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M Fardeau

Publications and source records attributed to M Fardeau.

At least 73 records · Page 4Linked to original sources
PubMed1998

A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.

Desmin-related myopathies (DRM) are inherited neuromuscular disorders characterized by adult onset and delayed accumulation of aggregates of desmin, a protein belonging to the type III intermediate filament family, in the sarcoplasma of skeletal and cardiac muscles. In this paper, we have mapped the locus for DRM in a large French pedigree to a 26-cM interval in chromosome 11q21-23. This region contains the alphaB-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle. AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity. We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family. Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alphaB-crystallin as observed in muscle fibers from DRM patients. These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder.

Animals↗
PubMed1998

Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy.

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.

Adult↗
PubMed1998

Matrix metalloproteinases MMP-2 and MMP-9 in denervated muscle and injured nerve.

Nerve crush or axotomy results in a transient or longterm denervation accompanied by remodelling in nerve, muscle and neuromuscular junctions. These changes include an increased turnover of several extracellular matrix molecules and proliferation of Schwann cells in injured nerves. Given the role of matrix degrading metalloproteinases MMP-2 and MMP-9 (gelatinases-type IV collagenases) in extracellular matrix remodelling, we investigated their regulation and activation in denervated muscles and injured nerves in mice. For this, immunofluorescence using MMP-2 and MMP-9 antibodies was carried concomitantly with gelatin zymography and quantification of gelatinase activity using [3H]-gelatin substrate. Results show that in normal mouse muscles MMP-2 and MMP-9 are localized at the neuromuscular junctions, in Schwann cells and the perineurium of the intramuscular nerves. In denervated mouse muscles, MMP-2 immunolabelling persists at the neuromuscular junctions but decreases in the nerves whereas MMP-9 immunolabelling persists at the neuromuscular junctions but is enhanced in degenerated intramuscular nerves. Denervated muscles did not show any significant change of gelatinolytic activity or expression pattern, while injured nerves exhibited a transient increase of MMP-9 and activation of MMP-2. In conclusion, this study demonstrates that MMP-2 and MMP-9 are expressed at mouse neuromuscular junctions and that their localization and expression pattern appear not to be modified by denervation. Their modulation in injured nerves suggests they are involved in axonal degeneration and regeneration.

Animals↗
PubMed1998

Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36.

Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin alpha2 chain (or merosin), has been identified in these disorders. Mutations in LAMA2 cause CMD with complete or partial merosin deficiency, detectable by immunocytochemistry on muscle biopsies, and account for approximately 50% of CMD cases. In a large consanguineous family (11 siblings) comprising three children affected by CMD without merosin deficiency, we undertook a genomewide search by homozygosity mapping and analyzed 380 microsatellite markers. The affected children were homozygous for several markers on chromosome 1p35-36. We identified two additional consanguineous families with affected children who also showed linkage to this locus. A maximum cumulative LOD score of 4.48, at a recombination fraction of .00, was obtained with D1S2885. A consistent feature in these three families was the presence of early rigidity of the spine, scoliosis, and reduced vital capacity, as found in rigid-spine syndrome (RSS). This study is the first description of a locus for a merosin-positive CMD and will help to better define the nosology of RSS.

Adolescent↗
PubMed1998

Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic).

Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic). It is characterized by onset in childhood, generalized weakness increased by exertion, refractoriness to anticholinesterase drugs, and morphological abnormalities of the neuromuscular junctions (NMJs). The collagen-tailed form of AChE, which is normally concentrated at NMJs, is composed of catalytic tetramers associated with a specific collagen, COLQ. In CMS-Ic patients, these collagen-tailed forms are often absent. We studied a large family comprising 11 siblings, 6 of whom are affected by a mild form of CMS-Ic. The muscles of the patients contained collagen-tailed AChE. We first excluded the ACHE gene (7q22) as potential culprit, by linkage analysis; then we mapped COLQ to chromosome 3p24.2. By analyzing 3p24.2 markers located close to the gene, we found that the six affected patients were homozygous for an interval of 14 cM between D3S1597 and D3S2338. We determined the COLQ coding sequence and found that the patients present a homozygous missense mutation, Y431S, in the conserved C-terminal domain of COLQ. This mutation is thought to disturb the attachment of collagen-tailed AChE to the NMJ, thus constituting the first genetic defect causing CMS-Ic.

Acetylcholinesterase↗
PubMed1998

Hereditary inclusion body myopathies.

Hereditary inclusion body myopathies comprise autosomal recessive and autosomal dominant muscle disorders that have a variable clinical phenotype but share similar morphological features. These include rimmed vacuoles within muscle fibres and collections of intrasarcoplasmic and intranuclear tubulofilamentous inclusions, 16-18 nm in external diameter. The resemblances and the differences between the sporadic and the hereditary inclusion body myopathies are discussed. Recent advances in the identification of various proteins involved in these diseases are mentioned because they have provided better insight into their underlying pathophysiological mechanisms. Linkage studies have allowed the localization of the genetic defect of some hereditary inclusion body myopathies and related disorders, contributing to their individualization.

Genes, Dominant↗
PubMed1998

PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy.

Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the laminin alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy.

Child↗
PubMed1998

Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance.

Autosomal-dominant and -recessive myotonia congenita are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). We searched for mutations in this gene in 20 unrelated families with myotonia congenita. We identified 11 different mutations in 10 families. Two of five new mutations (Ala313Thr and Ile556Asn) were both autosomal recessive and dominant with either reduced penetrance or incomplete dominance. Mutations in the CLCN1 gene do not therefore necessarily behave in a classic Mendelian manner.

Adult↗
PubMed1998

Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy.

In a series of 100 patients exhibiting clinical and molecular features of facioscapulohumeral muscular dystrophy (FSHMD), five patients had conduction defects or arrhythmia in the absence of cardiovascular risk factors--namely, intraventricular conduction delay and supraventricular arrhythmia induced by electrophysiologic investigations (two patients), palpitations associated with supraventricular arrhythmia (one patient), severe atrioventricular block leading to pacemaker implantation (one patient), and ventricular tachycardia related to arrhythmogenic right ventricular cardiomyopathy (one patient). Patients with FSHMD may have cardiac involvement.

Adolescent↗
PubMed1998

[Functional imaging of human muscle].

Medical imaging is now giving access not only to anatomy but also to functions of organs in the human body. Functional imaging may yield a direct appreciation of the function of a given organ, as is the case when measuring ejection fraction of heart with SPECT. Alternately the approach is indirect. This is the case of cerebral functional imaging, either with PET or NMR, where the perfusion increase induced by neuronal activity is detected. Recent developments of NMR, combining imaging and spectroscopy, allow now to detect modification of physiological parameters induced by muscular activity. Indirect detection of muscle activity is very rich in information alternately requiring invasive techniques. Water shifts resulting from intense exercise are detected either from muscle volume increase or water signal modifications, using simple NMR sequences. Then it is easy to identify which muscle is involved in a given protocol. These water shifts, studied in various muscles and several types of exercise protocols, reflect the perfusion increase induced by exercise, and the contribution of metabolic products such as lactate. In some patients with metabolic myopathies a decreased adaptation of perfusion has been detected. Perfusion measurements, previously performed by using venous occlusion plethysmography or radioactive tracers, now benefit from recently developed MR techniques. Oxygenation of muscle may be measured either by spectroscopy of myoglobin, allowing a time resolution of 1 second, or by spectroscopic imaging allowing a spatial resolution of 1-2 cm in a few minutes. Muscle temperature may be non invasively monitored by diffusion-weighted MR. Direct detection of muscle activity is useful only in those muscles that cannot be directly observed. Ultrafast MR imaging may be used to study vocal cords or oculomotor muscles. More interesting is the measurement of contractility, either in myocardium or skeletal muscle, allowed by MR with spin-tagging. Another contribution of MR to muscle studies is the possibility to quantify muscle cross section and muscle volume, in order to normalize strength or metabolism measurements. Sequences using T1 or T2 differences between muscular and adipose tissue allow to quantify the true muscular volume in patients with neuromuscular disorders. Protocols combining several of these parameters by interleaved NMR measurements of perfusion, phosphorylated metabolites, lactate, myoglobin, now open the way to many comprehensive non-invasive pathophysiological studies.

Body Water↗
PubMed1997

Glycogen-storage disease type II (acid maltase deficiency): identification of a novel small deletion (delCC482+483) in French patients.

Glycogen-storage disease type II (GSD II, acid maltase deficiency, Pompe's disease) is caused by defects in the lysosomal acid alpha-glucosidase (GAA) gene. Clinically, patients with the severe infantile form of GSD II have muscle weakness and cardiomyopathy eventually leading to death before the age of two years. Patients with the juvenile or the adult form of GSD II present with myopathy with a slow progression over several years or decades. Apart from a common base substitution in intron1, designated IVS1(-13T-->G) and resulting in the aberrant splicing of exon 2, the other mutations recently discovered in the GAA gene are rare and often unique to single patients. In this paper, we identified a two-base frameshift deletion in three unrelated adult-onset GSD II patients. This small deletion lies in the first coding exon (exon 2) and results in a premature stop codon at the very 5' end of the coding sequence of the GAA gene. The three patients were compound heterozygotes and two of them had the common IVS1(-13G-->T) mutation on the second allele. We speculate that this novel deletion may be relatively frequent among French patients, possibly leading to the severe infantile phenotype of GSD II if it occurs in homozygous form.

Adult↗
PubMed1997

X-linked vacuolated myopathy: membrane attack complex deposition on muscle fiber membranes with calcium accumulation on sarcolemma.

Cytochemical localization of calcium on muscle fibers from patients with X-linked vacuolated myopathy demonstrated strong sarcolemmal or vacuolar calcium deposits in histologically abnormal muscle fibers. All membrane attack complex-positive fibers demonstrated such calcium accumulation. Total content of calcium was significantly elevated in muscles from patients with X-linked vacuolated myopathy compared to control muscles. Taken together, these results suggest that calcium accumulation on sarcolemma could be probably secondary to membrane attack complex deposition on the cell surface.

Calcium↗
PubMed1997

Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

Adult↗
PubMed1997

Transaction costs economics as a conceptual framework for the analysis of barriers to the diffusion of telemedicine.

Telemedecine has been talked about for more than 20 years, without it entering daily use with any success. Based on transaction costs economics, the present analysis of the exchange relationships between health care producers highlights certain characteristics of the current technical and legislative context, which leads to transaction costs. It also demonstrates that the introduction of telemedicine shifts the costs associated with agents' opportunism from patients to health-care producers themselves. All these costs may be considered nowadays to thwart the use of telemedicine. It is argued here that the Public Authorities and professionals of health care could act upon telemedicine in two fields: (1) intervention in the institutional environment aims notably at better defining the property rights of telemedicine, and so constitutes an unavoidable means of encouraging health-care producers to invest in new technology; and (2) implementation of organisational forms and mechanisms susceptible to regulating such telemedical relationships between health care producers-given the present institutional environment-constitutes an essential means for overcoming the immediate barriers blocking the diffusion of telemedicine.

Communication Barriers↗
PubMed1997

Oculopharyngeal muscular dystrophy in France.

The clinical, histopathological, ultrastructural and geographical data on 29 cases of oculopharyngeal muscular dystrophy (OPMD) identified by the authors in France is briefly presented. The mean age of the patients was 53.8 +/- 8.1 years. Onset symptoms were ptosis (14/29), dysphagia (12/29) and limb girdle weakness (3/29). The evolution of the disease was always progressive and followed different clinical patterns. The main histological changes in muscle biopsies were atrophic angulated fibers (29/29) and rimmed vacuoles (25/29); muscle fiber necrosis was very rare (1/29). The characteristic nuclear inclusions made of 8.5-nm filaments were observed in all cases, and found in 2-5% of the nuclei in a given ultrathin section. They are the morphological marker of the disease.

Adult↗
PubMed1997

Genealogical study of oculopharyngeal muscular dystrophy in France.

This work is based on 54 probands affected by oculopharyngeal muscular dystrophy (OPMD). The muscle biopsy of all these patients showed the presence of the intranuclear inclusions, specific of this disease. The residence of the probands is concentrated in three clusters: the Paris, Marseilles and Bordeaux regions. The genealogical study was carried out on 43 probands, 10 of which did not have any ascendance in France for more than two generations. The geographic origin of the 33 patients of French descent was distributed over numerous regions, not including the Paris and Marseilles regions where many patients lived. This geographic dispersion and the rarity of common genealogies of the probands, did not suggest the existence of a recent founder effect, in contrast to what is observed in the French-Canadian community. The existence of a link between French and French-Canadian families is currently being investigated.

Family Health↗
PubMed1997

Morphological changes in muscle fibers in oculopharyngeal muscular dystrophy.

The study of muscle biopsies of 29 cases of oculopharyngeal muscular dystrophy (OPMD) showed the two main morphological features of this disease: rimmed vacuoles (in 26 cases) and intranuclear inclusions (in all cases). These inclusions are made of 8.5 nm tubular filaments and the areas occupied by them are lighter than the surrounded nucleoplasm. This can be seen by light microscopy, facilitating the detection of the tubulo-filamentous inclusions which can only be identified with certitude by electron microscopy. In a given ultrathin section the area occupied by these inclusions varied from 2% to 5% of the nuclei. The intranuclear inclusions are the morphological marker of OPMD and their finding in a muscle biopsy allows the exact diagnosis of this disease. The origin and biochemical nature of the intranuclear inclusions is unknown.

Adult↗