Silent polymorphisms in the RYR1 gene do not\ud modify the phenotype of the p.4898 I>T\ud pathogenic mutation in central core disease:\ud a case report

Background: Central core disease is a congenital myopathy, characterized by presence of central core-like areas in\ud muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is\ud caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel.\ud Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three ‘hot spots’, with\ud particular attention to the C-terminal region. Recent next- generation sequencing methods are now identifying\ud multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult.\ud Case presentation: In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a\ud new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1\ud gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in\ud exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed\ud because patient’s daughter, mother and sister carried only the exon 98’s mutation, a synonymous variant that was\ud subsequently found in the frequency of 013–0,05 of alleles. Further next generation sequencing study of the whole\ud RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and\ud 8 polymorphisms in heterozygosis.\ud Conclusions: Considering that patient’s relatives showed no pathologic phenotype, and the phenotype presented\ud by the patient is within the range observed in other central core disease patients with the same mutation, it was\ud concluded that the c.14256 A > C polymorphism alone is not responsible for disease, and the associated additional\ud silent polymorphisms are not acting as modifiers of the primary pathogenic mutation in the affected patient. The\ud case described above illustrates the present reality where new methods for wide genome screening are becoming\ud more accessible and able to identify a great variety of mutations and polymorphisms of unknown function in\ud patients and their families.Fundação de Amparo a Pesquisa do Estado de São Paulo - Centro de Pesquisa, Inovação e Difusão (FAPESP-CEPID)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-INCT)Associação Brasileira de Distrofia Muscular (ABDIM)CAPES-COFECU

BILATERALIDADE, ALTERIDADE, EXTERIORIDADE E A COERCITIVIDADE DO DIREITO NA ERA DA INFORMAÇÃO

O presente artigo trata de desdobramentos que estão diretamente relacionados à responsabilidade jurí­dica relativos aos atos praticados no "ciberespaço", verificando o surgimento de novos obstáculos à aplicação da lei, com sua legitimidade de tratamento, bem como abrindo espaço para a coercitividade marginal, tendo em vista a rapidez e ineficácia do arrependimento dos atos de expressão efetivados nos meios digitais. Analisa-se, portanto, como principais aspectos nesse estudo a bilateralidade, tendo como binômio definidor a relação "direitos-deveres"; a alteridade, como elemento alvo do tratamento do direito a relação entre os sujeitos; a exterioridade, como expressão de atos no mundo real; e a coercitividade que se tem no âmbito jurí­dico e no marginal (aqui entendido como aquele exercido pela sociedade fora da razoabilidade). Na sociedade da informação, cada um dos elementos que o estudo propõe trazem consigo significação própria, haja vista o alcance que tal sociedade apresenta a cada ato que a ela é submetido

Myoclonus dystonia and muscular dystrophy: ɛ-sarcoglycan is part of the dystrophin-associated protein complex in brain

BACKGROUND: Myoclonus-dystonia is a neurogenic movement disorder caused by mutations in the gene encoding ɛ-sarcoglycan. By contrast, mutations in the α-, β-, γ-, and δ-sarcoglycan genes cause limb girdle muscular dystrophies. The sarcoglycans are part of the dystrophin-associated protein complex in muscle that is disrupted in several types of muscular dystrophy. Intriguingly, patients with myoclonus-dystonia have no muscle pathology; conversely, limb-girdle muscular dystrophy patients have not been reported to have dystonia-associated features. To gain further insight into the molecular mechanisms underlying these differences, we searched for evidence of a sarcoglycan complex in the brain. METHODS: Immunoaffinity chromatography and mass spectrometry were used to purify ubiquitous and brain-specific ɛ-sarcoglycan directly from tissue. Cell models were used to determine the effect of mutations on the trafficking and assembly of the brain sarcoglycan complex. RESULTS: Ubiquitous and brain-specific ɛ-sarcoglycan isoforms copurify with β-, δ-, and ζ-sarcoglycan, β-dystroglycan, and dystrophin Dp71 from brain. Incorporation of a muscular dystrophy-associated β-sarcoglycan mutant into the brain sarcoglycan complex impairs the formation of the βδ-sarcoglycan core but fails to abrogate the association and membrane trafficking of ɛ- and ζ-sarcoglycan. CONCLUSIONS: ɛ-Sarcoglycan is part of the dystrophin-associated protein complex in brain. Partial preservation of ɛ- and ζ-sarcoglycan in brain may explain the absence of myoclonus dystonia-like features in muscular dystrophy patients. © 2016 International Parkinson and Movement Disorder Society

Neuromuscular disorders: genes, genetic counseling and therapeutic trials

Abstract Neuromuscular disorders (NMD) are a heterogeneous group of genetic conditions, with autosomal dominant, recessive, or X-linked inheritance. They are characterized by progressive muscle degeneration and weakness. Here, we are presenting our major contributions to the field during the past 30 years. We have mapped and identified several novel genes responsible for NMD. Genotype-phenotype correlations studies enhanced our comprehension on the effect of gene mutations on related proteins and their impact on clinical findings. The search for modifier factors allowed the identification of a novel "protective"; variant which may have important implication on therapeutic developments. Molecular diagnosis was introduced in the 1980s and new technologies have been incorporated since then. Next generation sequencing greatly improved our capacity to identify disease-causing mutations with important benefits for research and prevention through genetic counseling of patients' families. Stem cells researches, from and for patients, have been used as tools to study human genetic diseases mechanisms and for therapies development. The clinical effect of preclinical trials in mice and canine models for muscular dystrophies are under investigation. Finally, the integration of our researches and genetic services with our post-graduation program resulted in a significant output of new geneticists, spreading out this expertise to our large country

Correlação entre o tempo de realização de diferentes atividades físicas por portadores de distrofia muscular de Duchenne

DMD is a disease determined by genetic disturbance of recessive character linked to the chromosome X, that determines the deficiency or absence in the distrofin production in the muscular cellular membrane, carting a progressive and irreversible dysfunction, mainly of the skeletal musculature. The functional evaluation of the children carriers of DMD is extensive and exhaustive for child and for physical therapist. The search of information and methods that promote the facilitation or simplification of the routines of functional evaluation has been conducting to the research of correlations among the time of development of functional activities. The goal of this study was to determine and to research possible correlations among the time used to realize physical activities (to go up stairway, to go down stairway, to lift of the chair and to pass from sitting on the floor to standing through the Maneuver of Gowers) in 15 children (6 to 10 years old) with DMD. The children were filmed accomplishing the proposed physical activities, in five serial evaluations during one year, separated by a period of three months. The time for each activity was measured for each child. We confirmed the heterogeneity of the evolution of the disease, in the studied activities, as expected. We found lineal relationship among the functional activities and the age, and the presence of direct lineal correlation between the accomplishment of the Maneuver of Gowers and the functional activities. Up stairway was the activity of larger correlation.A DMD é uma doença determinada por um distúrbio genético de caráter recessivo ligada ao cromossomo X, que determina a deficiência ou ausência na produção de distrofina na membrana celular muscular, acarretando uma disfunção progressiva e irreversível, principalmente da musculatura esquelética. A avaliação funcional das crianças portadoras de DMD é extensa e exaustiva, tanto para criança, quanto para o fisioterapeuta. A procura de informações e métodos que promovam a facilitação ou simplificação das rotinas de avaliação fisioterápica tem conduzido à pesquisa de correlações entre o tempo de desenvolvimento de atividades funcionais. O objetivo desse estudo foi determinar e pesquisar possíveis correlações entre o tempo utilizado na realização de diferentes atividades físicas, a saber, subir escada, descer escada, levantar da cadeira e passar da postura de sedestação no solo para bipedestação (através da Manobra de Gowers) em 15 crianças (de 6 a 10 anos) portadoras de Distrofia Muscular de Duchenne. As crianças foram filmadas realizando as atividades físicas propostas, em cinco avaliações consecutivas durante um ano, separadas por um período de três meses. Posteriormente cronometrou-se o tempo para realização das atividades. Confirmou-se a heterogeneidade da evolução da doença, para as atividades estudadas, como esperado. Encontrou-se relação linear entre as atividades funcionais estudadas e a idade, e a presença de correlação linear direta entre a realização da Manobra de Gowers e as atividades funcionais, sendo o subir escada a atividade de maior correlação