Biomedical subjects

M Fardeau

Publications and source records attributed to M Fardeau.

At least 37 records · Page 2Linked to original sources

PubMed2000

Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation.

OBJECTIVE: To characterize the phenotypes of patients with juvenile and adult-onset acid maltase deficiency (AMD) in the French population and correlate them with genetic defects. BACKGROUND: AMD is an autosomal recessive disorder caused by the absence of the enzyme acid a-glucosidase (GAA). Patients are generally compound heterozygotes for various mutations in the GAA gene. The most common mutant allele is a -13T to G transversion in intron 1. METHODS: The authors performed a clinical, biochemical, and genetic study on 21 unrelated patients with juvenile and adult-onset AMD. RESULTS: Although onset of progressive muscle weakness occurred during adulthood in all cases but one, presence of mild, nonprogressive muscular symptoms appearing during childhood was detected in 16 patients. Eighteen patients had a similar clinical pattern with pelvic girdle muscle weakness predominating in glutei and thigh adductors. Restrictive respiratory insufficiency with vital capacity less than 60% was noted in eight patients, and respiratory failure was the first manifestation in two cases. All patients but one were compound heterozygotes, and 17 carried the IVS1 (-13T ---> G) transversion (one patient was homozygous for this mutation). The two mutated alleles were identified in 10 cases, with 13 different mutations detected in the GAA gene. There was no clear correlation between the type of mutation and phenotype. CONCLUSIONS: This study shows a high genetic heterogeneity of juvenile and adult AMD in the French population. The absence of genotype-phenotype correlation suggests a complex physiopathology that requires further investigations.

Adolescent↗

PubMed2000

Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions.

Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the sarcoglycans. In particular, sarcospan was absent in a gamma-sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the gamma-sarcoglycan gene, which causes premature truncation of gamma-sarcoglycan without affecting assembly of the mutant gamma-sarcoglycan into a complex with alpha-, beta- and delta-sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of gamma-sarcoglycan is critical for the functioning of the entire sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper sarcoglycan-sarcospan expression and function.

Adult↗

PubMed2000

Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP).

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene in a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was -2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP.

Carrier Proteins↗

PubMed2000

High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation.

We studied 54 living relatives from a large French kindred, among which 17 members presented with a cardiomyopathy transmitted on an autosomal dominant mode. Five of these individuals had clinical manifestations of muscle disease phenotypically consistent with Emery-Dreifuss muscular dystrophy. Genetic analysis of this kindred had demonstrated a nonsense mutation in the LMNA gene located on chromosome 1q11-q23. This gene encodes lamins A and C, proteins of the nuclear lamina located on the inner face of the nuclear envelope. We retrospectively determined the cause of death of 15 deceased family members, 8 of whom had died suddenly, 2 as a first and single manifestation of the disease. The six other cases had histories of arrhythmias and left ventricular dysfunction before dying suddenly, and three of them died despite the prior implantation of a permanent pacemaker. The mean age of onset of cardiac symptoms among affected living family members was 33 years (range 15-47 years), and the first symptoms were due to marked atrioventricular conduction defects or sinus dysfunction, requiring the implantation of permanent pacemakers in seven cases. Myocardial dysfunction accompanied by ventricular arrhythmias developed rapidly in the course of the disease and resulted in severe dilated cardiomyopathy requiring cardiac transplantation in three cases. In conclusion, in patients presenting a life-threatening familial or sporadic cardiac restricted phenotype similar to that described here, mutations in the lamins A and C gene should be looked for. In the genotypically affected individuals, cardiological and electrophysiological follow-up should be performed to prevent sudden death that could occur rapidly in the evolution of such disease.

Adolescent↗

PubMed2000

Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27-31.

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling, autosomal-dominant disorder of connective tissue and is characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament, and fascia and by congenital malformation of the great toes. To identify the chromosomal location of the FOP gene, we conducted a genomewide linkage analysis, using four affected families with a total of 14 informative meioses. Male-to-male transmission of the FOP phenotype excluded X-linked inheritance. Highly polymorphic microsatellite markers covering all human autosomes were amplified by use of PCR. The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0). Crossover events localize the putative FOP gene within a 36-cM interval bordered proximally by D4S1625 and distally by D4S2417. This interval contains at least one gene involved in the bone morphogenetic protein-signaling pathway.

Chromosome Mapping↗

PubMed2000

[Miyoshi distal myopathy: specific signs and incidence].

We report 21 French patients (12 males and 9 females), presenting a distal myopathy of Miyoshi type. The main clinical features of these patients were 1) onset in late adolescence or early adulthood (mean age: 20.3 years), 2) early and predominant involvement of the posterior compartment muscles of legs, 3) marked elevation of serum CK (from 10 to 50 times the normal value), 4) dystrophic features with a necrotic regeneration pattern without vacuole in muscle biopsy. All cases were sporadic and a consanguinity of parents was found in five cases. The clinical course was relatively mild: twelve patients could walk without aid; However four patients were severely disabled. Four patients were initially considered as having polymyositis; corticosteroids and immunosuppressive drugs were always inefficient. A genetic linkage to chromosome 2 was ascertained in five cases. In our experience the Miyoshi distal myopathy is the most common form of distal myopathy, particularly in young patients.

Adolescent↗

PubMed2000

X-linked vacuolar myopathies: two separate loci and refined genetic mapping.

X-linked vacuolar myopathies can be divided into two forms: one that is associated with cardiomyopathy and mental retardation (XVCM-MR) and a second form, termed X-linked myopathy with excessive autophagy (XMEA), that spares cardiac muscle and has no central nervous system involvement. In this article, we demonstrate linkage between XMEA and markers on chromosome Xq28 and assign the XMEA gene locus to the most telomeric 10.5 cM of chromosome X. We also show that XVCM-MR is not allelic to XMEA.

Adolescent↗

PubMed2000

[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material with mutation of the alphaB-cristallin gene].

Two familial cases of a myopathy remarkable by the presence of a granulo-filamentar, electron dense material were reported in 1978. In a second step, in 1988, it was demonstrated that this material contained an abnormally-phosphorylated desmin. During the last twenty years, the occurrence of new cases in this family confirmed the autosomal dominant inheritance of the disease, and made it potentially informative for molecular genetics studies. This allowed first to map the disease on chromosome11q21-23, and afterwards to identify a mutation within a gene coding for a chaperone protein, alphaBcrystallin. An extensive clinical, pathological and genetic study of this princeps family is herein reported in detail. First, it showed the possible detection of histopathological changes in presymptomatic patients. Second, it allowed to demonstrate the simultaneous occurrence of both alphaBcrystallin and desmin in the granulo-filamentar aggregates. Third, this study provided a precise knowledge of the evolution rate of the disease. The analysis of similar observations reported in the literature clearly shows the clinical, pathological and genetic heterogeneity of this new neuro-muscular disorder.

Actin Cytoskeleton↗

PubMed2000

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.

Adolescent↗

PubMed2000

Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases.

Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple small zones of sarcomeric disorganization and lack of oxidative activity ("minicores") in muscle fibers. The dinical expression of MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries are poorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, we analyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause. According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistent phenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insufficiency and scoliosis ("classical" form). Other forms were characterized by pharyngolaryngeal involvement and total lack of head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with marked hand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found in every subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This phenotype classification should be helpful when undertaking research into the molecular defects that cause MmD.

Biopsy↗

PubMed2000

["MELAS" (A3243G) mutation of mitochondrial DNA: a study of the relationships between the clinical phenotype in 19 patients and morphological and molecular data].

Nineteen patients were found to harbor the mitochondrial DNA A3243G mutation associated with MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). Eight of them had presented with stroke-like episodes and therefore had a clinical diagnosis of MELAS syndrome. The other 11 patients had no strokes and presented with generally less severe multisystemic disease. In the two groups, we compared muscle morphology, biochemical activities of muscle respiratory chain, and genetic characteristics: proportion and tissue distribution of the mutation, sequence of the 22 transfer RNA genes of the mitochondrial DNA. The proportion of mutant mtDNA in muscle was always greater than in blood. The number of patients in the two groups was too low to reach significant values. However, the patients with a MELAS syndrome presented with more severe respiratory chain abnormalities and with a proportion of the A3243G mutation that was both higher and more uniformly distributed among tissues. For symptoms others than stroke-like episodes, we did not observe any correlation with the level of mutant mtDNA in muscle. The analysis of the 22 tRNA sequences did not show differences between the two groups, and no co-inherited modifying tRNA genes could explain the variability of severity in our patients.

Adult↗

PubMed1999

Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the alpha-tropomyosin gene TPM3. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3' end of the 20. 8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.

Australia↗

PubMed1999

Expression of matrix metalloproteinases 2 and 9 in regenerating skeletal muscle: a study in experimentally injured and mdx muscles.

Matrix metalloproteinases (MMPs) cooperatively degrade all components of the extracellular matrix (ECM). Remodeling of ECM during skeletal muscle degeneration and regeneration suggests a tight regulation of matrix-degrading activity during muscle regeneration. In this study, we investigated the expression of MMP-2 and MMP-9, in normal muscles and their regulation during regeneration process. We further investigated their secretion by C2C12 myogenic cell line. Two models of muscle degeneration-regeneration were used: (1) normal muscles in which necrosis was experimentally induced by cardiotoxin injection; (2) mdx muscles which exhibit recurrent signs of focal myofiber necrosis followed by successful regeneration. MMPs were studied by zymography; their free activity was quantified using 3H-labeled gelatin substrate and mRNA expression was followed by Northern hybridization. Muscle degeneration-regeneration was analyzed by conventional morphological methods and in situ hybridization was performed on muscle sections to identify the cells expressing these MMPs. Results show that MMP-2, but not MMP-9 expression, is constitutive in normal muscles. Upon injury, the active form of MMP-2 is transiently increased, whereas MMP-9 is induced within 24 h and remains present for several days. Quantitative assays of free gelatinolytic activity show a progressive and steady increase that culminates at 7 days postinjury and slowly returns to normal levels. In adult mdx mice, both pro and active forms of MMP-2 and MMP-9 are expressed. Northern blot results support these findings. Zymography of C2C12-conditioned medium shows that myogenic cells produce MMP-2. By in situ hybridization we localized MMP-9 mRNA in inflammatory cells and putative activated satellite cells in injured muscles. Our data allow the correlation of the differential expression of pro and/or active forms of MMP-2 and MMP-9 with different stages of the degeneration-regeneration process: MMP-9 expression is related to the inflammatory response and probably to the activation of satellite cells, whereas MMP-2 activation is concomitant with the regeneration of new myofibers.

Animals↗

PubMed1999

A diagnostic fluorescent marker kit for six limb girdle muscular dystrophies.

The autosomal progressive muscular dystrophies which are grouped together under the term limb girdle muscular dystrophies (LGMD) are diseases characterized by a progressive impairment of the proximal limb muscles and myopathic changes on electromyogram and muscle biopsy. Eight independent purely recessive genetic entities have been recognized in this group of diseases by genetic localization or causative gene identification. We have developed fluorescent genetic markers bracketing six of these loci (LGMD2A-LGMD2F). The marker loci were genotyped in 96 LGMD2 families leading to genetic definition of 25 of them either with a high likelihood or with a suggested localization (7 LGMD2A, 5 LGMD2B, 4 LGMD2C, 4 LGMD2D, 2 LGMD2E and 3 LGMD2F). In addition, 18 families were excluded for all six tested loci; for 45 of the 53 remaining families at least one exclusion could be demonstrated. This kit, which makes the rapid genetic testing of LGMD2 families possible, may be useful in a diagnostic process.

Chromosome Mapping↗

PubMed1999

Genetic heterogeneity of congenital muscular dystrophy with rigid spine syndrome.

Rigid spine syndrome is a neuromuscular disorder characterised by early rigidity of the spine due to axial muscle contractures, generally associated with muscle weakness, limb-joint contractures, and often respiratory failure. This phenotype may be associated with several muscular diseases. In cases of merosin-positive congenital muscular dystrophies (CMD) with rigid spine syndrome, we have recently identified a new locus (RSMD1) on chromosome 1p35-36. In the present study, we report the clinical, morphological and genetic analysis of other patients affected by a CMD with rigid spine syndrome from nine consanguineous families. Homozygosity mapping showed that the disease was linked to RSMD1 in one of the nine families. The other families were excluded from RSMD1, and the patients presented highly variable phenotypes suggesting the involvement of more than one gene defect in rigid spine syndrome. Nevertheless, a subgroup of patients who never walked, and had very early rigidity of the spine and scoliosis, may be considered for further genetic analysis.

Adult↗

PubMed1999

Adult onset reducing body myopathy.

We report the case of a 28 year-old woman with left scapuloperoneal syndrome since the age of 24. The course was slowly progressive and diffuse weakness was observed 4 years later. Serum creatine kinase levels were moderately elevated (x3 normal value) and EMG showed mixed neurogenic and myogenic patterns. Muscle biopsy showed type I predominance and numerous reducing bodies in muscle fibers. Reducing bodies were strongly immunoreactive with antibodies to dystrophin, alpha-sarcoglycan, vimentin and ubiquitin. Desmin immunoreactivity was increased at the periphery of some reducing bodies but alphaB crystallin, alpha actinin, titin and nebulin were negative. Western blot analysis showed an increase in dystrophin, vimentin and desmin expression. Ultrastructurally, reducing bodies were composed of tubulofilamentous material, 17 nm in diameter, and immunoreactive with anti-Dys 2 antibody. Granulofilamentous material, immunoreactive with anti-desmin antibody was observed at the periphery of some reducing bodies. This report further highlights the proteinic composition of reducing bodies and shows that late onset reducing body myopathy may occur.

Adult↗

PubMed1999

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

Child↗

PubMed1999

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.

Amino Acid Sequence↗