RESUMO
AIMS: Dynamin-2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2-linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin-2 CNM-causing mutation influences the CNS function. METHODS: Heterozygous mice harbouring the p.R465W mutation in the dynamin-2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. RESULTS: HTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin-2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. CONCLUSION: Our findings suggest that the dynamin-2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.
Assuntos
Dinamina II , Miopatias Congênitas Estruturais , Animais , Camundongos , Modelos Animais de Doenças , Dinamina II/genética , Dinamina II/metabolismo , Músculo Esquelético/metabolismo , Mutação , Miopatias Congênitas Estruturais/genética , Neurônios/metabolismo , Transmissão SinápticaRESUMO
Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.
Assuntos
Doenças Musculares , Distrofia Muscular do Cíngulo dos Membros , Chile , Perfil Genético , Humanos , Debilidade Muscular/genética , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genéticaRESUMO
Idiopathic Inflammatory Myopathies (IIMs) have been studied within the framework of autoimmune diseases where skeletal muscle appears to have a passive role in the illness. However, persiting weakness even after resolving inflammation raises questions about the role that skeletal muscle plays by itself in these diseases. "Non-immune mediated" hypotheses have arisen to consider inner skeletal muscle cell processes as trigger factors in the clinical manifestations of IIMs. Alterations in oxidative phosphorylation, ATP production, calcium handling, autophagy, endoplasmic reticulum stress, among others, have been proposed as alternative cellular pathophysiological mechanisms. In this study, we used skeletal muscle-derived cells, from healthy controls and IIM patients to determine mitochondrial function and mitochondrial ability to adapt to a metabolic stress when deprived of glucose. We hypothesized that mitochondria would be dysfunctional in IIM samples, which was partially true in normal glucose rich growing medium as determined by oxygen consumption rate. However, in the glucose-free and galactose supplemented condition, a medium that forced mitochondria to function, IIM cells increased their respiration, reaching values matching normal derived cells. Unexpectedly, cell death significantly increased in IIM cells under this condition. Our findings show that mitochondria in IIM is functional and the decrease respiration observed is part of an adaptative response to improve survival. The increased metabolic function obtained after forcing IIM cells to rely on mitochondrial synthesized ATP is detrimental to the cell's viability. Thus, therapeutic interventions that activate mitochondria, could be detrimental in IIM cell physiology, and must be avoided in patients with IIM.
Assuntos
Apoptose/fisiologia , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/patologia , Miosite/patologia , Trifosfato de Adenosina/análise , Idoso , Autoanticorpos/imunologia , Doenças Autoimunes/patologia , Células Cultivadas , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/fisiologia , Pessoa de Meia-Idade , Fosforilação Oxidativa , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Immune-mediated necrotizing myopathy with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase is a subgroup of idiopathic inflammatory myopathies mainly described in adults and requiring long term immunomodulatory therapy for remission. Pediatric patients have been reported as small series or sporadic cases. We report an eight-year-old girl with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, presenting with subacute proximal limb weakness, high creatine kinase and a muscle biopsy displaying necrotizing pattern, initially diagnosed as limb-girdle muscular dystrophy, but subsequently negative genetic testing. A noteworthy spontaneous improvement in her weakness suggested the possibility of an acquired autoimmune myopathy, confirmed by positive testing of anti-HMGCR antibodies titers. After four years of follow-up, she maintains normal strength with high levels of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody. This patient shows that spontaneous fluctuations and spontaneous long-lasting symptomatic remission can occur in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy. Some patients could present a wane and wax clinical course, an important aspect when assessing response to therapy.
Assuntos
Doenças Autoimunes , Hidroximetilglutaril-CoA Redutases/imunologia , Miosite , Autoanticorpos , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Criança , Feminino , Humanos , Miosite/sangue , Miosite/imunologia , Miosite/patologia , Miosite/fisiopatologia , Remissão EspontâneaRESUMO
Dysferlinopathy is an autosomal recessive muscular dystrophy resulting from mutations in the dysferlin gene. Absence of dysferlin in the sarcolemma and progressive muscle wasting are hallmarks of this disease. Signs of oxidative stress have been observed in skeletal muscles of dysferlinopathy patients, as well as in dysferlin-deficient mice. However, the contribution of the redox imbalance to this pathology and the efficacy of antioxidant therapy remain unclear. Here, we evaluated the effect of 10 weeks diet supplementation with the antioxidant agent N-acetylcysteine (NAC, 1%) on measurements of oxidative damage, antioxidant enzymes, grip strength and body mass in 6 months-old dysferlin-deficient Bla/J mice and wild-type (WT) C57 BL/6 mice. We found that quadriceps and gastrocnemius muscles of Bla/J mice exhibit high levels of lipid peroxidation, protein carbonyls and superoxide dismutase and catalase activities, which were significantly reduced by NAC supplementation. By using the Kondziela's inverted screen test, we further demonstrated that NAC improved grip strength in dysferlin deficient animals, as compared with non-treated Bla/J mice, without affecting body mass. Together, these results indicate that this antioxidant agent improves skeletal muscle oxidative balance, as well as muscle strength and/or resistance to fatigue in dysferlin-deficient animals.
Assuntos
Acetilcisteína/administração & dosagem , Antioxidantes/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular do Cíngulo dos Membros/dietoterapia , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Índice de Massa Corporal , Modelos Animais de Doenças , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Resultado do TratamentoRESUMO
Dysferlinopathy is a genetic human disease caused by mutations in the gene that encodes the dysferlin protein (DYSF). Dysferlin is believed to play a relevant role in cell membrane repair. However, in dysferlin-deficient (blAJ) mice (a model of dysferlinopathies) the recovery of the membrane resealing function by means of the expression of a mini-dysferlin does not arrest progressive muscular damage, suggesting the participation of other unknown pathogenic mechanisms. Here, we show that proteins called connexins 39, 43 and 45 (Cx39, Cx43 and Cx45, respectively) are expressed by blAJ myofibers and form functional hemichannels (Cx HCs) in the sarcolemma. At rest, Cx HCs increased the sarcolemma permeability to small molecules and the intracellular Ca2+ signal. In addition, skeletal muscles of blAJ mice showed lipid accumulation and lack of dysferlin immunoreactivity. As sign of extensive damage and atrophy, muscles of blAJ mice presented elevated numbers of myofibers with internal nuclei, increased number of myofibers with reduced cross-sectional area and elevated creatine kinase activity in serum. In agreement with the extense muscle damage, mice also showed significantly low motor performance. We generated blAJ mice with myofibers deficient in Cx43 and Cx45 expression and found that all above muscle and systemic alterations were absent, indicating that these two Cxs play a critical role in a novel pathogenic mechanism of dysfernolophaties, which is discussed herein. Therefore, Cx HCs could constitute an attractive target for pharmacologic treatment of dyferlinopathies.
Assuntos
Conexina 43/genética , Conexinas/genética , Disferlina/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/prevenção & controle , Miofibrilas/genética , Animais , Cálcio/metabolismo , Conexina 43/deficiência , Conexinas/deficiência , Creatina Quinase/sangue , Creatina Quinase/genética , Modelos Animais de Doenças , Disferlina/deficiência , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação , Miofibrilas/metabolismo , Miofibrilas/patologia , Permeabilidade , Condicionamento Físico Animal , Teste de Desempenho do Rota-Rod , Sarcolema/metabolismoRESUMO
BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a group of neuromuscular disorders of heterogeneous genetic etiology with more than 30 directly related genes. LGMD is characterized by progressive muscle weakness involving the shoulder and pelvic girdles. An important differential diagnosis among patients presenting with proximal muscle weakness (PMW) is late-onset Pompe disease (LOPD), a rare neuromuscular glycogen storage disorder, which often presents with early respiratory insufficiency in addition to PMW. Patients with PMW, with or without respiratory symptoms, were included in this study of Latin American patients to evaluate the profile of variants for the included genes related to LGMD recessive (R) and LOPD and the frequency of variants in each gene among this patient population. RESULTS: Over 20 institutions across Latin America (Brazil, Argentina, Peru, Ecuador, Mexico, and Chile) enrolled 2103 individuals during 2016 and 2017. Nine autosomal recessive LGMDs and Pompe disease were investigated in a 10-gene panel (ANO5, CAPN3, DYSF, FKRP, GAA, SGCA, SGCB, SGCD, SGCG, TCAP) based on reported disease frequency in Latin America. Sequencing was performed with Illumina's NextSeq500 and variants were classified according to ACMG guidelines; pathogenic and likely pathogenic were treated as one category (P) and variants of unknown significance (VUS) are described. Genetic variants were identified in 55.8% of patients, with 16% receiving a definitive molecular diagnosis; 39.8% had VUS. Nine patients were identified with Pompe disease. CONCLUSIONS: The results demonstrate the effectiveness of this targeted genetic panel and the importance of including Pompe disease in the differential diagnosis for patients presenting with PMW.
Assuntos
Doença de Depósito de Glicogênio Tipo II/metabolismo , Doença de Depósito de Glicogênio Tipo II/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Debilidade Muscular/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Adolescente , Adulto , Brasil , Feminino , Humanos , América Latina , Masculino , México , Pessoa de Meia-Idade , Debilidade Muscular/patologia , Mutação/genética , Análise de Sequência de DNA , Adulto JovemRESUMO
METHODS: Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. RESULTS: We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. CONCLUSION: Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.
Assuntos
Doenças Neurodegenerativas/diagnóstico , Atrofias Musculares Espinais da Infância/diagnóstico , Adolescente , Adulto , Biópsia , Criança , Chile/epidemiologia , Estudos de Coortes , Eletromiografia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Neurodegenerativas/mortalidade , Doenças Neurodegenerativas/terapia , Fenótipo , Prevalência , Características de Residência , Respiração Artificial , Escoliose/cirurgia , Fatores Socioeconômicos , Atrofias Musculares Espinais da Infância/mortalidade , Atrofias Musculares Espinais da Infância/terapia , Adulto JovemRESUMO
ABSTRACT Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. Methods This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. Results We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. Conclusion Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.
La Atrofia Muscular Espinal (AME) ha concitado mucha atención en los últimos 2 años debido a la aprobación del primer tratamiento intratecal para esta enfermedad neurodegenerativa. América Latina necesita desarrollar la demografía de AME, un acceso oportuno al diagnóstico y un seguimiento apropiado de los pacientes que incorporen los estándares de atención recomendados por expertos. Estos son pasos esenciales para orientar las futuras políticas de salud en esta enfermedad. Métodos Este es un estudio descriptivo de una cohorte de pacientes con AME de todo el país. Se analizaron los datos clínicos, motores, funcionales, sociales y el estado nutricional, respiratorio y esquelético de los pacientes. También medimos el número de copias del gen SMN2 en esta población. Resultados se reclutaron 92 pacientes, 50 varones; 23 AME tipo 1, 36 AME tipo 2 y 33 AME tipo 3. La edad media al diagnóstico genético fue de 5, 24 y 132 meses respectivamente. Evaluamos el número de copias de SMN2 en 57 pacientes. Un 69,6% de los pacientes con AME tipo 1 estaban traqueostomízados y gastrostomizados , un 65% de los pacientes con AME tipo 2 usaban ventilación nocturna no invasiva y el 37% de toda la cohorte presentaba una cirugía de escoliosis. Conclusión Esta cohorte chilena de pacientes con AME tuvo acceso oportuno al diagnóstico genético, asistencia ventilatoria, apoyo nutricional y cirugía de escoliosis, sin embargo, la atención ventilatoria para AME tipo 1 continúa aun basándose principalmente en la traqueostomía. En esta serie, AME tipo 1 está subrepresentada, probablemente debido a las restricciones en el acceso al diagnóstico temprano y la tasa de mortalidad alta y temprana.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Criança , Adolescente , Adulto , Adulto Jovem , Atrofias Musculares Espinais da Infância/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Fenótipo , Respiração Artificial , Escoliose/cirurgia , Fatores Socioeconômicos , Biópsia , Atrofias Musculares Espinais da Infância/mortalidade , Atrofias Musculares Espinais da Infância/terapia , Chile/epidemiologia , Características de Residência , Prevalência , Estudos de Coortes , Doenças Neurodegenerativas/mortalidade , Doenças Neurodegenerativas/terapia , Predisposição Genética para Doença , Eletromiografia , GenótipoRESUMO
Congenital myasthenic syndromes (CMS) are neuromuscular transmission disorders caused by mutations in genes encoding neuromuscular junction proteins. A 61-year-old female and her older sister showed bilateral ptosis, facial and proximal limb weakness, and scoliosis since childhood. Another female sibling had milder signs, while other family members were asymptomatic. Facial nerve repetitive stimulation in the proband showed decrement of muscle responses. Single fiber EMG revealed increased jitter and blocking. Muscle biopsy showed type 2-fiber atrophy, without tubular aggregates. Mutational analysis in the three affected siblings revealed two compound heterozygous mutations in DOK7: c.1457delC, that predicts p.Pro486Argfs*13 and truncates the protein C-terminal domain, and c.473G>A, that predicts p.Arg158Gln and disruption of the dok7-MuSK interaction in the phosphotyrosine binding (PTB) domain. Unaffected family members carried only one or neither mutation. Discussion: Two of the affected sisters showed marked improvement with salbutamol treatment, which illustrates the benefits of a correct diagnosis and treatment of DOK7-CMS.
RESUMO
Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.
Assuntos
Actinas/metabolismo , Dinamina II/genética , Predisposição Genética para Doença , Células Musculares/metabolismo , Mutação , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/metabolismo , Actinas/química , Animais , Modelos Animais de Doenças , Dinamina II/metabolismo , Ativação Enzimática , Expressão Gênica , Estudos de Associação Genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Camundongos , Mioblastos/metabolismo , Miopatias Congênitas Estruturais/patologia , Ligação Proteica , Multimerização Proteica , Transporte ProteicoAssuntos
Colágeno Tipo VI/genética , Contratura/genética , Queloide/genética , Distrofias Musculares/congênito , Adolescente , Contratura/complicações , Feminino , Humanos , Queloide/etiologia , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/complicações , Distrofias Musculares/genética , Mutação de Sentido Incorreto , Pele/lesões , Torcicolo/complicações , Torcicolo/congênito , Adulto JovemRESUMO
BACKGROUND: Mutations in the gene encoding for dysferlin cause recessive autosomal muscular dystrophies called dysferlinopathies. These mutations induce several alterations in skeletal muscles, including, inflammation, increased membrane permeability and cell death. Despite the fact that the etiology of dysferlinopathies is known, the mechanism that explains the aforementioned alterations is still elusive. Therefore, we have now evaluated the potential involvement of connexin based hemichannels in the pathophysiology of dysferlinopathies. RESULTS: Human deltoid muscle biopsies of 5 Chilean dysferlinopathy patients exhibited the presence of muscular connexins (Cx40.1, Cx43 and Cx45). The presence of these connexins was also observed in human myotubes derived from immortalized myoblasts derived from other patients with mutated forms of dysferlin. In addition to the aforementioned connexins, these myotubes expressed functional connexin based hemichannels, evaluated by ethidium uptake assays, as opposed to myotubes obtained from a normal human muscle cell line, RCMH. This response was reproduced in a knock-down model of dysferlin, by treating RCMH cell line with small hairpin RNA specific for dysferlin (RCMH-sh Dysferlin). Also, the presence of P2X7 receptor and the transient receptor potential channel, TRPV2, another Ca(2+) permeable channels, was detected in the myotubes expressing mutated dysferlin, and an elevated resting intracellular Ca(2+) level was found in the latter myotubes, which was in turn reduced to control levels in the presence of the molecule D4, a selective Cx HCs inhibitor. CONCLUSIONS: The data suggests that dysferlin deficiency, caused by mutation or downregulation of dysferlin, promotes the expression of Cx HCs. Then, the de novo expression Cx HC causes a dysregulation of intracellular free Ca(2+) levels, which could underlie muscular damage associated to dysferlin mutations. This mechanism could constitute a potential therapeutical target in dysferlinopathies.
Assuntos
Conexinas/metabolismo , Proteínas de Membrana/deficiência , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/deficiência , Biópsia , Sinalização do Cálcio , Linhagem Celular , Disferlina , Humanos , Espaço Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação/genética , Receptores Purinérgicos P2X7/metabolismo , Sarcolema/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
INTRODUCTION: MRI characterization of dysferlinopathy has been mostly limited to the lower limbs. We aimed to broaden the MRI description of dysferlinopathy and to correlate it with objective measures of motor dysfunction. METHODS: Sequential whole-body axial MRI was performed in 27 patients with genetically confirmed dysferlinopathy classified according to disease duration. Spearman correlations of fatty infiltration scores versus Motor Function Measure (MFM) were calculated. RESULTS: Significant fatty infiltration was symmetrically present in early stages mainly in the posterior compartments of legs and thighs, thigh adductors, pelvic girdle, and some paravertebral muscles and the subscapularis. Later, fatty infiltration involved leg and thigh anterior compartments, arms and forearms, paravertebral, and trunk muscles. MRI infiltration score correlated positively with disease duration and negatively with MFM scale. CONCLUSIONS: We expand MRI characterization of dysferlinopathy and provide evidence for use of MRI scoring combined with motor functional scales to assess the natural course of disease. Muscle Nerve, 2016 Muscle Nerve 54: 203-210, 2016.
Assuntos
Imageamento por Ressonância Magnética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Imagem Corporal Total , Adolescente , Criança , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Músculo Esquelético/diagnóstico por imagem , Estudos Retrospectivos , Estatísticas não Paramétricas , Adulto JovemRESUMO
INTRODUCTION: Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a cohort of patients with dysferlinopathy, using validated scales. METHODS: Thirty-one patients with genetically confirmed dysferlinopathy were assessed using the motor function measure (MFM), Modified Rankin Scale (MRS), Muscle Research Council (MRC) scale, serum creatine kinase (CK) assessment, baseline spirometry data, and echocardiographic and electrophysiologic studies. RESULTS: MFM and MRC scores showed a significant negative correlation with disease duration and inverse correlation with MRS, but not with onset age, clinical phenotype, or CK levels. Percent forced vital capacity (%FVC) correlated negatively with disease duration and onset age. Eight known pathogenic mutations were identified recurrently, 4 of which accounted for 79% of the total. CONCLUSIONS: The results suggest that MFM is a reliable outcome measure that may be useful for longitudinal follow-up in dysferlinopathy. Recurrent mutations suggest a founder effect in the Chilean population.
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Avaliação da Deficiência , Pessoas com Deficiência , Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Adolescente , Adulto , Estudos de Coortes , Creatina Quinase/sangue , Disferlina , Eletromiografia , Potencial Evocado Motor/fisiologia , Extremidades/fisiopatologia , Feminino , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas Musculares/sangue , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/sangue , Condução Nervosa/genética , Respiração , Espirometria , Estatísticas não Paramétricas , Capacidade Vital/fisiologia , Adulto JovemRESUMO
La Enfermedades Neuromusculares (ENM) son un conjunto de enfermedades con síntomas clínicos que varían según la edad de presentación y el tipo de afectación primaria (mús- culo, unión neuromuscular, nervios o motoneurona inferior). Los pacientes en la segunda década de la vida, edad en la que se desarrolla la adolescencia, presentan síntomas diferentes de la hipotonía o retraso en los hitos motores, propios de las ENM en edades mas tempranas. En este período es necesario mantener un alto nivel de sospecha clínica porque los signos y síntomas de las ENM pueden ser sutiles, de lenta evolución y no ser referidos directamente por el paciente afectado. Esta situación favorece el subdiagnóstico y diagnóstico tardío de estas afecciones. Conocer estos síntomas y signos favorece la sospecha y diagnóstico precoz así como un manejo y cuidados apropiados según cada patología. En esta revisión se hace énfasis en el amplio espectro de la sintomatología que debe ser considerada cuando se sospecha la existencia de una ENM.
Neuromuscular disorders (NMD) include a multiplicity of different diseases with variable clinical symptoms according to age of presentation and type of primary involvement (muscle, neuromuscular junction, nerve or spinal motor neuron). Patients in their second decade of life, when adolescence arises, have distinctive symptoms different from hypotonia or motor milestone developmental delay, which are commonly seen in the early childhood. To be attentive to this clinical diversity is important in order to suspect a NMD, since occasionally the signs or symptoms can be subtle and potentially overlooked by the clinician until later in life. In this review we emphasize the broad spectrum of symptomatology that should be considered when suspecting a NMD during adolescence, to enhance the recognition of these pathologies and be aware of them for a better and earlier workup.
Assuntos
Humanos , Adolescente , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/terapia , Sinais e Sintomas , Debilidade Muscular , Doenças Neuromusculares/etiologia , Doenças Neuromusculares/genéticaRESUMO
INTRODUCTION: Muscle biopsy is usually diagnostic in nemaline myopathy (NM), but some patients may show nonspecific findings, leading to pitfalls in diagnosis. Muscle MRI is a helpful complementary tool. METHODS: We assessed the clinical, histopathological, MRI, and molecular findings in a 19-year-old patient with NM in whom 2 muscle biopsies with ultrastructural examination showed no nemaline bodies. We analyzed the degree and pattern of muscle MRI involvement of the entire body, including the tongue and pectoral muscles. RESULTS: Muscle MRI abnormalities in sartorius, adductor magnus, and anterior compartment muscles of the leg suggested NM. A previously unreported fatty infiltration of the tongue was found. A third biopsy after the muscle MRI showed scant nemaline bodies. A novel heterozygous de novo ACTA1 c.611C>T/p.Thr204Ile mutation was detected. CONCLUSIONS: We highlight the contribution of muscle imaging in addressing the genetic diagnosis of ACTA1-related NM.
Assuntos
Músculo Esquelético/patologia , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Actinas/genética , Biópsia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Miopatias da Nemalina/diagnóstico , Miopatias Congênitas Estruturais , Adulto JovemRESUMO
Congenital unilateral overgrowth of the upper extremity affecting only the muscle tissue is rare. We describe on the clinical, histopathological, and neuroimaging findings in a 6-year-old girl with a congenital, non-progressive muscle enlargement of the entire left upper limb with an ipsilateral hand deformity. No cutaneous stigmata or additional features were detected. Sanger sequencing for the AKT1, PIK3CA, and PTEN genes identified an activating c.3140A>G, p.H1047R mutation in the PIK3CA gene from the affected muscle DNA. We demonstrate that isolated congenital muscular upper limb overgrowth with aberrant hand muscles is another condition related genetically to the PIK3CA-related overgrowth spectrum.
Assuntos
Deformidades Congênitas da Mão/enzimologia , Deformidades Congênitas da Mão/genética , Músculo Esquelético/anormalidades , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Sequência de Bases , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Hipertrofia , Recém-Nascido , Imageamento por Ressonância Magnética , Dados de Sequência Molecular , Músculo Esquelético/patologia , RadiografiaRESUMO
Dynamin-2 is a pleiotropic GTPase whose best-known function is related to membrane scission during vesicle budding from the plasma or Golgi membranes. In the nervous system, dynamin-2 participates in synaptic vesicle recycling, post-synaptic receptor internalization, neurosecretion, and neuronal process extension. Some of these functions are shared with the other two dynamin isoforms. However, the involvement of dynamin-2 in neurological illnesses points to a critical function of this isoform in the nervous system. In this regard, mutations in the dynamin-2 gene results in two congenital neuromuscular disorders. One of them, Charcot-Marie-Tooth disease, affects myelination and peripheral nerve conduction, whereas the other, Centronuclear Myopathy, is characterized by a progressive and generalized atrophy of skeletal muscles, yet it is also associated with abnormalities in the nervous system. Furthermore, single nucleotide polymorphisms located in the dynamin-2 gene have been associated with sporadic Alzheimer's disease. In the present review, we discuss the pathogenic mechanisms implicated in these neurological disorders.