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Biomedical subjects

Bruno Eymard

Publications and source records attributed to Bruno Eymard.

At least 19 recordsLinked to original sources
PubMed2007

Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies.

Myofibrillar myopathy (MFM) encompasses a genetically heterogeneous group of human diseases caused by mutations in genes coding for structural proteins of muscle. Mutations in the intermediate filament (IF) protein desmin (DES), a major cytoskeletal component of myocytes, lead to severe forms of "desminopathy," which affects cardiac, skeletal, and smooth muscle. Most mutations described reside in the central alpha-helical rod domain of desmin. Here we report three novel mutations--c.1325C>T (p.T442I), c.1360C>T (p.R454W), and c.1379G>T (p.S460I)--located in desmin's non-alpha-helical carboxy-terminal "tail" domain. We have investigated the impact of these and four--c.1237G>A (p.E413K), c.1346A>C (p.K449T), c.1353C>G (p.I451M), and c.1405G>A (p.V469M)--previously described "tail" mutations on in vitro filament formation and on the generation of ordered cytoskeletal arrays in transfected myoblasts. Although all but two mutants (p.E413K, p.R454W) assembled into IFs in vitro and all except p.E413K were incorporated into IF arrays in transfected C2C12 cells, filament properties differed significantly from wild-type desmin as revealed by viscometric assembly assays. Most notably, when coassembled with wild-type desmin, these mutants revealed a severe disturbance of filament-formation competence and filament-filament interactions, indicating an inherent incompatibility of mutant and wild-type protein to form mixed filaments. The various clinical phenotypes observed may reflect altered interactions of desmin's tail domain with different components of the myoblast cytoskeleton leading to diminished biomechanical properties and/or altered metabolism of the individual myocyte. Our in vitro assembly regimen proved to be a very sensible tool to detect if a particular desmin mutation is able to cause filament abnormalities.

Adult↗
PubMed2006

Sleep disorders in childhood-onset myotonic dystrophy type 1.

Slowness, fatigue, and learning difficulties are common in young patients with myotonic dystrophy type 1. These features may indicate poor sleep quality. The aim of this study was to search for sleep disorders in this population. This prospective study used questionnaires, genetic testing, night-time polysomnography and multiple sleep latency tests to evaluate objective daytime sleepiness. Twenty-one patients were included. Mean age was 15.0+/-3.0. Age of onset of myotonic disorders was after birth and before 10 years old. Age of diagnosis was 12.0+/-2.9. Fatigue was reported by 76% of patients, while somnolence was present in 52%. Sleep was disturbed by numerous microarousals (mean 16.6+/-7.3/h of sleep) caused by abnormal respiratory events (6/21 patients) and/or periodic limb movements (8/21 patients). In young patients with DM1, complaints of fatigue and/or somnolence should lead to a polysomnography to look for sleep apnea syndrome and/or periodic limb movement, which were present in two-thirds of our population.

Adolescent↗
PubMed2006

Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy.

Centronuclear myopathy (CNM) is a slowly progressive congenital myopathy characterized by abnormal centrally located nuclei in a large number of muscle fibres. Recently, different missense mutations affecting the middle domain of the dynamin 2 (DNM2) have been shown to cause autosomal dominant CNM. In order to better define the phenotype of DNM2-related CNM, we report here on the clinical and muscle imaging findings of 10 patients harbouring DNM2 mutations. DNM2-CNM is characterized by slowly progressive muscular weakness usually beginning in adolescence or early adulthood. In addition to bilateral ptosis, our data show that distal muscle weakness often exceeds proximal involvement. Furthermore, electrophysiological investigations frequently demonstrated signs of mild axonal peripheral nerve involvement, and electromyographical examination may show neuropathic changes in addition to the predominant myopathic changes. These features overlap with findings seen in the phenotype of DNM2-related autosomal dominant Charcot-Marie-Tooth disease type 2B. In all 10 DNM2-CNM patients, muscle computer tomography assessment showed a consistent pattern of muscular involvement and a characteristic temporal course with early and predominant distal muscle involvement, and later affection of the posterior thigh compartment and gluteus minimus muscles. The recognition of this specific imaging pattern of muscle involvement--distinct to the reported patterns in other congenital myopathies--may enable a better selection for direct genetic testing.

Adolescent↗
PubMed2006

Shared blood and muscle CD8+ T-cell expansions in inclusion body myositis.

Inclusion body myositis (IBM) is the most frequent inflammatory myopathy over the age of fifty. Pathological findings suggest that two processes may contribute to IBM pathogenesis: a primary degenerative process affecting muscle fibre and/or an autoimmune process mediated by major histocompatibility complex (MHC) class-I-restricted cytotoxic CD8+ T cells. Previous studies have demonstrated that muscle-infiltrating CD8+ T cells in IBM display restricted expression of T-cell receptor (TCR)-BV families or evidenced oligoclonal T-cell expansions. This study was performed to investigate whether blood T cells similarly exhibit clonal expansions due to the recirculation of muscle-infiltrating T cells in the periphery. For this, we studied the T-cell repertoire of 17 IBM patients by complementarity-determining-region (CDR) 3 length distribution (immunoscope) analysis of TCR-B transcripts. Mean age was 68 years (range 53-88) and mean duration of the disease was 6.5 years (2-20). Oligoclonal T-cell expansions were observed in the blood of IBM patients. The quantitative average perturbation D index was significantly increased in IBM patients [D = 13.7% +/- 1.2%, mean +/- standard error of measurement (SEM)] as compared with 17 age-matched controls suffering from connective tissue diseases not associated with T-cell repertoire perturbation, that is, dermatomyositis (DM) and systemic sclerosis (9.3 +/- 0.6%, P < 0.005). Nevertheless, there was no correlation between the level of blood perturbation and muscle inflammation. Sorting experiments showed that these perturbations were due to oligoclonal expansions of CD8+ T cells. In the three IBM patients analysed, we could relate the blood expansions to T-cell clones also found in muscle. The clonally expanded blood T cells dramatically responded to interleukin-2 (IL-2) in vitro, suggesting that they had been primed in vivo, presumably in response to yet unknown muscle auto-antigens. Together, our results indicate that clonally expanded muscle-infiltrating CD8+ T cells re-circulate in the blood and support the concept of a CD8+ T-cell-mediated autoimmune component in IBM, similarly to what is observed in polymyositis (PM).

Aged↗
PubMed2006

Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis.

OBJECTIVE: Our objective was to investigate a role of the intracellular tyrosine phosphatase PTPN22*R620W variant in autoimmune myasthenia gravis (MG), considering disease heterogeneity. METHODS: We used a case-control design, comparing 470 patients and 296 controls, all French whites. Patients were categorized depending on the presence of a thymoma and serum anti-titin antibodies. RESULTS: The 620W risk allele was increased in 293 nonthymoma patients without anti-titin antibodies (odds ratio, 1.97; 95% confidence interval, 1.32-2.97, p = 0.00059) but not in nonthymoma patients with anti-titin antibodies or in thymoma patients. INTERPRETATION: Our genetic findings strengthen the concept that these groups of patients correspond to etiologically distinct disease entities.

Adult↗
PubMed2006

Cold extends electromyography distinction between ion channel mutations causing myotonia.

OBJECTIVE: Myotonias are inherited disorders of the skeletal muscle excitability. Nondystrophic forms are caused by mutations in genes coding for the muscle chloride or sodium channel. Myotonia is either relieved or worsened by repeated exercise and can merge into flaccid weakness during exposure to cold, according to causal mutations. We designed an easy electromyography (EMG) protocol combining repeated short exercise and cold as provocative tests to discriminate groups of mutations. METHODS: Surface-recorded compound muscle action potential was used to monitor muscle electrical activity. The protocol was applied on 31 unaffected control subjects and on a large population of 54 patients with chloride or sodium channel mutations known to cause the different forms of myotonia. RESULTS: In patients, repeated short exercise test at room temperature disclosed three distinct abnormal patterns of compound muscle action potential changes (I-III), which matched the clinical symptoms. Combining repeated exercise with cold exposure clarified the EMG patterns in a way that enabled a clear correlation between the electrophysiological and genetic defects. INTERPRETATION: We hypothesize that segregation of mutations into the different EMG patterns depended on the underlying pathophysiological mechanisms. Results allow us to suggest EMG guidelines for the molecular diagnosis, which can be used in clinical practice.

Action Potentials↗
PubMed2006

Long-term results of cricopharyngeal myotomy in oculopharyngeal muscular dystrophy.

OBJECTIVE: To analyze long-term results of extramucosal cricopharyngeal myotomy in oculopharyngeal muscular dystrophy. STUDY DESIGN: The preoperative and postoperative evaluations including symptoms, type of feeding, weight, and functional examinations were retrospectively evaluated in 39 patients. Results were defined postoperatively as successful, partial, or failed. SETTING: University hospital. RESULTS: In the short term, 25 patients showed a complete remission of symptoms, 10 showed a marked improvement, and 4 exhibited no improvement at all (success rate of 90%). Long-term evaluation during a mean follow-up of 4 years showed that of the 35 improved patients, 12 exhibited a recurrence of dysphagia (mean time of 39 months). In 3 of these 12 patients, a revision transmucosal endoscopic cricopharyngeal myotomy was performed with a successful outcome in 2. Of the 4 patients who initially showed no improvement, 1 was improved by transmucosal myotomy. CONCLUSION: Extramucosal cricopharyngeal myotomy improves dysphagia in oculopharyngeal muscular dystrophy patients during the first few years but one third of the patients exhibited a recurrence of symptoms within 3 years. Revision by transmucosal endoscopic myotomy may be performed. EBM RATING: C-4.

Aged↗
PubMed2006

Loss of podocyte dysferlin expression is associated with minimal change nephropathy.

We report a case of limb-girdle muscular dystrophy type 2B (LGMD2B) associated with minimal change disease. Immunohistochemical examination of quadriceps muscle showed a deficiency in dysferlin in sarcolemma, and dysferlin gene analysis showed 3370 G missense mutation, leading us to the diagnosis of LGMD2B. The patient also developed glomerular proteinuria. We also explored urinary protein levels in 3 other patients with dysferlinopathy and found microalbuminuria with albumin excretion of 0.14 to 0.18 g/d in 2 patients. Renal abnormalities during LGMD2B and kidney dysferlin expression have never been reported. Renal biopsy showed a lack of glomerular dysferlin expression compared with a positive immunohistochemical marking in patients with idiopathic minimal change nephropathy and healthy controls. We therefore suggest that dysferlin is present in glomeruli and may be associated with glomerular permeability.

Adult↗
PubMed2005

Mutations in dynamin 2 cause dominant centronuclear myopathy.

Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.

Actins↗
PubMed2005

Hsp27-2D-gel electrophoresis is a diagnostic tool to differentiate primary desminopathies from myofibrillar myopathies.

Small heat shock proteins prevent abnormal protein folding and accumulation. We analyzed the expression of hsp27 and alphaB-crystallin in skeletal muscle specimens of patients with desminopathies, plectinopathies, myotilinopathy, and other myofibrillar myopathies by means of differential centrifugation, 2D-gel electrophoresis, Western blotting, and mass spectrometry. Hsp27-P82 and -P15 as well as alphaB-crystallin-P59 and -P45 are the major serine phosphorylation isoforms in normal and diseased human skeletal muscle. 2D-gel-electrophoresis revealed spots of hsp27 in a range of pH 5.3-6.4 in samples of all skeletal muscle specimens, except for the seven desminopathies. They indicated a shift of the main hsp27-spot to alkaline pH degrees, which may help to differentiate primary desminopathies from other myopathies with structural pathology of the desmin cytoskeleton.

Amino Acid Sequence↗
PubMed2005

Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial.

BACKGROUND: The optimal dose of intravenous immunoglobulin (IVIG) in acute exacerbation of myasthenia gravis remains unknown. Increasing the treatment duration might provide added efficacy. OBJECTIVE: To determine the optimal dose of IVIG for treating myasthenia gravis exacerbation. DESIGN: Randomized double-blind placebo-controlled multicenter trial designed to demonstrate superiority of the 2 g/kg dose over the 1 g/kg dose of IVIG, conducted between November 13, 1996, and October 26, 2002. PARTICIPANTS: One hundred seventy-three patients aged 15 to 85 years with acute exacerbation of myasthenia gravis. INTERVENTION: Participants were randomly assigned to receive 1 g/kg of IVIG on day 1 and placebo on day 2 (group 1) vs 1 g/kg of IVIG on 2 consecutive days (group 2). MAIN OUTCOME MEASURE: Improvement in the myasthenic muscular score after 2 weeks. RESULTS: The mean improvements in the myasthenic muscular scores after 2 weeks were 15.49 points (95% confidence interval, 12.09-18.90 points) in group 1 and 19.33 points (95% confidence interval, 15.82-22.85 points) in group 2. However, the difference between the 2 groups was not significant (effect size, 3.84 [95% confidence interval, -1.03 to 8.71]; P = .12). CONCLUSION: This trial found no significant superiority of 2 g/kg over 1 g/kg of IVIG in the treatment of myasthenia gravis exacerbation.

Adolescent↗
PubMed2005

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies.

DYSF encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B, the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 34 unrelated patients from various ethnic origins. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected. All together, 54 sequence variations were identified in DYSF, 50 of which predicting either a truncated protein or one amino-acid substitution and most of them (34 out of 54) being novel. In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."

Child↗
PubMed2005

Exercise tolerance and daily life in McArdle's disease.

McArdle's disease is a common disorder of muscle metabolism and is due to myophosphorylase deficiency. The major complaint of patients with this disease is effort intolerance. Although the clinical features of affected patients are well known, their daily lifestyle is not well documented. The main objective of this work was to assess their mean daily energy expenditure (DEE) and compare it with control subjects. Thirty patients and 87 control subjects completed a questionnaire. A 3-day self-record of daily physical activities was used to estimate the mean DEE for patients and control subjects. A separate section of the questionnaire was used to assess patients' clinical features and daily lifestyle. The DEE of patients (44.1 +/- 6.9 kcal/kg) was not significantly different from control subjects (44.5 +/- 5.6 kcal/kg). Half of the patients with McArdle's disease performed a daily physical leisure activity as sport, sometimes at a high level (17%). Despite large individual variation, physical abilities and patients' symptoms were negatively correlated. Physical leisure activity significantly decreased the sensation of muscle pain (P < 0.03). These findings show that patients with McArdle's disease do not have a strictly sedentary lifestyle. Moreover, physical exercise appears to have positive effects on the main clinical features, such as effort intolerance. Thus, regular, moderate physical activity may be beneficial in McArdle's disease.

Activities of Daily Living↗
PubMed2005

The origin of tubular aggregates in human myopathies.

Tubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation and role of which are still unclear, the present study reports the electron microscopic analysis and protein characterization of tubular aggregates in six patients with 'tubular aggregate myopathy'. Three of the six patients also presented with myasthenic features. A large panel of immunochemical markers located in the sarcoplasmic reticulum, T-tubules, mitochondria, and nucleus was used. Despite differences in clinical phenotype, the composition of tubular aggregates, which contained proteins normally segregated differently along the sarcoplasmic reticulum architecture, was similar in all patients. All of these proteins, calsequestrin, RyR, triadin, SERCAs, and sarcalumenin, are involved in calcium uptake, storage, and release. The dihydropyridine receptor, DHPR, specifically located in the T-tubule, was also present in tubular aggregates in all patients. COX-2 and COX-7 mitochondrial proteins were not found in tubular aggregates, despite being observed close to them in the muscle fibre. The nuclear membrane protein emerin was found in only one case. Electron microscopy revealed vesicular budding from nuclei, and the presence of SAR-1 GTPase protein in tubular aggregates shown by immunochemistry, in all patients, suggests that tubular aggregates could arise from endoplasmic reticulum exit sites. Taken together, these results cast new light on the composition and significance of tubular aggregates.

Adult↗
PubMed2005

[Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene].

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

Animals↗
PubMed2004

MUSK, a new target for mutations causing congenital myasthenic syndrome.

We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

Adult↗