protocol pattern recognition in early onset nm disorders
Neuromuscular Disorders, 2012Co-Authors: Susana Quijanoroy, Daniela Avilasmirnow, Robert Y CarlierAbstract:Abstract A paediatric and adult whole-body MRI (WB-MRI) protocol using a 1.5-T MRI system was used to examine 117 individuals (106 patients, 11 asymptomatic relatives). Genetic diagnosis was obtained in 38 subjects ( RYR1 , LMNA , COL6 , DNM2 , GAA , TPM2 , SGCA , MYH7 , NEB , SMN , FKBP14 ). T1-TSE WB-MRI sequences were abnormal in 67% of patients and 27% of asymptomatic relatives. Multiple striped signal abnormalities (‘tiger-like’) were very specific for COLVI-related myopathy. Distinct involvement of muscles in the head, neck, trunk, girdles and limbs was observed in patients with RYR1 , SEPN1 , GAA , LMNA or TPM2 mutations. Abnormalities and pattern recognition were more frequent in patients studied due to rigid spine syndrome (80% abnormal, recognisable in 75% of cases), hyperlaxity syndrome (75%; 50%) or with confirmed myopathy but absence of these markers (71%; 40%). Pattern was consistent with the molecular diagnosis in 97%. Mild clinical involvement was revealed by muscle testing in three parents with abnormal WB-MRI. The Garches WB-MRI protocol is suitable for a large spectrum of adults and children with early-onset neuromuscular disorders and can be used as an effective screening test in relatives. Recognition of characteristic patterns of abnormalities is improved by whole-body scanning compared with sequential MRI and, therefore, diagnostic impact is greater.
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new morphologic and genetic findings in cap disease associated with β tropomyosin TPM2 mutations
Neurology, 2008Co-Authors: Monica Ohlsson, Susana Quijanoroy, Anders Oldfors, Niklas Darin, G Brochier, E Lacene, D Avilasmirnow, M Fardeau, Homa TajsharghiAbstract:OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndro ...
Josine M De Winter - One of the best experts on this subject based on the ideXlab platform.
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force sarcomere length relations in patients with thin filament myopathy caused by mutations in neb acta1 TPM2 tpm3 kbtbd13 klhl40 and klhl41
Biophysical Journal, 2015Co-Authors: Barbara Joureau, N Romero, Josine M De Winter, Christopher T Pappas, Edoardo Malfatti, Alan H Beggs, Nigel F Clarke, Carol C Gregorio, Henk GranzierAbstract:Background: Mutations in NEB, ACTA1, TPM2, TPM3, KBTBD13, KLHL40 and −41 lead to thin filament myopathies, such as nemaline myopathy, congenital fiber type disproportion and cap disease. A hallmark feature of these myopathies is muscle weakness. Here, we aimed to elucidate whether mutations in NEB, ACTA1, TPM2, TPM3, KBTBD13, KLHL40 and KLHL41 affect the maximal force generating capacity of muscle fibers. Subsequently, by determining the sarcomere length-dependence of force, we investigated whether changes in thin filament length contributed to muscle weakness.Methods: Biopsies from NM, CFTD, and CAP patients (n=39) with mutations in NEB, ACTA1, TPM2, TPM3, KBTBD13, KLHL40 or KLHL41 were compared to biopsies from healthy controls (n=9). Using permeabilized muscle fibers, maximal active tension was determined at incremental sarcomere lengths (range 2.0-3.5 µm) to obtain the force-sarcomere length relationship.Results: The maximal active tension (Fmax (in mN/mm2, mean±SEM)) was significantly lower in biopsies from NEB (46±5), ACTA1 (48±4), TPM2 (71±8), TPM3 (85±10), KBTBD13 (78±3), KLHL40 (2.8±0.2) and KLHL41 (63±4) patients compared to biopsies of controls (129±7).No shift in the force-sarcomere length relationship was observed in TPM3, TPM2, KBTBD 13, KLHL 40 and KLHL41 patients. In contrast, several patients with ACTA1 and NEB mutations showed a leftward shift of the force-sarcomere length relationship indicating shorter thin filaments. Furthermore, the slope of the descending limb of the force-sarcomere length relationship in these patients is less steep than the slope of the CTRL curve, suggesting heterogeneity of thin filaments.Conclusion: Our data suggest that mutations in NEB and ACTA1 result in changes in thin filament length. Insights in the mechanisms underlying weakness in patients with thin filament mutations are necessary to improve specific treatment strategies.
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force sarcomere length relations in patients with thin filament myopathy caused by mutations in neb acta1 TPM2 and tpm3
Biophysical Journal, 2014Co-Authors: Josine M De Winter, Barbara Joureau, Coen A C OttenheijmAbstract:Mutations in the nebulin gene (NEB), skeletal muscle alpha-actin1 gene (ACTA1), beta-tropomyosin 2 gene (TPM2) and alpha-tropomyosin 3 gene (TPM3) lead to thin filament myopathies, such as nemaline myopathy (NM), congenital fiber type disproportion (CFTD) and cap disease (CAP). A hallmark feature of these myopathies is muscle weakness. Here, we aimed to elucidate the effect of NEB, ACTA1, TPM2 and TPM3 mutations on thin filament length by determining the sarcomere length-dependence of force.Quadriceps biopsies from NM, CFTD, and CAP patients (n=18) with mutations in the NEB, ACTA1, TPM2 or TPM3 were compared to biopsies from controls (n=3). Using permeabilized muscle fibers, maximal active tension was determined at incremental sarcomere lengths (range 2.0-3.5 μm) to obtain the force-sarcomere length relationship.The maximal active tension (Fmax (in mN/mm2, mean±SD)) was significantly lower in biopsies from severe NEB (18±5), mild NEB (76±5), severe ACTA1 (54±13) and severe TPM3 (95±14) patients compared to biopsies of controls (164±17), whereas no significant changes in Fmax were observed in biopsies from mild ACTA1 (139±27), mild TPM2 (1201±8) and mild TPM3 (156±13) patients. The classification of severity is based on the age of onset.No shift in the force-sarcomere length relationship was observed in mild ACTA1, TPM3 and TPM2 patients. Interestingly, in contrast to patients with ACTA1, TPM2 and TPM3 mutations, fiber preparations from both mildly and severly affected NEB patients showed a leftward shift of the force-sarcomere length relationship (a leftward shift of the force-sarcomere length relationship indicates shorter thin filaments).Our data suggest that mutations in NEB result in the most pronounced changes in thin filament length. Insights in the mechanisms underlying weakness in patients with thin filament mutations are necessary to improve specific treatment strategies.
Coen A C Ottenheijm - One of the best experts on this subject based on the ideXlab platform.
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force sarcomere length relations in patients with thin filament myopathy caused by mutations in neb acta1 TPM2 and tpm3
Biophysical Journal, 2014Co-Authors: Josine M De Winter, Barbara Joureau, Coen A C OttenheijmAbstract:Mutations in the nebulin gene (NEB), skeletal muscle alpha-actin1 gene (ACTA1), beta-tropomyosin 2 gene (TPM2) and alpha-tropomyosin 3 gene (TPM3) lead to thin filament myopathies, such as nemaline myopathy (NM), congenital fiber type disproportion (CFTD) and cap disease (CAP). A hallmark feature of these myopathies is muscle weakness. Here, we aimed to elucidate the effect of NEB, ACTA1, TPM2 and TPM3 mutations on thin filament length by determining the sarcomere length-dependence of force.Quadriceps biopsies from NM, CFTD, and CAP patients (n=18) with mutations in the NEB, ACTA1, TPM2 or TPM3 were compared to biopsies from controls (n=3). Using permeabilized muscle fibers, maximal active tension was determined at incremental sarcomere lengths (range 2.0-3.5 μm) to obtain the force-sarcomere length relationship.The maximal active tension (Fmax (in mN/mm2, mean±SD)) was significantly lower in biopsies from severe NEB (18±5), mild NEB (76±5), severe ACTA1 (54±13) and severe TPM3 (95±14) patients compared to biopsies of controls (164±17), whereas no significant changes in Fmax were observed in biopsies from mild ACTA1 (139±27), mild TPM2 (1201±8) and mild TPM3 (156±13) patients. The classification of severity is based on the age of onset.No shift in the force-sarcomere length relationship was observed in mild ACTA1, TPM3 and TPM2 patients. Interestingly, in contrast to patients with ACTA1, TPM2 and TPM3 mutations, fiber preparations from both mildly and severly affected NEB patients showed a leftward shift of the force-sarcomere length relationship (a leftward shift of the force-sarcomere length relationship indicates shorter thin filaments).Our data suggest that mutations in NEB result in the most pronounced changes in thin filament length. Insights in the mechanisms underlying weakness in patients with thin filament mutations are necessary to improve specific treatment strategies.
