Biomedical subjects

M Fardeau

Publications and source records attributed to M Fardeau.

At least 145 records · Page 8Linked to original sources

PubMed1993

Infantile familial cardiomyopathy due to mitochondrial complex I and IV associated deficiency.

Two brothers, aged 27 and 20 months, born from consanguineous healthy parents, presented with cardiomyopathy, lactic acidosis and carnitine abnormalities in serum and muscle, without clinical evidence of muscle involvement. The histochemical reaction for cytochrome c oxidase (COX) activity was negative in all muscle fibres, although the holoenzyme and subunits were present at a normal level, as shown by immunocytochemistry. The COX activity was, respectively, 5 and 25% of control values, in muscle biopsies. Partial deficiency of complex IV was confirmed in fresh isolated muscle mitochondria from patient 2 and was associated with a defect of complex I. Patient 1 died at age 3 yr 6 months. Partial improvement of cardiomyopathy in patient 2 was obtained under carnitine therapy, but seizures occurred and CT scan and magnetic resonance imaging (MRI) revealed thalamic hypodensity. Thus, the disorder appears to be progressive despite the clinical stabilization of the cardiomyopathy. This further demonstrates the complexity and clinical heterogeneity of combined respiratory chain complex deficiencies.

Biopsy↗

PubMed1993

Deficiency of dystrophin-associated proteins in Duchenne muscular dystrophy patients lacking COOH-terminal domains of dystrophin.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a cytoskeletal protein tightly associated with a large oligomeric complex of sarcolemmal glycoproteins including dystroglycan, which provides a linkage to the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosis. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycoprotein complex. However, truncated dystrophin lacking these domains was reported to be localized to the sarcolemma in four DMD patients recently. Here we report that all of the dystrophin-associated proteins are drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains of dystrophin are required for the proper interaction of dystrophin with the dystrophin-associated proteins and also support our hypothesis that the loss of the dystrophin-associated proteins in the sarcolemma leads to severe muscular dystrophy even when truncated dystrophin is present in the subsarcolemmal cytoskeleton.

Biopsy↗

PubMed1993

[Cardiac involvement in certain muscular diseases. Apropos of 216 cases].

Myopathy may be associated with very variable cardiac involvement, the expression of which is related to the type of neuromuscular disease and also to the individual. This retrospective study, performed between 1986 and 1991, was undertaken to determine the prevalence of cardiac involvement in myopathy. A total of 216 subjects with an average age of 34 years were reviewed by clinical examination, ECG, echocardiography and Holter ECG monitoring. Some patients also underwent complementary radionuclide (scintigraphy, angiography) and electrophysiological investigations. The results confirmed cardiac disease in over a half of patients. Although 3/4 of the patients were asymptomatic from the cardiac point of view at the time of evaluation, the severity of certain lesions led to a number of specific therapeutic interventions. This suggests that simple, non-invasive cardiac diagnostic procedures should be undertaken systematically in the early stages of myopathic disease.

Adolescent↗

PubMed1993

Deficiency of the 50 kDa dystrophin associated glycoprotein (adhalin) in severe autosomal recessive muscular dystrophies in children native from European countries.

A large oligomeric complex of sarcolemmal glycoproteins is associated with dystrophin, the protein absent in Duchenne muscular dystrophy (DMD). The dystrophin-glycoprotein complex spans the sarcolemma, providing a link between the subsarcolemmal cytoskeleton and the extracellular matrix. It was recently shown that one component of this complex, the 50 kDa dystrophin-associated glycoprotein (50 DAG or adhalin), is deficient in severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype (SCARMD). This disease, initially described in Tunisia, was also reported in patients from other North-African and Middle-Eastern countries. It has not been known whether this disease exists in other populations or regions of the world. The present study provides immunocytochemical evidence of 50 DAG specific deficiency in muscle biopsies of European sporadic patients (three French, one Italian and one Greek) who clinically presented with a Duchenne or Becker-like muscular dystrophy. This study demonstrates that SCARMD exists in distinct European populations. Without knowing the status of the 50 kDa, such patients could be either undiagnosed or misdiagnosed as Duchenne, Becker or limb girdle muscular dystrophy. Their accurate diagnosis, which is essential for genetic counseling and eventual future therapies, is now possible by immunocytochemical analysis of the 50 DAG in the biopsied skeletal muscle.

Adult↗

PubMed1993

[Cellular therapy and gene therapy: perspectives in neuromuscular pathology].

Identification of the gene coding for the protein (dystrophin) which is lacking or abnormal in Duchenne or Becker type human muscular dystrophies was a decisive turning point in neuro-muscular pathology. Since that time, a considerable number of gene abnormalities have been identified or at least localized. The severity of these diseases, their steady evolution and the absence of any efficient drug therapy, have lead to the development of new therapeutic approaches based on restoring the genetic capacities of the muscle cell. There are two possibilities for therapy. The first is based on the transfer of myogenic cells derived from the 'satellite' cells normally present at the periphery of muscle fibers. The results obtained from a murine model of Duchenne dystrophy ('mdx' mouse) were very promising. However, the results from application of the same techniques to the canine model (GRMDX) or to affected children are, at the present time, disappointing. A number of biological questions remain to be solved before this technique can be more extensively applied to humans. The second possibility is based on gene transfer, through a viral vector. The adenovirus is presently a possible vector. The first experimental results, on 'mdx' mice, are again very encouraging. Extension of these studies to the canine model is a necessary prerequisite for any human application. It should be noted that these two approaches are complementary. Their future applications may depend on the diffuse or selective nature of the skeletal muscle atrophy, and on whether cardiac and respiratory muscles are involved.

Adenoviridae↗

PubMed1993

Mild deficiency of dystrophin-associated proteins in Becker muscular dystrophy patients having in-frame deletions in the rod domain of dystrophin.

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. The resulting sarcolemmal instability is presumed to render muscle fibers susceptible to necrosis. In the present study, we investigated the status of the dystrophin-associated proteins in the skeletal muscle from patients with Becker muscular dystrophy (BMD), a milder allelic form of DMD. BMD patients having in-frame deletions in the rod domain of dystrophin showed a mild to moderate reduction in all of the dystrophin-associated proteins in the sarcolemma, but this reduction was not as severe as that in DMD patients. The reduction of the immunostaining for the dystrophin-associated proteins showed a good correlation with that for dystrophin in both intensity and distribution. Our results indicate that (1) the abnormality of the sarcolemmal glycoprotein complex, which is similar to but milder than that in DMD patients, also exists in these BMD patients and (2) the rod domain of dystrophin is not crucial for the interaction with the dystrophin-associated proteins.

Adolescent↗

PubMed1992

Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy.

X-linked recessive Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a membrane cytoskeletal protein. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoprotein. The dystrophin-glycoprotein complex has been proposed to span the sarcolemma to provide a link between the subsarcolemmal cytoskeleton and the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a large reduction in all of the dystrophin-associated protein. We have investigated the possibility that a deficiency of a dystrophin-associated protein could be the cause of severe childhood autosomal recessive muscular dystrophy (SCARMD) with a DMD-like phenotype. Here we report the specific deficiency of the 50K dystrophin-associated glycoprotein (M(r) 50,000) in sarcolemma of SCARMD patients. Therefore, the loss of this glycoprotein is a common denominator of the pathological process leading to muscle cell necrosis in two forms of muscular dystrophy, DMD and SCARMD.

Biopsy↗

PubMed1992

Class II MHC antigens in normal human skeletal muscle.

Class II MHC antigen expression has been investigated in muscle tissue and cultured cells from normal human skeletal muscle by light and electron immunocytochemistry. In muscle tissue, these antigens were detected in satellite cells, interstitial cells, and blood vessels. In cultures, muscle cells were stained with a pan-reactive anti-HLA class II antibody and with isotypes specific for DP, DQ, and DR. The staining was present on mononucleated cells and persisted on myotubes; it was stronger for DR and DQ isotypes than for DP. At the subcellular level, staining was located not only at the cell surface, but also next to the endoplasmic reticulum and in the cytosol. Thus, myosatellite cells and aneurally cultured cells from human normal skeletal muscle express class II MHC antigens. Moreover, the myotube staining and the presence of gold particles inside the cells suggested synthesis of these antigens after myoblast fusion.

Fluorescent Antibody Technique↗

PubMed1992

Chronic intestinal pseudoobstruction with myopathy and ophthalmoplegia. A muscular biochemical study of a mitochondrial disorder.

The association of chronic intestinal pseudoobstruction with ophthalmoplegia has been reported previously in visceral myopathies. We report a case of this association in which muscle mitochondria had a crystalline appearance, a dense core, and decreased cytochrome c oxidase and succinate cytochrome c reductase activities. The absence of evident mitochondrial DNA deletion in the skeletal muscle of this patient does not exclude the possibility of localized deletion or mutation of mitochondrial DNA in digestive muscle.

Chronic Disease↗

PubMed1992

Localization of dystrophin and dystrophin-related protein at the electromotor synapse and neuromuscular junction in Torpedo marmorata.

The immunological identification of dystrophin isoforms at the neuromuscular junction and Torpedo marmorata electromotor synapse was attempted using various antibodies. A polyclonal antibody raised against electrophoretically purified dystrophin from T. marmorata electrocyte has been thoroughly investigated. This antibody recognized dystrophin in the electric tissue as well as sarcolemmal and synaptic neuromuscular junction dystrophin in all studies species (T. marmorata, rat, mice and human) at serum dilutions as high as 1:10,000. At variance, no staining of either the sarcolemma or neuromuscular junction was observed in Duchenne muscular dystrophy or mdx mice skeletal muscles. In these muscles, other members of the dystrophin superfamily, in particular the dystrophin-related protein(s) encoded by autosomal genes are present. These data thus demonstrate the specificity of our antibodies for dystrophin. Anti-dystrophin-related protein antibodies [Khurana et al. (1991) Neuromusc. Disorders 1, 185-194] which gave a strong immunostaining of the neuromuscular junction in various species, including T. marmorata, cross-reacted weakly with the postsynaptic membrane of the electrocyte. Taken together, these observations are in favor of the existence of a protein very homologous to dystrophin at the electromotor synapse in T. marmorata, whereas both dystrophin and dystrophin-related protein co-localize at the neuromuscular junction as in all species studied. The electrocyte thus offers the unique opportunity to study the interaction of dystrophin with components of the postsynaptic membrane.

Animals↗

PubMed1992

Analysis of the tissue distribution and inheritance of heteroplasmic mitochondrial DNA point mutation by denaturing gradient gel electrophoresis in MERRF syndrome.

MERRF (Myoclonic Epilepsy and Ragged-Red Fibres) syndrome is one of the maternally inherited diseases for which a mitochondrial DNA (mtDNA) point mutation has recently been identified. The mutation is always heteroplasmic, that is normal and mutant mtDNA coexist within the same individual. We studied mtDNA heteroplasmy in two families with MERRF syndrome, using a denaturing gradient gel electrophoresis technique that avoids the errors in the evaluation of wild/mutant mtDNA ratios caused by restriction enzyme cutting in the situation of amplification of a heteroplasmic DNA. In two patients, the proportion of muscle mutant mtDNA was in agreement with the severity of muscle mitochondrial proliferation, energy defect and fibre type I predominance. In nine patients from three generations of one family, mutant mtDNA proportion in leukocytes was in relative agreement with the clinical severity of the disease. Transmission of mutant mtDNA through these three generations did not show any tendency toward homoplasmy. Homogeneity of the mutant mtDNA proportion among different tissues from one patient was demonstrated in brain, liver, muscle and heart but a possibility of divergence of the mutant mtDNA proportion during mitosis was documented in cultured skin fibroblasts.

Adolescent↗

PubMed1992

Cognitive functions in Duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy.

In order to clarify cognitive functions in Duchenne muscular dystrophy (DMD), we performed a new controlled neuropsychological study. IQ (WISC-R), verbal skills (fluency, confrontation naming and syntax comprehension) and memory abilities (BEM) were studied in two matched groups; 24 DMD children and 17 spinal muscular atrophy (SMA) children aged 12-16 yr. A significant difference appeared between the DMD and SMA patients: only in the DMD group were there significant disabilities in certain specific functions and normal scores in others. Despite similar education, the DMD children more often had significantly greater learning disabilities. There were more DMD left-handers. Verbal IQ was significantly low whereas performance IQ was at a normal level. DMD children also performed poorly in reading tasks and in some memory functions such as story recall and verbal recognition. Specific cognitive disabilities in certain DMD children, not seen in SMA children, suggest a relationship with a DMD genetic disorder.

Adolescent↗

PubMed1992

Decreased cerebral glucose utilization in myotonic dystrophy.

To test the hypothesis that cerebral metabolism is altered in myotonic dystrophy (MyD), we investigated cerebral glucose kinetics and utilization in 11 adult patients with MyD and 14 healthy controls, using 18F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) and dynamic positron emission tomography. Estimation of rate constants in MyD revealed a reduction of FDG delivery to the brain. Cortical glucose utilization rate was reduced by about 20% in MyD. These findings may be related to the presence of neurologic impairment in MyD and prompt further investigations on the metabolic and clinical features of brain dysfunction in this disease.

Adult↗

PubMed1992

Exercise intolerance in patients with McArdle's disease or mitochondrial myopathies.

OBJECTIVES: To assess respiratory and metabolic adaptations in patients with phosphorylase deficiency and mitochondrial myopathies using maximal exercise tests. PATIENTS AND METHODS: Five patients with McArdle's disease and five patients with mitochondrial myopathies performed the same incremental maximal exercise test. Their respiratory gas exchanges and the variation of the venous blood metabolites--lactate (LACT), pyruvate (PYR), alanine (ALA), ammonia (NH3)--were studied in comparison with the results of fourteen control subjects who performed the same test. RESULTS: Compared with controls, the two groups of patients displayed a similar significant decrease of their maximal VO2. In McArdle's patients the limitation of the maximal oxygen consumption was associated with a low respiratory exchange ratio (RER), a high VE/VO2, and characteristic metabolic data: no rise of LACT and PYR, a decrease of ALA and an important rise of NH3. In mitochondrial myopathies low VO2 max were due to a leftwards shift, i.e. towards low powers of exercise, of LACT, PYR, NH3 and ALA values. However the pattern of increase of LACT, PYR and NH3, exponential, and of ALA, linear, as well as respiratory exchange ratios were similar to control values. In this case, the limitation of oxygen consumption was due to a lack of the usual substrate, pyruvate. Low respiratory exchange ratio demonstrated that the muscle metabolism had a tendency to shift to lipid oxidation. CONCLUSION: These results suggest that patients with McArdle's disease may improve their muscle energy production by endurance training which enhances lipid metabolism, whereas in mitochondrial myopathies, the energy production by oxidation of pyruvate or lipids may be improved only by enzymatic substitution.

Adult↗

PubMed1992

Linkage studies in facioscapulohumeral muscular dystrophy (FSHD).

Facioscapulohumeral muscular dystrophy (FSHD) has been localized to the 4q35-qter region of chromosome 4. Linkage analyses of two polymorphic markers from the region, D4S139 and D4S163, have been carried out using four large multigenerational FSHD families. The results indicate that both markers are closely linked to FSHD, with D4S139 being the closest proximal marker to FSHD.

Chromosome Mapping↗

PubMed1991

A homologue of dystrophin is expressed at the neuromuscular junctions of normal individuals and DMD patients, and of normal and mdx mice. Immunological evidence.

Polyclonal and monoclonal antibodies, which recognize different regions and epitopes of the dystrophin molecule, bind to a protein of Mr 400,000 which is present in extracts of mdx muscle from regions which contain neuromuscular junctions (NMJ) and is absent from those which do not. This NMJ-associated homologue of dystrophin has at least 2 epitopes which are different to usual Xp21 form of dystrophin expressed along the sarcolemma of muscle fibres in normal muscles. This protein is also expressed at the NMJ of a DMD patient who lacks the first 52 exons of the Xp21 dystrophin gene and it must therefore be translated from a different gene transcript.

Animals↗

PubMed1991

Skeletal muscle involvement in human immunodeficiency virus infection.

In addition to muscle changes due to peripheral nervous system involvement, primary myopathic changes associated with the human immunodeficiency virus (HIV) have also been described. We studied seven cases: two had developed an acquired immunodeficiency syndrome (AIDS), four had seroconverted to HIV but were otherwise asymptomatic, one was HIV seronegative when the biopsy was performed and one was biopsied twice. Besides the HIV no other infectious agent was detected. Muscle biopsies showed: (a) muscle fiber necrosis and regeneration; (b) inflammatory changes with moderate perivascular infiltration; and (c) unusual myofibrillary disorganization. Immunocytochemical techniques using anti-HIV monoclonal antibodies showed the presence of the virus in one biopsy. HIV-RNA was detected by in situ hybridization in the same biopsy. With both techniques the HIV was detected in isolated mononuclear cells in the muscle endomysium and not within the muscle fibers. Muscle involvement associated with HIV infection may be related, at least in some cases, to the presence of the virus in interstitial cells.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Intracranial arachnoid cysts in myotonic dystrophy.

Clinically apparent brain dysfunction is common in myotonic dystrophy. In a sample of fourteen adult patients with the definite form of this disease, brain magnetic resonance imaging detected frequent white matter abnormalities and ventriculomegaly. In addition, two patients exhibited an intracranial arachnoid cyst, a condition of neurosurgical interest that could be related to the generalized dysmaturational process present in this disease. Patients with myotonic dystrophy deserve a careful screening for brain involvement. Further MRI studies should ascertain the actual prevalence of brain anomalies in myotonic dystrophy and define the role of this procedure in the workup of this disease.

Adult↗