The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Francesco Zorzato - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyridine receptor (DHPR, CACNA1S) Congenital Myopathy
Acta Neuropathologica, 2017Co-Authors: Vanessa Schartner, Pinki Munot, Ivana Dabaj, Irina T. Zaharieva, Susan Treves, Norma B Romero, Sandra Donkervoort, Edoardo Malfatti, Tyler Mark Pierson, Francesco ZorzatoAbstract:Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of Congenital Myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
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Dihydropyridine receptor (DHPR, CACNA1S) Congenital Myopathy
Acta Neuropathologica, 2017Co-Authors: Vanessa Schartner, Pinki Munot, Ivana Dabaj, Irina T. Zaharieva, Susan Treves, Norma B Romero, Sandra Donkervoort, Edoardo Malfatti, Tyler Mark Pierson, Francesco ZorzatoAbstract:Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of Congenital Myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
Jorge A Bevilacqua - One of the best experts on this subject based on the ideXlab platform.
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p 9 9 a novel de novo mutation in acta1 causes a Congenital Myopathy with misleading type 1 fiber predominance and a peculiar mri
Neuromuscular Disorders, 2013Co-Authors: Claudia Castiglioni, Denise Cassandrini, Fabiana Fattori, Emanuele Bellacchio, Karin Alvarez, Anthony V Damico, Roger Gejman, Jorge Diaz, F M Santorelli, Jorge A BevilacquaAbstract:Nemaline Myopathy is a genetically heterogeneous disease showing wide clinical variability. Disease severity and prognosis range from neonatal death to almost normal motor function. We report on a 19-year-old boy with reportedly absence of fetal movements. He was severely hypotonic at birth with dolichocephaly, weak facial movements, bilateral clubfoot and feeding difficulties, requiring nasogastric tube feeding; gastrostomy was applied at age 3 months and removed at 12. Motor milestones were delayed: walking at 24 months, with marked foot drop. He has always been unable to eat solid foods because of impaired chewing. Since the age of 8 he is on nocturnal BiPAP. A first muscle biopsy of the quadriceps at age 8 months, and a second biopsy of vastus lateralis performed at age 10 years, both showed variability in fiber diameter, marked type 1 fiber predominance (90%), with neither evidence of endomysial fibrosis nor nemaline bodies. A third biopsy of the right deltoid muscle at age 19 showed marked fibrosis and dystrophic features with proliferation of nemaline bodies. Current neurological examination showed a young intelligent man with nasal voice, generalized weakness, ptosis, and no limitation of ocular movements. The MRI showed marked involvement of glutei muscles, together with involvement of sartorius, tibialis anterior and peroneus longus. Sequencing of ACTA1 in blood DNA detected a novel heterozygous de novo variant. The new mutation affects a highly preserved Threonine. No mutations were detected in SEPN1 and TPM3. We report on a long follow-up in a patient with a Congenital Myopathy related to a de novo mutation in ACTA1. Of the 3 muscle biopsies performed, the first 2 were not contributory for diagnosis and the clinical presentation did not offer additional clinical clues. The last muscle biopsy performed in adulthood revealed nemaline rods prompting specific molecular investigations and ultimately allowing a genetic diagnosis.
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recessive ryr1 mutations cause unusual Congenital Myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization
Neuropathology and Applied Neurobiology, 2011Co-Authors: Jorge A Bevilacqua, Ana Ferreiro, Nicole Monnier, Marcus Bitoun, B Eymard, S Monges, Fabiana Lubieniecki, Ana Lia Taratuto, Annie Laquerriere, Kristin ClaeysAbstract:J. A. Bevilacqua, N. Monnier, M. Bitoun, B. Eymard, A. Ferreiro, S. Monges, F. Lubieniecki, A. L. Taratuto, A. Laquerriere, K. G. Claeys, I. Marty, M. Fardeau, P. Guicheney, J. Lunardi and N. B. Romero (2011) Neuropathology and Applied Neurobiology37, 271–284 Recessive RYR1 mutations cause unusual Congenital Myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization Aims: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of Congenital Myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). Methods: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. Results: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. Conclusion: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A Congenital Myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related Congenital Myopathy.
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Recessive RYR1 mutations cause unusual Congenital Myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization.
Neuropathology and Applied Neurobiology, 2011Co-Authors: Jorge A Bevilacqua, Ana Ferreiro, Nicole Monnier, Marcus Bitoun, B Eymard, S Monges, Fabiana Lubieniecki, Ana Lia Taratuto, Annie Laquerriere, Kristin ClaeysAbstract:AIMS: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of Congenital Myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). METHODS: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. RESULTS: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. CONCLUSION: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A Congenital Myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related Congenital Myopathy.
Nicole Monnier - One of the best experts on this subject based on the ideXlab platform.
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Congenital Myopathy with focal loss of cross-striations revisited
Neuromuscular disorders : NMD, 2012Co-Authors: Nicol C. Voermans, Heinz Jungbluth, Nicole Monnier, Joel Lunardi, Eleonora Aronica, Michael Swash, M. De VisserAbstract:In 1977 Wijngaarden et al. reported a Dutch family with a Congenital Myopathy characterized by external ophthalmoplegia and a remarkable histological feature, focal loss of cross-striations. A small number of other families with similar clinical and pathological features led to the consideration of this Congenital Myopathy as a distinct entity. Here we present more than 30years of follow-up from the Dutch family and report recently identified compound heterozygous mutations in the skeletal muscle ryanodine receptor (RYR1) gene, c.10627-2A>G and p.Arg3539His (c.10616G>A). Focal loss of cross-striations on muscle biopsy is another histopathological feature that should raise the possibility of RYR1 involvement.
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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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recessive ryr1 mutations cause unusual Congenital Myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization
Neuropathology and Applied Neurobiology, 2011Co-Authors: Jorge A Bevilacqua, Ana Ferreiro, Nicole Monnier, Marcus Bitoun, B Eymard, S Monges, Fabiana Lubieniecki, Ana Lia Taratuto, Annie Laquerriere, Kristin ClaeysAbstract:J. A. Bevilacqua, N. Monnier, M. Bitoun, B. Eymard, A. Ferreiro, S. Monges, F. Lubieniecki, A. L. Taratuto, A. Laquerriere, K. G. Claeys, I. Marty, M. Fardeau, P. Guicheney, J. Lunardi and N. B. Romero (2011) Neuropathology and Applied Neurobiology37, 271–284 Recessive RYR1 mutations cause unusual Congenital Myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization Aims: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of Congenital Myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). Methods: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. Results: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. Conclusion: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A Congenital Myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related Congenital Myopathy.
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Recessive RYR1 mutations cause unusual Congenital Myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization.
Neuropathology and Applied Neurobiology, 2011Co-Authors: Jorge A Bevilacqua, Ana Ferreiro, Nicole Monnier, Marcus Bitoun, B Eymard, S Monges, Fabiana Lubieniecki, Ana Lia Taratuto, Annie Laquerriere, Kristin ClaeysAbstract:AIMS: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of Congenital Myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). METHODS: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. RESULTS: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. CONCLUSION: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A Congenital Myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related Congenital Myopathy.
Pinki Munot - One of the best experts on this subject based on the ideXlab platform.
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stac3 variants cause a Congenital Myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility
Human Mutation, 2018Co-Authors: I Zaharieva, Pinki Munot, Anna Sarkozy, A Manzur, Gina L Ogrady, John Rendu, E Malfatti, Helge Amthor, Laurent ServaisAbstract:SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive Congenital Myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with Congenital Myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.
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Dihydropyridine receptor (DHPR, CACNA1S) Congenital Myopathy
Acta Neuropathologica, 2017Co-Authors: Vanessa Schartner, Pinki Munot, Ivana Dabaj, Irina T. Zaharieva, Susan Treves, Norma B Romero, Sandra Donkervoort, Edoardo Malfatti, Tyler Mark Pierson, Francesco ZorzatoAbstract:Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of Congenital Myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
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Dihydropyridine receptor (DHPR, CACNA1S) Congenital Myopathy
Acta Neuropathologica, 2017Co-Authors: Vanessa Schartner, Pinki Munot, Ivana Dabaj, Irina T. Zaharieva, Susan Treves, Norma B Romero, Sandra Donkervoort, Edoardo Malfatti, Tyler Mark Pierson, Francesco ZorzatoAbstract:Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of Congenital Myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
Edoardo Malfatti - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyridine receptor (DHPR, CACNA1S) Congenital Myopathy
Acta Neuropathologica, 2017Co-Authors: Vanessa Schartner, Pinki Munot, Ivana Dabaj, Irina T. Zaharieva, Susan Treves, Norma B Romero, Sandra Donkervoort, Edoardo Malfatti, Tyler Mark Pierson, Francesco ZorzatoAbstract:Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of Congenital Myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
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Dihydropyridine receptor (DHPR, CACNA1S) Congenital Myopathy
Acta Neuropathologica, 2017Co-Authors: Vanessa Schartner, Pinki Munot, Ivana Dabaj, Irina T. Zaharieva, Susan Treves, Norma B Romero, Sandra Donkervoort, Edoardo Malfatti, Tyler Mark Pierson, Francesco ZorzatoAbstract:Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of Congenital Myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
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bilateral foot drop as predominant symptom in nebulin neb gene related core rod Congenital Myopathy
European Journal of Medical Genetics, 2015Co-Authors: Edoardo Malfatti, Vilma-lotta Lehtokari, Fabiana Lubieniecki, S Monges, Ursula Schaeffer, Osorio Abath Neto, K Kiiski, A L Taratuto, Carina Wallgrenpettersson, Jocelyn LaporteAbstract:Abstract Background Congenital myopathies (CM) are a group of rare inherited muscle disorders characterized by particular histopathological alterations on muscle biopsy. Core-rod Myopathy is a CM presenting with cores and rods as distinctive muscle morphological features. Methods/results: We describe 3 young patients presenting Congenital core-rod Myopathy with bilateral foot-drop associated with autosomal recessive nebulin gene (NEB) mutations detected by exome sequencing. Conclusions This report illustrates that core-rod Congenital Myopathy with foot-drop is frequently associated with NEB gene mutations and should be considered in the differential diagnosis of early onset distal myopathies.
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o 22 autosomal dominant core Congenital Myopathy caused by a mutation in the myh7 gene
Neuromuscular Disorders, 2013Co-Authors: N Romero, Edoardo Malfatti, T Xie, U Schaeffer, Michel Fardeau, J F LaporteAbstract:Autosomal dominant (AD) Central core disease (CCD) named currently Congenital Myopathy with core is an inherited disorder characterised by the presence of cores which are well-limited rounded areas devoid of any oxidative staining. The cores extend almost along the full length of the fibres; these areas correspond to sarcomeric disorganisation, Z line streaming and absence of mitochondria. Genetic studies of AD-CCD families demonstrated the presence of heterozygous mutations in the RYR1 gene in the large majority of families. However, this gene was excluded in some families, suggesting a genetic heterogeneity of AD-Core myopathies (Romero et al., 2005). To enlarge the genetic spectrum of autosomal dominant Congenital myopathies with cores demonstrating mutations in a second gene. AD-CCD family with three affected members: the mother and two of three siblings. The symptoms began during the early childhood with delayed motor development. Later they develop proximal weakness, hypertrophy of calves, scapular winging and significant weakness (amyotrophic) of quadriceps and tibialis anterior. No cardiac or ocular involvement was noted. The muscle biopsies sections showed a particular pattern: relatively large and eccentric cores (placed near the subsarcolemmal regions) associated with type 1 predominance and fibre type disproportion in a patient. The large majority of the cores have abrupt borders. Electron microscopy confirmed the presence of multiple large disorganised sarcomeric areas as characteristic unstructured and structured cores. Moreover, some fibres contain focal disorganised areas. Exome sequencing analysis identified a heterozygous missense mutation L1723P in MYH7 segregating with the disease and affecting a conserved residue in the tail domain. With this study we describe MYH7 as a second causative gene for AD-CCD in addition to RYR1 . Our study enlarges the genetic spectrum of AD-CCD myopathies.