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Biomedical subjects

M Fardeau

Publications and source records attributed to M Fardeau.

At least 127 records · Page 7Linked to original sources
PubMed1995

Thiosulfate reduction, an important physiological feature shared by members of the order thermotogales.

Several members of the order Thermotogales in the domain Bacteria, viz., Thermotoga neapolitana, Thermotoga maritima, Thermosipho africanus, Fervidobacterium islandicum, and Thermotoga strain SEBR 2665, an isolate from an oil well, reduced thiosulfate to sulfide. This reductive process enhanced cellular yields and growth rates of all the members but was more significant with the two hyperthermophiles T. neapolitana and T. maritima. This is the first report of such an occurrence in this group of thermophilic and hyperthermophilic anaerobic bacteria. The results suggest that thiosulfate reduction is important in the geochemical cycling of sulfur in anaerobic thermal environments such as the slightly acidic and neutral-pH volcanic hot springs and oil reservoirs.

Journal Article↗
PubMed1995

The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies.

Clinical differences exist between the three forms of myotubular myopathy. They differ regarding age at onset, severity of the disease, and prognosis, and also regarding some of the clinical characteristics. The autosomal dominant form mostly has a later onset and milder course than the X linked form, and the autosomal recessive form is intermediate in both respects. These differences are, however, quantitative rather than qualitative. Muscle biopsy studies of family members are useful in some cases, and immunohistochemical staining of desmin and vimentin may help distinguish between the X linked and autosomal forms. Determining the mode of inheritance and prognosis in individual families, especially those with a single male patient, still poses a problem. Current molecular genetic results indicate that the gene for the X linked form is located in the proximal Xq28 region. Further molecular genetic studies are needed to examine the existence of genetic heterogeneity in myotubular myopathy and to facilitate diagnosis.

DNA↗
PubMed1995

A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype.

We describe two adult siblings who had had mild GM2 gangliosidosis since childhood. They presented with spinal muscular atrophy and dysarthria, and one sibling also had mental disturbances. Laboratory studies established the diagnosis of the B1 variant of GM2 gangliosidosis, because the hexosaminidase (Hex) A deficiency was not present upon testing with the unsulfated synthetic substrate 4-methylumbelliferyl N-acetylglucosaminide. HEXA gene analysis proved that the patients are compound heterozygotes for the previously identified G533-->A mutation and for a new mutation, G1171-->A, at exon 11. This new mutation affects a conserved amino acid and results in a Val-->Met substitution at position 391 of the HEXA gene. Full sequence of the alpha-subunit cDNA of Hex A revealed no other mutation. Assays for Hex A activities in patients suspected of having GM2 gangliosidosis should be performed with the sulfated substrate 4-methylumbelliferyl N-acetylglucosamine 6-sulfate.

Adult↗
PubMed1995

Etiology and pathogenesis of the muscular dystrophies.

Despite intensive research efforts, the cause of the muscular dystrophies has remained elusive for many decades. In the late 1980s, major advances in molecular genetics have led to the discovery of the dystrophin gene and its protein product, dystrophin. Mutations in the dystrophin gene result in dystrophin deficiency, which constitutes the pathogenetic basis of Duchenne and Becker muscular dystrophy. This major breakthrough set the scene for the ongoing discovery of the molecular basis of the muscular dystrophies. Several muscular dystrophies are caused by mutations in specific genes, which lead to deficiency of structural proteins of the sarcolemma other than dystrophin and to enzymatic dysfunction. Other muscular dystrophies have been mapped to different chromosomal loci, and in most of them, the identification of the molecular defect is ongoing. The elucidation of the molecular basis of the muscular dystrophies has a major impact on the understanding of their pathogenetic mechanisms, their nosological classification, their diagnosis and prevention, and, for the first time, offers perspectives for the development of causal treatment strategies.

Chromosome Aberrations↗
PubMed1995

Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region.

A young girl with a clinically moderate form of myotubular myopathy was found to carry a cytogenetically detectable deletion in Xq27-q28. The deletion had occurred de novo on the paternal X chromosome. It encompasses the fragile X (FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49, DXS256, DXS258, DXS305, and DXS497) were found intact. As the X-linked myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage analysis, the present observation suggested that MTM1 is included in the deletion. However, a significant clinical phenotype is unexpected in a female MTM1 carrier. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Such unbalanced inactivation may account for the moderate MTM1 phenotype and for the mental retardation that later developed in the patient. This observation is discussed in relation to the hypothesis that a locus modulating X inactivation may lie in the region. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome phenotype but no myotubular myopathy, in light of recent linkage data on recombinant MTM1 families, led to a considerable refinement of the position of the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.

Adult↗
PubMed1994

Additional case of female monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy due to opposite X-chromosome inactivation.

A pair of female monozygotic (MZ) twins, heterozygous carriers for a deletion in the DMD gene and discordant for the clinical manifestations of Duchenne muscular dystrophy, were analyzed by molecular studies, in situ hybridization, and methylation pattern of X chromosomes to search for opposite X inactivation as an explanation of their clinical discordance. Results in lymphocytes and skin fibroblast cell lines suggest a partial mirror inactivation with the normal X chromosome preferentially active in the unaffected twin, and the maternal deleted X chromosome preferentially active in the affected twin. A review shows that MZ female twins discordant for X-linked diseases are not uncommon. Twinning and X inactivation may be interrelated and could explain the female twins discordant for X-linked traits.

Base Sequence↗
PubMed1994

[Severe cardiomyopathy revealing amylopectinosis. Two cases in adolescents from the same family].

Type IV glycogen storage disease, also termed Andersen's disease or amylopectinosis, is a rare autosomic recessive hereditary disease usually caused by a deficit in glycogen branching enzyme. We report our observation of two siblings with type IV glycogen storage disease who had normal branching enzyme activity. The initial symptom was severe heart failure. A 14-year-old boy, born to consanguinous parents, was seen for severe global heart failure. Growth retardation had been diagnosed since the age of 6 and abnormal fatigability since the age of 12. Muscle and endomyocardium biopsies revealed abnormal glycogen storage with normal branching enzyme activity. The patient's condition improved after symptomatic treatment, but death occurred due to infectious complications after orthoptic heart transplantation. One year later, the proband's 12-year-old sister, with an uneventful personal medical history, was hospitalized for severe left ventricular failure. Muscle and liver biopsies demonstrated the same anomalies, again without branching enzyme deficiency in the liver. Heart failure was controlled with symptomatic care and the patient's current condition remains satisfactory. This observation demonstrates the clinical expression of familial type IV glycogen storage disease in patients with normal branching enzyme activity. Age at onset is quite variable, reported from 5 to 70 years, as is the clinical course before diagnosis.

Adolescent↗
PubMed1994

Expression of dystrophin-associated proteins in dystrophin-positive muscle fibers (revertants) in Duchenne muscular dystrophy.

The dystrophin-glycoprotein complex spans the sarcolemma to provide a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix in skeletal muscle. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins in the sarcolemma, thus causing the disruption of the dystrophin-glycoprotein complex and the loss of the linkage to the extracellular matrix. This is presumed to lead to sarcolemmal instability which could render muscle fibers susceptible to necrosis. In DMD, a very small percentage of muscle fibers show dystrophin staining along the sarcolemma, presumably due to a second in-frame deletion in the dystrophin gene. However, the functional significance of these rare dystrophin-positive muscle fibers (revertants) in DMD has been unclear. Here we report the co-expression of the dystrophin-associated proteins with dystrophin in revertants of DMD skeletal muscle. Our results suggest that the entire dystrophin-glycoprotein complex is restored in revertants and, thus, the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix is restored in these muscle fibers.

Cytoskeletal Proteins↗
PubMed1994

Expression of a recombinant dystrophin in mdx mice using adenovirus vector.

Genetic deficiencies may be compensated by delivery of the appropriate gene to the affected tissue(s) by somatic gene transfer. In this study, recombinant adenoviruses (defective for replication) carrying a cDNA coding for a truncated dystrophin or 'minidystrophin' (Ad.dys), associated to adenoviruses carrying a beta-galactosidase reporter gene (Ad.beta gal), were administered locally to evaluate the biochemical correction of the genetic defect in mdx mice mutants. Both genes were placed under the control of muscle specific regulatory elements. Two weeks after a single intramuscular injection of Ad.dys, injected muscles showed a significant increase in the percentage of dystrophin positive fibres when compared to muscles either untreated or injected with Ad.beta gal only. Intramuscular injection of the adenoviral expression vectors elicited a local deleterious effect on muscle morphology, rarefaction of myofibres at the site of injection, calcifications and fibrosis were much more marked in comparison to control muscles injected with vehicle. beta-galactosidase was exclusively expressed within myofibres in a segmental fashion. Regional co-localization of beta-galactosidase and dystrophin expression gives further support to the demonstration of adenoviral induced expression of the recombinant genes.

Adenoviridae↗
PubMed1994

Expression of dystrophin-associated glycoproteins during human fetal muscle development: a preliminary immunocytochemical study.

An immunocytochemical study was performed on quadriceps muscle from eight fetuses ranging from 12 weeks of gestation to term, using antibodies against the dystrophin-associated proteins, in order to evaluate the developmental expression of these proteins. For comparison, antibodies against dystrophin and utrophin were also used. The expression of the 59 kDa dystrophin-associated protein was simultaneous with that of dystrophin, which is also a subsarcolemmal protein. The extracellular glycoprotein of 156 kDa (alpha-dystroglycan) and the transmembrane glycoprotein of 43 kDa (beta-dystroglycan) appeared to be expressed later. The transmembrane glycoproteins of 50 kDa (adhalin) and 35 kDa were fully expressed at an even later stage of fetal muscle development. This study suggests that the subsarcolemmal proteins may have an essential role in the assembly of the transmembrane and extracellular components of the dystrophin-glycoprotein complex during fetal muscle development. The knowledge obtained from observing the developmental expression of these proteins may contribute to the understanding of the molecular mechanism of their different involvement in muscle disorders.

Cytoskeletal Proteins↗
PubMed1994

Correlation between decreased myocardial glucose phosphorylation and the DNA mutation size in myotonic dystrophy.

BACKGROUND: Myotonic dystrophy, the most common form of adult dystrophy, has been shown to be caused by amplification of CTG triplet repeat in the 3' untranslated region of a protein kinase gene located on chromosome 19. Impaired glucose metabolism has been suggested as a possible explanation of brain and skeletal muscle involvement in this multisystem disease. We investigated whether myocardial glucose metabolism is impaired in myotonic dystrophy and whether this impairment is related to the size of the mutation. METHODS AND RESULTS: The myocardial metabolic rate for glucose (MMRGlu, mumol.min-1.g-1), K1 (blood-to-tissue transfer constant), k2 (tissue-to-blood transfer constant), and k3 (phosphorylation rate constant) were determined in 7 control subjects and 12 patients with myotonic dystrophy by using parametric images generated from dynamic cardiac positron emission tomography (PET) and 18F-fluoro-2-deoxy-glucose studies. The expansion of the CTG triplet repeats was analyzed in patients with the probe cDNA25 after EcoRI digestion. Nonparametric tests were used to compare quantitative variables between control subjects and patients. The correlations between the size of the mutation and PET parameters were studied by linear regression. MMRGlu and k3 were significantly decreased in patients compared with control subjects (0.39 +/- 0.20 versus 0.64 +/- 0.25, P = .03, and 0.09 +/- 0.07 versus 0.24 +/- 0.21, P = .03, respectively), whereas K1 and k2 were not statistically different between control subjects and patients. MMRGlu and k3 correlate inversely with the length of the CTG triplet repeat (r = -.65 and P = .03 for MMRGlu, and r = -.85 and P = .001 for k3, respectively). CONCLUSIONS: In myotonic dystrophy, the observed reductions in MMRGlu and phosphorylation are inversely linked to the length of the mutation. This observation suggests that impaired modulation of a protein kinase involved in myocardial hexokinase activation may give a pathophysiological schema to relate the molecular defect and the abnormal myocardial metabolism in myotonic dystrophy.

Adult↗
PubMed1994

[Muscular reconstruction by myogenic cell graft].

We have developed an experimental model to test the ability of cultured satellite cells to form new muscle fibers when grafted in an irreversibly injured muscle. Association of X-irradiation to autotransplantation reduced extensor digitorum longus muscles of adult rats to a cystic structure formed by a peripheral rim of surviving muscle fibers surrounding a central space devoid of myofibers. Grafting autologous satellite cells, multiplied and labelled in vitro, into this central space gave rise to new myotubes which developed and matured to form fully differentiated myofibers. Mecanophysiological recordings confirmed the improvement of functional parameters particularly a 4 fold increase of twitch and tetanic tensions in grafted muscles. Furthermore, we examined the role of old basal lamina in architectural organisation of the reconstituted muscle by electron microscopy and immunofluorescence using antibodies to laminin, fibronectin, type IV collagen and heparan sulfate proteoglycan. We observed the persistence of immunoreactivity to all components; anti-laminin antibodies for example, evidenced a clear fascicular organization of ghost basal lamina which are progressively repopulated by the grafted cells. We finally investigated in vivo proliferation of the grafted cells by an autoradiographic study of H3-thymidine incorporation in the regenerated fibers and demonstrate that grafted cells proliferate for, at least, 1 week after cell grafting.

Analysis of Variance↗
PubMed1994

Genetic heterogeneity of severe childhood autosomal recessive muscular dystrophy with adhalin (50 kDa dystrophin-associated glycoprotein) deficiency.

Severe autosomal recessive muscular dystrophy (SCARMD), McKusick n. 253700, has been originally described in North-African populations, in which significant linkage has been established with DNA markers mapping to the proximal region of the long arm of chromosome 13, without evidence for heterogeneity of the SCARMD locus in these populations. A striking feature of this disease is the isolated deficiency of adhalin, a sarcolemmal 50 kDa dystrophin-associated glycoprotein. We report a non-inbred French family with a milder progressive form of muscular dystrophy affecting subjects of both sexes. The parents are not affected suggesting an autosomal recessive transmission. In 4 siblings displaying mild to overt clinical signs of muscular dystrophy, serum creatine kinase was high, and muscle specimens showed variable degree of necrosis-regeneration with little fibrosis. In the 4 cases adhalin was completely absent in muscle sections, whereas dystrophin and the other members of the dystrophin-associated protein complex were normal, except for the 35 kDa dystrophin-associated glycoprotein which was decreased as usually observed in SCARMD. Linkage and homogeneity analysis using 4 microsatellite markers of chromosome 13q that are linked to the North-African SCARMD locus were performed in this family. Results show that the morbid locus involved in this family does not map to the same region as the SCARMD locus. This second locus may be involved in sporadic cases of muscular dystrophy with adhalin deficiency that have been reported in Europe.

Adolescent↗
PubMed1994

Congenital muscular dystrophy with merosin deficiency.

Congenital muscular dystrophy is one of the most frequent and severe childhood muscular dystrophies. Several forms of this disease have been described. The form associated with marked central nervous system disturbances, frequent in Japan, is known as Fukuyama congenital muscular dystrophy and was recently linked to chromosome 9. The most frequent form observed in occidental countries appears to be clinically characterized by exclusive involvement of skeletal muscle, and has been identified by clinico-pathological features which are often fallacious. A predominant histopathological feature is the marked increase in endomysial collagen tissue. We investigate whether laminin, a major component of the extracellular matrix, which is linked to the subsarcolemmal cytoskeleton by a large oligomeric complex of dystrophin-associated glycoproteins, could be involved in this form. We observed a specific absence of merosin, the laminin M chain, in 13 patients affected by classical non-Japanese form of congenital muscular dystrophy. This result allows the precise identification of a particular form of congenital muscular dystrophy and gives a clue to understanding its molecular pathogenesis.

Child↗
PubMed1993

Ubiquitin and beta-amyloid-protein in inclusion body myositis (IBM), familial IBM-like disorder and oculopharyngeal muscular dystrophy: an immunocytochemical study.

We used immunocytochemistry to identify ubiquitin and beta-amyloid-protein in muscle biopsies from patients with three neuromuscular disorders characterized by the presence of rimmed vacuoles in muscle fibres: inclusion body myositis (IBM), familial IBM-like disorder and oculopharyngeal muscular dystrophy (OPMD). Labelling with anti-ubiquitin antibodies was observed in all three diseases, but it was frequent in IBM, less common in familial IBM-like disorder and rare in OPMD. This labelling is thought to correspond to the presence of IBM-type filaments (16-18 nm in external diameter) which are characteristic but not specific for IBM or familial IBM-like disorder, as they may also occur in other diseases including OPMD. Labelling with anti-beta-amyloid-protein antibody was seen in a few fibres in IBM but not in the other two conditions. The structures labelled with this antibody have yet to be determined. Labelling with anti-ubiquitin or anti-beta-amyloid-protein antibodies was not correlated with the presence of acid phosphatase activity.

Adult↗