The Experts below are selected from a list of 843 Experts worldwide ranked by ideXlab platform
J Philpot - One of the best experts on this subject based on the ideXlab platform.
-
demyelinating peripheral neuropathy in Merosin deficient congenital muscular dystrophy
Journal of Child Neurology, 1995Co-Authors: Zamir Shorer, Caroline Sewry, Francesco Muntoni, J Philpot, V DubowitzAbstract:It has recently been shown that Merosin, a laminin variant, is deficient in a proportion of patients with congenital muscular dystrophy. Merosin is a heterotrimer composed of the α2, β1, and γ1 subunits, and further studies have shown that it is the α2 subunit that is deficient in these patients. Because the α2 subunit is also expressed in S-Merosin, found in Schwann cells, we have investigated whether peripheral nerve function is also affected in these patients. Motor nerve conduction velocities and sensory distal latencies were examined in 25 cases of congenital muscular dystrophy and the results correlated with the Merosin expression in their muscle biopsies. All but two of the 10 Merosin-deficient cases had reduced motor nerve conduction, whereas all the Merosin-positive cases had normal results. Analysis of the biopsies of these two cases showed that they produced Merosin in reduced amounts, in contrast to all other Merosin-deficient patients that produced no or only traces of Merosin. Sensory nerve ...
-
clinical phenotype in congenital muscular dystrophy correlation with expression of Merosin in skeletal
Neuromuscular Disorders, 1995Co-Authors: J Philpot, Caroline Sewry, J M Pennock, V DubowitzAbstract:Abstract It has recently been shown that Merosin, an extracellular matrix protein linked to the dystrophin-associated glycoproteins, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). We have undertaken a detailed study of the clinical features and brain imaging in 24 cases of CMD in relation to the Merosin status. Immunocytochemistry showed that Merosin was present in 13 cases and markedly deficient in 11. In the Merosin-positive cases, the maximum motor achievement was independent walking in 11, walking with support in one and sitting unsupported in one (currently 18 months old). In contrast, none of the Merosin-deficient cases achieved independent ambulation. Two achieved walking with support, nine standing with support. In addition, nine of the 11 Merosin-deficient cases had a creatine kinase level greater than 2000 whereas only one Merosin-positive case had this degree of elevation. Magnetic resonance imaging of the brain was carried out on 15 of the children. All eight Merosin-positive cases had normal scans whereas all seven of the Merosin-deficient cases had significant changes in the white matter. This study has demonstrated that children with Merosin-deficient CMD have a more severe clinical phenotype and associated white matter changes on brain imaging.
-
localization of Merosin negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping
Human Molecular Genetics, 1994Co-Authors: Dominique Hillaire, Anne Leclerc, Sabine Faure, Haluk Topaloglu, Nuchanard Chiannllkulchai, Pascale Guicheney, Laurent Grinas, Patricia Legos, J Philpot, Teresinha EvangelistaAbstract:Congenital muscular dystrophies (CMD) are autosomalrecessive, heterogeneous disorders. The commonestforms are the Fukuyama CMD (FCMD), associated withmental retardation and structural brain anomalies, andclassical (occidental) CMD, with pure muscle expres-sion. FCMD has been localized to chromosome 9q31 -q33. Following the discovery of Merosin deficiency insome CMD cases, we have localized, by homozygositymapping and linkage analysis (Zmax = 5.6; 0 = 0.0 formarker AFM127xb2) in four merosln-negatlve familiesa CMD gene In a 16 cM region of chromosome 6q2 inthe region of the laminin M chain gene. In threeconsanguineous, Merosin-positive, CMD families therewas no linkage to either chromosome 6q2 or9q31 - q33.INTRODUCTIONCongenital muscular dystrophies (CMDs), are autosomalrecessive severe muscle diseases of early onset and the mostfrequent cause of severe neonatal hypotonia of muscular origin(1 -3). Clinical manifestations occur at birth or in the first monthsof life and consist of muscle hypotonia and weakness, markedlydelayed motor milestones, severe and early contractures, oftenassociated with joint deformities. Serum creatine kinase isvariably raised, up 10 times normal, but may be normal. Thehistological changes in muscle biopsies consist of markedvariation in muscle fibre size, a few necrotic and regeneratingfibres, marked increase in endomysial collagen tissue, variableadipous tissue and no specific ultrastructural features. Untilrecently the diagnosis of CMD has been based on the clinicalpicture and the morphological changes in the muscle biopsy.Within the group of diseases classified as CMDs, variousdistinct phenotypes have been defined. The two more commonforms are the classical CMD, without clinical involvement ofthe central nervous system, although imaging changes in the whitematter may be found on magnetic resonance imaging (MRI), andthe Fukuyama type (FCMD) prevalent in Japan, associated withsevere mental retardation and major structural brain abnormalities(4,5). The association in one patient from a consanguineousfamily of both FCMD and group A xeroderma pigmentosum,led to the localization of FCMD gene to chromosome 9q31 —q33 (6).The marked increase in connective tissue in muscle hassuggested that an abnormality of one of the components of theextracellular matrix could be involved in the pathogenesis of thisdisease (7). However, our initial studies (8,9) failed to detectspecific changes in extracellular matrix proteins. As it wasdemonstrated that a large oligomeric complex of sarcolemmalglycoproteins associated with dystrophin provides a link betweenthe subsarcolemmal cytoskeleton and laminin (10,11), a majorcomponent of the extracellular matrix, we have investigatedwhether one of the laminin subunits (12,13) could be involvedin CMD. Furthermore, a partial Merosin reduction was observedin some cases of FCMD (14). This showed a specific absenceof Merosin (laminin M chain) in thirteen patients out of twentyaffected by classical, non-Fukuyama, form of CMD (15). SimilarMerosin negative results were obtained by C.A.Sewry andV.Dubowitz in ten out of twenty two cases, and by K.P.Campbellin three patients (personal communications). As the laminin Mchain gene (LAMM) has been mapped to chromosome 6q22—q23(16) and the FCMD was localized in chromosome 9q31-q32(6), we focused our analysis in CMD consanguineous families(either with or without Merosin deficiency) on these twochromosomes. The high consanguinity led us to use homozygositymapping (17), with highly polymorphic markers consistingexclusively of (CA)
Reed, Umbertina Conti - One of the best experts on this subject based on the ideXlab platform.
-
Distrofia muscular congênita. Parte II: revisão da patogênese e perspectivas terapêuticas
Academia Brasileira de Neurologia - ABNEURO, 2009Co-Authors: Reed, Umbertina ContiAbstract:The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with Merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscle-eye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. São caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. O quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. Os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de Merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MEB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos
-
Complexo distrofina-glicoproteínas associadas na distrofia muscular congênita: análise imuno-histoquímica em 59 casos
Academia Brasileira de Neurologia - ABNEURO, 2005Co-Authors: Ferreira, Lucio Gobbo, Marie, Suely Kazue, Liu, Enna Cristina, Resende, Maria Bernadete Dutra, Carvalho, Mary Souza, Scaff Milberto, Reed, Umbertina ContiAbstract:The congenital muscular dystrophies (CMD) are heterogeneous muscular diseases with early and dystrophic pattern on muscle biopsy. Many different subtypes have been genetically identified and most phenotypes not yet identified belong to the Merosin-positive (MP) CMD subgroup. OBJECTIVE: To analyze the immunohistochemical expression of the main proteins of the dystrophin-glycoproteins associated complex in muscle biopsy of patients with different CMD phenotypes, for investigating a possible correlation with clinical and histopathological data. METHOD: Fifty-nine patients with CMD had clinical, histopathological and immunohistochemical data evaluated: 32 had MP-CMD, 23 CMD with Merosin deficiency (MD-CMD), one Ullrich phenotype and three Walker-Warburg disease. RESULTS: Dystrophin and dysferlin were normal in all; among the patients with MD-CMD, Merosin deficiency was partial in nine who showed the same clinical severity as those with total deficiency; the reduced expression of a-sarcoglycan (SG) and alpha-dystroglycan (DG) showed statistically significant correlation with severe MD-CMD phenotype. CONCLUSION: There is a greater relationship between Merosin and the former proteins; among MP-CMD patients, no remarkable immunohistochemical/phenotypical correlations were found, although the reduced expression of beta-DG had showed statistically significant correlation with severe phenotype and marked fibrosis on muscular biopsy.A distrofia muscular congênita (DMC) é doença muscular heterogênea, de início precoce e padrão histopatológico de distrofia. Diversos subtipos foram geneticamente identificados e os fenótipos ainda não identificados pertencem em geral ao subgrupo de DMC Merosina-positiva (MP). OBJETIVO: Analisar a expressão imuno-histoquímica das principais proteínas do complexo distrofina-glicoproteínas associadas na biópsia muscular de pacientes com diferentes fenótipos de DMC, a fim de investigar uma eventual correlação com o quadro clínico e histopatológico. MÉTODO: Cinqüenta e nove pacientes com DMC foram avaliados clinicamente e sua biópsia muscular, histopatologica e imuno-histoquimicamente: 32 eram MP, 23 Merosina-deficiente (MD), um mostrava fenótipo Ullrich e três síndrome de Walker-Warburg. RESULTADOS: Distrofina e disferlina foram normais em todos; nove pacientes MD apresentavam déficit parcial de Merosina, porém com a mesma gravidade clínica daqueles com deficiência total. CONCLUSÃO: A hipoexpressão de a-sarcoglicana (SG) and alfa-distroglycan (DG) se correlacionou estatisticamente com o grave fenótipo MD, assim indicando maior correlação entre a Merosina e as referidas proteínas; entre os pacientes MP, apesar da hipoexpressão de beta-DG ter se correlacionado significativamente com fenótipo e histopatologia mais grave, não houve correlação clínica/imuno-histoquímica valorizável
-
Dystrophin-glycoproteins associated in congenital muscular dystrophy: immunohistochemical analysis of 59 Brazilian cases
Academia Brasileira de Neurologia - ABNEURO, 2005Co-Authors: Ferreira, Lucio Gobbo, Marie, Suely Kazue, Liu, Enna Cristina, Resende, Maria Bernadete Dutra, Carvalho, Mary Souza, Reed, Umbertina ContiAbstract:The congenital muscular dystrophies (CMD) are heterogeneous muscular diseases with early and dystrophic pattern on muscle biopsy. Many different subtypes have been genetically identified and most phenotypes not yet identified belong to the Merosin-positive (MP) CMD subgroup. OBJECTIVE: To analyze the immunohistochemical expression of the main proteins of the dystrophin-glycoproteins associated complex in muscle biopsy of patients with different CMD phenotypes, for investigating a possible correlation with clinical and histopathological data. METHOD: Fifty-nine patients with CMD had clinical, histopathological and immunohistochemical data evaluated: 32 had MP-CMD, 23 CMD with Merosin deficiency (MD-CMD), one Ullrich phenotype and three Walker-Warburg disease. RESULTS: Dystrophin and dysferlin were normal in all; among the patients with MD-CMD, Merosin deficiency was partial in nine who showed the same clinical severity as those with total deficiency; the reduced expression of a-sarcoglycan (SG) and alpha-dystroglycan (DG) showed statistically significant correlation with severe MD-CMD phenotype. CONCLUSION: There is a greater relationship between Merosin and the former proteins; among MP-CMD patients, no remarkable immunohistochemical/phenotypical correlations were found, although the reduced expression of beta-DG had showed statistically significant correlation with severe phenotype and marked fibrosis on muscular biopsy
V Dubowitz - One of the best experts on this subject based on the ideXlab platform.
-
High resolution magnetic resonance imaging of the brain in the dy/dy mouse with Merosin-deficient congenital muscular dystrophy.
Neuromuscular disorders : NMD, 2000Co-Authors: D J Dubowitz, C A Sewry, J M Tyszka, R A Moats, M Scadeng, V DubowitzAbstract:Magnetic resonance imaging (MRI) abnormalities in the cerebral white matter are a consistent feature of Merosin-deficient human congenital muscular dystrophy, a disease caused by a primary defect in the expression of the laminin alpha2 chain of Merosin. To investigate the relationship between imaging changes and Merosin deficiency we undertook a MRI study in the dy/dy mouse, an animal model for this form of human congenital muscular dystrophy. High resolution in vivo imaging was performed on anaesthetized animals (two homozygous dy/dy mutants and two heterozygous dy/DY controls, aged 2.5 months) in a dedicated 11.7T magnetic resonance imaging scanner. T(1) and T(2) weighted images were normal in all mice and white matter changes were not seen at a stage of maturity when MRI changes are already very striking in human patients. Cerebral MRI abnormalities do not appear to be a feature of dy/dy mice, despite the virtual absence of Merosin expression in the dy/dy mouse brain. Possible causes for this absence of MRI changes, and implications for the pathogenesis of the MRI changes in humans are reviewed.
-
demyelinating peripheral neuropathy in Merosin deficient congenital muscular dystrophy
Journal of Child Neurology, 1995Co-Authors: Zamir Shorer, Caroline Sewry, Francesco Muntoni, J Philpot, V DubowitzAbstract:It has recently been shown that Merosin, a laminin variant, is deficient in a proportion of patients with congenital muscular dystrophy. Merosin is a heterotrimer composed of the α2, β1, and γ1 subunits, and further studies have shown that it is the α2 subunit that is deficient in these patients. Because the α2 subunit is also expressed in S-Merosin, found in Schwann cells, we have investigated whether peripheral nerve function is also affected in these patients. Motor nerve conduction velocities and sensory distal latencies were examined in 25 cases of congenital muscular dystrophy and the results correlated with the Merosin expression in their muscle biopsies. All but two of the 10 Merosin-deficient cases had reduced motor nerve conduction, whereas all the Merosin-positive cases had normal results. Analysis of the biopsies of these two cases showed that they produced Merosin in reduced amounts, in contrast to all other Merosin-deficient patients that produced no or only traces of Merosin. Sensory nerve ...
-
clinical phenotype in congenital muscular dystrophy correlation with expression of Merosin in skeletal
Neuromuscular Disorders, 1995Co-Authors: J Philpot, Caroline Sewry, J M Pennock, V DubowitzAbstract:Abstract It has recently been shown that Merosin, an extracellular matrix protein linked to the dystrophin-associated glycoproteins, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). We have undertaken a detailed study of the clinical features and brain imaging in 24 cases of CMD in relation to the Merosin status. Immunocytochemistry showed that Merosin was present in 13 cases and markedly deficient in 11. In the Merosin-positive cases, the maximum motor achievement was independent walking in 11, walking with support in one and sitting unsupported in one (currently 18 months old). In contrast, none of the Merosin-deficient cases achieved independent ambulation. Two achieved walking with support, nine standing with support. In addition, nine of the 11 Merosin-deficient cases had a creatine kinase level greater than 2000 whereas only one Merosin-positive case had this degree of elevation. Magnetic resonance imaging of the brain was carried out on 15 of the children. All eight Merosin-positive cases had normal scans whereas all seven of the Merosin-deficient cases had significant changes in the white matter. This study has demonstrated that children with Merosin-deficient CMD have a more severe clinical phenotype and associated white matter changes on brain imaging.
Pascale Guicheney - One of the best experts on this subject based on the ideXlab platform.
-
Merosin deficient congenital muscular dystrophy autosomal recessive mdc1a mim 156225 lama2 gene coding for alpha2 chain of laminin
European Journal of Human Genetics, 2002Co-Authors: Valerie Allamand, Pascale GuicheneyAbstract:Congenital muscular dystrophies (CMDs) are a highly heterogeneous group of neuromuscular disorders. A subgroup displays a specific deficiency in a protein of the extracellular matrix, the alpha2 chain of laminin-2 (Merosin). A number of mutations in the gene encoding this protein have been identified in patients who present with a severe phenotype and white matter changes.
-
identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine on chromosome 1p35 36
American Journal of Human Genetics, 1998Co-Authors: Behzad Moghadaszadeh, Caroline Sewry, Francesco Muntoni, Haluk Topaloglu, F M S Tome, Isabelle Desguerre, Sylvana Pavek, Michele Mayer, Michel Fardeau, Pascale GuicheneyAbstract:Summary Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin α2 chain (or Merosin), has been identified in these disorders. Mutations in LAMA2 cause CMD with complete or partial Merosin deficiency, detectable by immunocytochemistry on muscle biopsies, and account for ∼50% of CMD cases. In a large consanguineous family (11 siblings) comprising three children affected by CMD without Merosin deficiency, we undertook a genomewide search by homozygosity mapping and analyzed 380 microsatellite markers. The affected children were homozygous for several markers on chromosome 1p35-36. We identified two additional consanguineous families with affected children who also showed linkage to this locus. A maximum cumulative LOD score of 4.48, at a recombination fraction of .00, was obtained with D1S2885. A consistent feature in these three families was the presence of early rigidity of the spine, scoliosis, and reduced vital capacity, as found in rigid-spine syndrome (RSS). This study is the first description of a locus for a Merosin-positive CMD and will help to better define the nosology of RSS.
-
localization of Merosin negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping
Human Molecular Genetics, 1994Co-Authors: Dominique Hillaire, Anne Leclerc, Sabine Faure, Haluk Topaloglu, Nuchanard Chiannllkulchai, Pascale Guicheney, Laurent Grinas, Patricia Legos, J Philpot, Teresinha EvangelistaAbstract:Congenital muscular dystrophies (CMD) are autosomalrecessive, heterogeneous disorders. The commonestforms are the Fukuyama CMD (FCMD), associated withmental retardation and structural brain anomalies, andclassical (occidental) CMD, with pure muscle expres-sion. FCMD has been localized to chromosome 9q31 -q33. Following the discovery of Merosin deficiency insome CMD cases, we have localized, by homozygositymapping and linkage analysis (Zmax = 5.6; 0 = 0.0 formarker AFM127xb2) in four merosln-negatlve familiesa CMD gene In a 16 cM region of chromosome 6q2 inthe region of the laminin M chain gene. In threeconsanguineous, Merosin-positive, CMD families therewas no linkage to either chromosome 6q2 or9q31 - q33.INTRODUCTIONCongenital muscular dystrophies (CMDs), are autosomalrecessive severe muscle diseases of early onset and the mostfrequent cause of severe neonatal hypotonia of muscular origin(1 -3). Clinical manifestations occur at birth or in the first monthsof life and consist of muscle hypotonia and weakness, markedlydelayed motor milestones, severe and early contractures, oftenassociated with joint deformities. Serum creatine kinase isvariably raised, up 10 times normal, but may be normal. Thehistological changes in muscle biopsies consist of markedvariation in muscle fibre size, a few necrotic and regeneratingfibres, marked increase in endomysial collagen tissue, variableadipous tissue and no specific ultrastructural features. Untilrecently the diagnosis of CMD has been based on the clinicalpicture and the morphological changes in the muscle biopsy.Within the group of diseases classified as CMDs, variousdistinct phenotypes have been defined. The two more commonforms are the classical CMD, without clinical involvement ofthe central nervous system, although imaging changes in the whitematter may be found on magnetic resonance imaging (MRI), andthe Fukuyama type (FCMD) prevalent in Japan, associated withsevere mental retardation and major structural brain abnormalities(4,5). The association in one patient from a consanguineousfamily of both FCMD and group A xeroderma pigmentosum,led to the localization of FCMD gene to chromosome 9q31 —q33 (6).The marked increase in connective tissue in muscle hassuggested that an abnormality of one of the components of theextracellular matrix could be involved in the pathogenesis of thisdisease (7). However, our initial studies (8,9) failed to detectspecific changes in extracellular matrix proteins. As it wasdemonstrated that a large oligomeric complex of sarcolemmalglycoproteins associated with dystrophin provides a link betweenthe subsarcolemmal cytoskeleton and laminin (10,11), a majorcomponent of the extracellular matrix, we have investigatedwhether one of the laminin subunits (12,13) could be involvedin CMD. Furthermore, a partial Merosin reduction was observedin some cases of FCMD (14). This showed a specific absenceof Merosin (laminin M chain) in thirteen patients out of twentyaffected by classical, non-Fukuyama, form of CMD (15). SimilarMerosin negative results were obtained by C.A.Sewry andV.Dubowitz in ten out of twenty two cases, and by K.P.Campbellin three patients (personal communications). As the laminin Mchain gene (LAMM) has been mapped to chromosome 6q22—q23(16) and the FCMD was localized in chromosome 9q31-q32(6), we focused our analysis in CMD consanguineous families(either with or without Merosin deficiency) on these twochromosomes. The high consanguinity led us to use homozygositymapping (17), with highly polymorphic markers consistingexclusively of (CA)
Françoise Pons - One of the best experts on this subject based on the ideXlab platform.
-
Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cerebral white matter
Neuromuscular Disorders, 1997Co-Authors: Bernard Echenne, François Rivier, A.j. Jellali, M. Azais, Dominique Mornet, Françoise PonsAbstract:Abstract A girl born from consanguineous Turkish parents had marked hypotonia from birth and delayed milestones. She was able to stand unaided by 3 years of age with then progressive worsening of motor abilities. She had a severe non-progressive mental deficiency. Epilepsy occurred by 6 years of age. Ophthalmological investigation was normal. A marked white matter high signal was seen on magnetic resonance imaging without cortical dysplasia. Dystrophic changes were seen on muscle biopsy. Two brothers had had a similar history with early death. Muscular immunocytochemical studies showed a normal staining for dystrophin and all dystrophin related glycoproteins (including 43 and 50 DAG). Merosin staining was normal. This case differs from Fukuyama's congenital dystrophy, from Merosin negative congenital muscular dystrophy, or from other congenital muscular dystrophy with CNS dysfunction. It underlines the heterogeneity of congenital muscular dystrophy and the non-specific aspect of white matter changes on neuro-imaging.