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OBJECTIVES: Myasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient. DESIGN: Prospective, observational, digital, longitudinal real-world study. SETTING: Adult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG. OUTCOME MEASURES: Data was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I-V). RESULTS: Baseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I-V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I-IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I-IV. CONCLUSIONS: MG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity.
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Miastenia Gravis , Qualidade de Vida , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Atividades Cotidianas , Estudos Prospectivos , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients. METHODS: Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited. RESULTS: Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30-57) years and most patients showed a limb-girdle (n = 26) or distal (n = 10) phenotype. However, compared with EO dysferlinopathy patients (n = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p = 0.01), and higher NSAD (p = 0.008) and ACTIVLIM scores (p = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; p = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p = 0.021), no differences in dysferlin protein expression were found on Western blot. CONCLUSIONS: Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.
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Proteínas Musculares , Distrofia Muscular do Cíngulo dos Membros , Adulto , Feminino , Humanos , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Estudos RetrospectivosRESUMO
Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies.
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Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Adulto , Feminino , Filaminas/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , FenótipoRESUMO
Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.
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Doenças Musculares/genética , Mutação/genética , Miotonia Congênita/genética , Retículo Sarcoplasmático/metabolismo , Adolescente , Adulto , ATPases Transportadoras de Cálcio/genética , Criança , Feminino , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Fenótipo , Adulto JovemRESUMO
INTRODUCTION: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. METHODS: We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. RESULTS: All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). DISCUSSION: Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.
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Potenciais de Ação/fisiologia , Eletrodiagnóstico/métodos , Músculo Esquelético/fisiopatologia , Miotonia Congênita/diagnóstico , Nervo Ulnar/fisiopatologia , Estimulação Elétrica , Eletromiografia , Teste de Esforço , Feminino , Humanos , Masculino , Mutação , Miotonia Congênita/genética , Miotonia Congênita/fisiopatologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genéticaRESUMO
Vascular involvement in Late Onset Pompe Disease, glycogen storage disease type II characterized by limb-girdle muscle and diaphragmatic weakness, is well documented. Abnormalities of posterior cerebral circulation have mostly been reported, whereas there are also cases of associated extracerebral arteriopathy. We report the case of a 42-year-old man diagnosed with LOPD a year after renal infarct due to renal artery fibromuscular dysplasia. We propose that the association of LOPD and arteriopathy should always be considered in clinical practice.
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Objectives: Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical-pathological changes and severity in a monocentric JDM cohort. Methods: Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty-six histopathological parameters were subjected to multivariate analysis. Results: Autoantibodies included anti-NXP2 (9/23), anti-TIF1γ (4/23), anti-MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ⩾ 20 (100.0% vs 25.0%); visual analogic score ⩾6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti-NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period. Conclusion: Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM.
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Adenosina Trifosfatases/imunologia , Autoanticorpos/imunologia , Proteínas de Ligação a DNA/imunologia , Dermatomiosite/complicações , Isquemia/etiologia , Músculo Esquelético/irrigação sanguínea , Adenosina Trifosfatases/metabolismo , Biomarcadores/metabolismo , Biópsia , Proteínas de Ligação a DNA/metabolismo , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Isquemia/diagnóstico , Isquemia/imunologia , Masculino , Músculo Esquelético/diagnóstico por imagem , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Research exploring the effects of physical exercise in auto-immune myasthenia gravis (MG) is scarce. The few existing studies present methodological shortcomings limiting the conclusions and generalisability of results. It is hypothesised that exercise could have positive physical, psychological as well as immunomodulatory effects and may be a beneficial addition to current pharmacological management of this chronic disease. The aim of this study is to evaluate the benefits on perceived quality of life (QOL) and physical fitness of a home-based physical exercise program compared to usual care, for patients with stabilised, generalised auto-immune MG. METHODS: MGEX is a multi-centre, interventional, randomised, single-blind, two-arm parallel group, controlled trial. Forty-two patients will be recruited, aged 18-70 years. Following a three-month observation period, patients will be randomised into a control or experimental group. The experimental group will undertake a 40-min home-based physical exercise program using a rowing machine, three times a week for three months, as an add-on to usual care. The control group will receive usual care with no additional treatment. All patients will be followed up for a further three months. The primary outcome is the mean change in MGQOL-15-F score between three and six months (i.e. pre-intervention and immediately post-intervention periods). The MGQOL-15-F is an MG-specific patient-reported QOL questionnaire. Secondary outcomes include the evaluation of deficits and functional limitations via MG-specific clinical scores (Myasthenia Muscle Score and MG-Activities of Daily Living scale), muscle force and fatigue, respiratory function, free-living physical activity as well as evaluations of anxiety, depression, self-esteem and overall QOL with the WHO-QOL BREF questionnaire. Exercise workload will be assessed as well as multiple safety measures (ECG, biological markers, medication type and dosage and any disease exacerbation or crisis). DISCUSSION: This is the largest randomised controlled trial to date evaluating the benefits and tolerance of physical exercise in this patient population. The comprehensive evaluations using standardised outcome measures should provide much awaited information for both patients and the scientific community. This study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02066519 . Registered on 13 January 2014.
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Terapia por Exercício/métodos , Tolerância ao Exercício , Músculo Esquelético/fisiopatologia , Miastenia Gravis/terapia , Adolescente , Adulto , Idoso , Terapia por Exercício/efeitos adversos , Feminino , França , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Miastenia Gravis/diagnóstico , Miastenia Gravis/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Aptidão Física , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento , Adulto JovemAssuntos
Eritrodermia Ictiosiforme Congênita/patologia , Erros Inatos do Metabolismo Lipídico/patologia , Músculo Esquelético/patologia , Doenças Musculares/patologia , Pele/patologia , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Biópsia , Criança , Éxons/genética , Feminino , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Eritrodermia Ictiosiforme Congênita/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Lipídeos/análise , Músculo Esquelético/química , Doenças Musculares/diagnóstico , Mutagênese Insercional , Coloração e RotulagemRESUMO
OBJECTIVES: To assess the value of major histocompatibility complex (MHC) class II antigen (HLA-DR) expression to distinguish anti-synthetase myopathy (ASM) from dermatomyositis (DM). METHODS: Muscle biopsies from patients with ASM (n = 33), DM without anti-synthetase antibodies (ASAb) (n = 17), and normal muscle biopsy (n = 10) were first reviewed. ASAb included anti-Jo1 (26/33), anti-PL12 (4/33), anti-PL7 (2/33), and anti-EJ (1/33). Immunohistochemistry was performed for MHC-I/HLA-ABC, MHC-II/HLA-DR, membrane attack complex (C5b-9), neural cell adhesion molecule (NCAM)/CD56 expression, and inflammatory cell subsets. Twenty-four ASM and 12 DM patients from another center were added for HLA-DR evaluation. RESULTS: Ubiquitous myofiber HLA-ABC expression was equally observed in ASM and DM (93.9% vs 100%, NS). In contrast, myofiber HLA-DR expression was found in 27/33 (81.8%) ASM (anti-Jo1: 23/26, 88.5%; others: 5/7, 71.4%) vs 4/17 (23.5%) DM patients (p < 0.001). HLA-DR was perifascicular in ASM, a pattern not observed in DM. In addition, C5b-9 deposition was observed on sarcolemma of non-necrotic perifascicular fibers in ASM, while, in DM, C5b-9was mainly detected in endomysial capillaries. CD8 cells were more abundant in ASM than in DM (p < 0.05), and electively located in perimysium or in perifascular endomysium. HLA-DR expression correlated positively with the CD8+ cells infiltrates. Strictly similar observations were made in the confirmatory study. CONCLUSION: ASM is characterized by strong myofiber MHC-II/HLA-DR expression with a unique perifascicular pattern, not described so far. HLA-DR detection must be included for routine myopathological diagnosis of inflammatory/dysimmune myopathies. HLA-DR expression in ASM may indicate a specific immune mechanism, possibly involving IFNγ.
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Dermatomiosite/metabolismo , Dermatomiosite/patologia , Antígenos HLA-DR/metabolismo , Miosite/metabolismo , Miosite/patologia , Adolescente , Adulto , Idoso , Biomarcadores , Feminino , Antígenos HLA/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Adulto JovemRESUMO
UNLABELLED: Macrophagic myofasciitis (MMF) is a specific histological lesion assessing the persistence of vaccine-derived aluminum oxyhydroxide in muscle tissue, at a site of previous immunization. Long-lasting MMF is usually detected in patients with arthromyalgias, chronic fatigue, and stereotyped cognitive dysfunction. MMF diagnosis requires muscle biopsy, an invasive procedure not suitable for the routine investigation of all patients with musculoskeletal pain. To help decision making in routine practice, we designed a retrospective analysis of 130 consecutive arthro-myalgic patients, previously immunized with aluminum-containing vaccines, in whom deltoid muscle biopsy was performed for diagnostic purposes. According to biopsy results, the patients were ascribed to either the MMF or the non-MMF group. MMF was diagnosed in 32.3% of the patients. MMF and non-MMF groups were similar according to both the injected vaccines and the delay between vaccination and biopsy. MMF patients had less frequent fibromyalgia than non-MMF patients (≥11 fibromyalgic tender points in 16.6 vs 55.5%, p < 0.04), and more often abnormal evoked potentials suggestive of CNS demyelination (38.5 vs 5.7%, p < 0.01). Predictive bioclinical scores based on simple variables such as the number of fibromyalgic tender points, arthralgias, and spinal pain, had sensitivity ranging from 50 to 88.1% and specificity from 36.4 to 76.1%. IN CONCLUSION: (i) most aluminum-containing vaccine receivers do not have long-lasting MMF in their muscle, but the prevalence of MMF among patients with arthromyalgia following immunization is substantial; (ii) patients with MMF have more CNS dysfunction and less fibromyalgic tender points than non-MMF patients; (iii) predictive scores may help to identify patients at high vs low risk of MMF.
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Artralgia/fisiopatologia , Fasciite/fisiopatologia , Fibromialgia/fisiopatologia , Dor Musculoesquelética/fisiopatologia , Miosite/fisiopatologia , Adolescente , Adulto , Idoso , Hidróxido de Alumínio/efeitos adversos , Artralgia/diagnóstico , Criança , Fasciite/induzido quimicamente , Fasciite/epidemiologia , Feminino , Fibromialgia/diagnóstico , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/diagnóstico , Miosite/induzido quimicamente , Miosite/epidemiologia , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Vacinas/química , Adulto JovemRESUMO
Myotonic dystrophy (DM) encompasses two gene defects, DM1 (myotonic dystrophy type 1) being currently the sole disorder leading to a childhood form of the disease. As consequence of the non coding unstable CTG repeat expansion mutation, DM1 presents as an extremely wide and diverse clinical continuum ranging from antenatal to late adult forms, the complexity of the disease being reinforced by multisystemic involvement. The congenital form appears as the most severe end of the phenotypic spectrum and may include marked neonatal hypotonia, respiratory failure, facial diplegia, contractures, and mental retardation. Brain involvement is the hallmark of childhood-onset DM1, distinguished by a normal neonatal period, with learning difficulties as the main presenting symptom, resulting from various degrees of mental delay, psychopathological manifestations, speech defects, hypersomnolence, and fatigue. In contrast, muscle weakness remains usually moderate in childhood, limited to facial weakness, ptosis, and dysarthria, until a decline from the second decade. Orthopedic manifestations including kyphoscoliosis and equinovarus may require surgery. Other organs involvement includes frequent abdominal symptoms, whereas endocrine disturbance is rare. Symptomatic cardiac arrhythmia, mainly exercise-induced, can be observed. While current treatment is mainly symptomatic, future clinical trials are expected following significant progress in pathophysiology and the recent development of molecular therapy approaches.
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Distrofia Miotônica/diagnóstico , Progressão da Doença , Humanos , Lactente , Mutação , Distrofia Miotônica/genética , Proteínas Serina-Treonina Quinases/genética , Índice de Gravidade de DoençaRESUMO
Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Processamento Alternativo/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Debilidade Muscular/genética , Distrofia Miotônica/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Linhagem Celular , Éxons/genética , Humanos , Camundongos , Debilidade Muscular/fisiopatologia , Distrofia Miotônica/fisiopatologia , Proteínas Nucleares/fisiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/fisiologia , Proteínas Supressoras de Tumor/fisiologiaRESUMO
The neuromuscular spindle (NMS) is a proprioceptive myofibrillar component of skeletal muscles that is necessary to maintain normal muscle tone and coordination. Recently, an excess of NMS has been reported as a congenital neuromuscular syndrome with a Noonan phenotype, now linked to Costello syndrome (CS). The vast majority of patients with CS have a de novo heterozygous mutation in the HRAS gene involved in the Ras/mitogen-activated protein kinase (MAPK) pathway. CS has many features in common with Noonan and cardiofaciocutaneous syndromes, also linked to activating mutations (but in other genes) of the Ras/MAPK pathway. This makes the orientation of molecular screening difficult. The observation of excess NMS in a 26-weeks'-gestation stillborn prompted us to screen the HRAS gene for mutation. The identification of a HRAS mutation made it possible to establish a diagnosis of CS. We conclude that the excess of NMS is the most reliable sign for the diagnosis of CS. Our findings also show the instrumental role of histological study of the skeletal muscles in the context of polyhydramnios and fetal hydrops.
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Síndrome de Costello/patologia , Fusos Musculares/patologia , Síndrome de Costello/genética , Feminino , Feto , Humanos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
In contrast with Steinert's disease (DM1), type 2 muscular dystrophy (DM2) is not known to be associated with a high prevalence of cardiac involvement. Our objective was to compare the results of detailed cardiac investigations in populations of DM2 and DM1 patients, and in controls. Thirty-eight DM2 patients (17 males; age=57.1+/-15.2years) were investigated for possible heart involvement, and their results compared with 76 age-sex matched DM1 patients and 76 controls. Cardiac abnormalities were present in 15 DM2 patients, including conductive defects in 14, systolic dysfunction in 6, supraventricular arrhythmias in 6 and stroke in 5 patients and were significantly more frequent than in controls. When compared to DM1 patients, conductive defects were less frequent, supraventricular arrhythmias had similar prevalence and there was a trend towards more frequent left ventricular dysfunction in DM2 patients. Our study suggests that systematic cardiac investigations should be recommended in these patients.
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Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/fisiopatologia , Transtornos Miotônicos/epidemiologia , Transtornos Miotônicos/fisiopatologia , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/fisiopatologia , Adulto , Idoso , Arritmias Cardíacas/diagnóstico , Estudos de Casos e Controles , Comorbidade , Ecocardiografia/normas , Eletrocardiografia/normas , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos , Parada Cardíaca/etiologia , Parada Cardíaca/metabolismo , Parada Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Transtornos Miotônicos/genética , Prevalência , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Disfunção Ventricular Esquerda/diagnósticoRESUMO
Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.
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Proteínas de Membrana/genética , Proteínas Musculares/genética , Mutação/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Disferlina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico , Distrofias Musculares/genéticaRESUMO
The diagnosis of Type 2 myotonic dystrophy (DM2/proximal myotonic myopathy) is often overlooked because of a nonspecific clinical presentation and muscle biopsy findings of a "denervation-like" pattern of unknown specificity that combines increased fiber size variation, central nucleation, small angulated fibers, Type 2 fiber atrophy, and nuclear clumps. We determined the presence of these features in 104 patients designated as having an unidentified myopathy from a series of 2,100 muscle biopsies. Because CCUG expansions form pathogenic ribonuclear accumulations that can be detected by in situ hybridization, we validated and then used automated (CCUG)8 in situ hybridization as a reference standard to evaluate the value of each histologic feature for DM2 detection, identifying 8 DM2-positive and 96 DM2-negative cases. Multivariate analyses identified the combination of Type 2 fiber atrophy and central nucleation as the most predictive of DM2 (sensitivity, 1.0; specificity, 0.92). These features were mutually exclusive in non-DM2 patients (p < 0.0001). The relevance of this combination of features was confirmed in an additional independent series (15 DM2-positive vs 17 DM2-negative). Further investigation revealed that central nucleation selectively affects Type 2 fibers in DM2 and, conversely, that it affects Type 1 fibers in DM1 (p < 0.0001). These results will facilitate the routine detection of DM2 and further support the concept that DM2 has a distinct pathophysiology involving type 2 myofibers.
Assuntos
Núcleo Celular/patologia , Fibras Musculares de Contração Rápida/patologia , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Proteínas de Ligação a RNA/genética , Idoso , Análise de Variância , Atrofia/genética , Atrofia/patologia , Expansão das Repetições de DNA/genética , Feminino , Humanos , Hibridização In Situ/métodos , Masculino , Pessoa de Meia-Idade , Fibras Musculares de Contração Rápida/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Genetically engineered mice (Myf5nLacZ/+, Myf5GFP-P/+) allowing direct muscle satellite cell (SC) visualization indicate that, in addition to being located beneath myofiber basal laminae, SCs are strikingly close to capillaries. After GFP(+) bone marrow transplantation, blood-borne cells occupying SC niches previously depleted by irradiation were similarly detected near vessels, thereby corroborating the anatomical stability of juxtavascular SC niches. Bromodeoxyuridine pulse-chase experiments also localize quiescent and less quiescent SCs near vessels. SCs, and to a lesser extent myonuclei, were nonrandomly associated with capillaries in humans. Significantly, they were correlated with capillarization of myofibers, regardless to their type, in normal muscle. They also varied in paradigmatic physiological and pathological situations associated with variations of capillary density, including amyopathic dermatomyositis, a unique condition in which muscle capillary loss occurs without myofiber damage, and in athletes in whom capillaries increase in number. Endothelial cell (EC) cultures specifically enhanced SC growth, through IGF-1, HGF, bFGF, PDGF-BB, and VEGF, and, accordingly, cycling SCs remained mainly juxtavascular. Conversely, differentiating myogenic cells were both proangiogenic in vitro and spatiotemporally associated with neoangiogenesis in muscular dystrophy. Thus, SCs are largely juxtavascular and reciprocally interact with ECs during differentiation to support angio-myogenesis.
Assuntos
Capilares/citologia , Células Endoteliais/fisiologia , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/fisiologia , Adulto , Idoso , Animais , Bromodesoxiuridina/metabolismo , Capilares/fisiologia , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Células Endoteliais/citologia , Endotélio Vascular/citologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/isolamento & purificação , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/citologia , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Neovascularização Fisiológica , Ratos , Células Satélites de Músculo Esquelético/efeitos dos fármacosRESUMO
UNLABELLED: This study reports a family affected by a new phenotype associated with dilated cardiomyopathy and quadriceps myopathy. METHODS: 29 family members underwent a physical and neurological examination, including an electromyogram and biopsy of muscle abnormalities. A cardiac examination was performed in all subjects. RESULTS: The family pedigree (n=72) demonstrated that transmission was autosomal dominant. Eleven subjects had cardiac involvement, only four had quadriceps muscle involvement. Cardiac impairment preceded neurological involvement. The mean age for neurological involvement was 44+/-0.8 years (range 43-45) and cardiac involvement was 37+/-7.9 years (range: 24-45). Cardiac involvement consisted of: hypokinetic dilated cardiomyopathy (64%); atrial fibrillation (100%); ventricular arrhythmias (64%); impaired conduction with bundle branch or complete atrio ventricular block (73%). Four patients required pacemakers and anti arrhythmic therapies. Four patients died: two of refractory heart failure and two of sudden death; two patients were resuscitated following cardiac arrest. Three patients required a prophylactic implantable cardiac defibrillator (ICD). Muscle morphological abnormalities were characterized by a variable number of fibers with rimmed vacuoles. The quadriceps deteriorated progressively without impairment of other muscles. Genotypic study showed a lamin A/C gene mutation. CONCLUSIONS: This family was affected by a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or arrhythmias and quadriceps myopathy. Cardiac abnormalities preceded neuromuscular disorders and defined the prognosis of this disease.
Assuntos
Cardiomiopatia Dilatada/genética , Lamina Tipo A/genética , Doenças Musculares/genética , Mutação , Músculo Quadríceps , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Once escaped from the quiescence niche, precursor cells interact with stromal components that support their survival, proliferation, and differentiation. We examined interplays between human myogenic precursor cells (mpc) and monocyte/macrophages (MP), the main stromal cell type observed at site of muscle regeneration. mpc selectively and specifically attracted monocytes in vitro after their release from quiescence, chemotaxis declining with differentiation. A DNA macroarray-based strategy identified five chemotactic factors accounting for 77% of chemotaxis: MP-derived chemokine, monocyte chemoattractant protein-1, fractalkine, VEGF, and the urokinase system. MP showed lower constitutive chemotactic activity than mpc, but attracted monocytes much strongly than mpc upon cross-stimulation, suggesting mpc-induced and predominantly MP-supported amplification of monocyte recruitment. Determination of [3H]thymidine incorporation, oligosomal DNA levels and annexin-V binding showed that MP stimulate mpc proliferation by soluble factors, and rescue mpc from apoptosis by direct contacts. We conclude that once activated, mpc, which are located close by capillaries, initiate monocyte recruitment and interplay with MP to amplify chemotaxis and enhance muscle growth.