From adhalinopathies to alpha-sarcoglycanopathies: an overview.
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Chromosome Mapping↗
Biomedical subjects
M Fardeau
Publications and source records attributed to M Fardeau.
Partial laminin alpha2 chain restoration in alpha2 chain-deficient dy/dy mouse by primary muscle cell culture transplantation.
Laminin-2 is a component of skeletal and cardiac basal lamina expressed in normal mouse and human. Laminin alpha2 chain (LAMA2), however, is absent from muscles of some congenital muscular dystrophy patients and the dystrophia muscularis (dy/dy) mouse model. LAMA2 restoration was investigated following cell transplantation in vivo in dy/dy mouse. Allogeneic primary muscle cell cultures expressing the beta-galactosidase transgene under control of a muscular promoter, or histocompatible primary muscle cell cultures, were transplanted into dy/dy mouse muscles. FK506 immunosuppression was used in noncompatible models. All transplanted animals expressed LAMA2 in these immunologically-controlled models, and the degrees of LAMA2 restoration were shown to depend on the age of the animal at transplantation, on muscle pretreatment, and on duration time after transplantation in some cases. LAMA2 did not always colocalize with new or hybrid muscle fibers formed by the fusion of donor myoblasts. LAMA2 deposition around muscle fibers was often segmental and seemed to radiate from the center to the periphery of the injection site. Allogeneic conditionally immortalized pure myogenic cells expressing the beta-galactosidase transgene were characterized in vitro and in vivo. When injected into FK506-immunosuppressed dy/dy mice, these cells formed new or hybrid muscle fibers but essentially did not express LAMA2 in vivo. These data show that partial LAMA2 restoration is achieved in LAMA2-deficient dy/dy mouse by primary muscle cell culture transplantation. However, not all myoblasts, or myoblasts alone, or the muscle fibers they form are capable of LAMA2 secretion and deposition in vivo.
Age Factors↗
Juvenile limb-girdle muscular dystrophy. Clinical, histopathological and genetic data from a small community living in the Reunion Island.
A series of patients affected by a muscular dystrophy, similar to the original description of a juvenile scapulo-humeral form by Erb in 1884 and fitting with the criteria used to define limb-girdle muscular dystrophies, was discovered in a small community living in the southern part of Reunion Island in the Indian Ocean. A detailed clinical analysis was conducted over 5 years on a cohort of 20 patients. This community presented a high degree of consanguinity as it was segregated from the majority of the island population for more than a century. In previous molecular genetic studies, the disease locus has been mapped to chromosome 15p. Mutations were recently identified in a gene located in this region encoding for muscle-specific calcium activated neutral protease (CANP3). Clinical, pathological, genetic and complete identification of the mutations are presented here, establishing, for the first time, precise clinico-genetic correlations in this form of autosomal recessive, juvenile, limb-girdle muscular dystrophy (LGMD).
Adolescent↗
Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430 kb region.
We have recently described a female patient with myotubular myopathy (MTM1) and an interstitial deletion at Xq28. Characterisation of the deletion allowed us to position the MTM1 gene to a 600 kb region between DXS304 and DXS497. In order to further restrict the region we screened for deletions in a set of 38 patients. We found two overlapping deletions in boys that in addition to MTM1 showed an unexpected abnormal genital development. As the latter phenotype is not found in the other non-deleted MTM1 patients, our observations are best explained by a contiguous gene syndrome. The deletions define a 430 kb region that contains the MTM1 gene and most likely a gene implicated in male sexual development. A high resolution physical map of this region is presented.
Base Sequence↗
The cost of treating COPD patients with long-term oxygen therapy in a French population.
OBJECTIVE: In greater Paris and its surrounding (as it is in all France), oxygen is home delivered by not-for-profit (NP) associations or profit-making (PM) health organizations. Both are financed by the national health insurance. This dual context and the current economic climate justify an economic evaluation of all respiratory care for patients with COPD receiving long-term oxygen therapy (LTO). This pragmatic approach identifies the variables that have the greatest impact on direct medical costs and estimates the annual cost for respiratory care per COPD patient. DESIGN: Retrospective study. SETTING: Health insurance scheme for self-employed professionals (CANAM). PATIENTS AND METHODS: Between July 1985 and March 1994, 234 patients registered in CANAM files began LTO, 24% in the PM sector, 76% in the NP sector, mainly using concentrator (78%), mean age of 74 +/- 10 years, male predominance (74%), PaO2 of 56.2 +/- 10.5 mm Hg, FEV1/FVC of 43 +/- 15%, and 51% having 1 or more severe illness(es) associated. The economic appraisal was performed on a representative sample of 61 patients and measured the total resources consumption for respiratory care per COPD patient and per year (physician visits and tests, drugs, physiotherapy, oxygen therapy, hospitalizations for acute respiratory failure, transport costs). RESULTS: A quarter of the patients in each sector did not meet the LTO prescription guidelines (PaO2 > 60 mm Hg). For patients having their oxygen delivered by NP sector, the total ambulatory cost for respiratory care was lower ($4,506 per patient and per year vs $5,399) because they mainly used concentrator, all the other direct ambulatory costs being equal. The total annual cost for respiratory care of a COPD patient receiving LTO amounted to $11,672 (NP and PM sectors merged). Oxygen therapy represented 73% of the total ambulatory cost. In a multiple linear regression model, hospitalization represented the largest share of cost, significantly higher when PaO2 was 55 mm Hg or less ($2,287 per patient per year vs $8,717). In contrast, none of the covariates (age, sex, PaO2, FEV1/FVC) influenced at a significant level the total cost of visits, tests, drugs, and physiotherapy, amounting to $1,507. CONCLUSION: As oxygen treatment plays an important role in the variation of costs, further pragmatic studies should help to better understand what are the real motivations to choose one mode of oxygen administration more than another and should determine factors that may lead physicians sometimes not to comply with clinical guidelines.
Aged↗
Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein.
Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders of early onset. Approximately half of CMD patients present laminin alpha2-chain (merosin) deficiency in muscle biopsies, and the disease locus has been mapped to the region of the LAMA2 gene (6q22-23) in several families. Recently, two nonsense mutations in the laminin alpha2-chain gene were identified in CMD patients exhibiting complete deficiency of the laminin alpha2-chain in muscle biopsies. However, a subset of CMD patients with linkage to LAMA2 show only partial absence of the laminin alpha2-chain around muscle fibers, by immunocytochemical analysis. In the present study we have identified a homozygous missense mutation in the alpha2-chain gene of a consanguineous Turkish family with partial laminin alpha2-chain deficiency. The T-->C transition at position 3035 in the cDNA sequence results in a Cys996-->Arg substitution. The mutation that affects one of the conserved cysteine-rich repeats in the short arm of the laminin alpha2-chain should result in normal synthesis of the chain and in formation and secretion of a heterotrimeric laminin molecule. Muscular dysfunction is possibly caused either by abnormal disulfide cross-links and folding of the laminin repeat, leading to the disturbance of an as yet unknown binding function of the laminin alpha2-chain and to shorter half-life of the muscle-specific laminin-2 and laminin-4 isoforms, or by increased proteolytic sensitivity, leading to truncation of the short arm.
Amino Acid Sequence↗
[Congenital muscular dystrophy with merosin deficiency: clinical, histopathological, immunocytochemical and genetic analysis].
A selective deficiency of a specific laminin isovariant, merosin made of M, B1 and B2 chains, was found in a series of 17 patients affected with congenital muscular dystrophy (CMD). The merosin deficiency was complete in 15 cases, and almost complete in two cases. An overexpression of the laminin A chain was seen in these biopsies, while B1 and B2 chains were normally expressed. Comparison of the clinical data with a series of 18 "merosin-non deficient" cases showed that the "merosin-deficient" cases were forming a more homogenous group than the "non-deficient" one. Hypotonia, contractures, motor development delay were generally more severe in the "merosin-deficient" series of cases. Moreover, white matter alterations were seen in most cases explored by MRI or scan imaging. A genetic linkage with a 6q2 locus, corresponding to the M chain gene localization, was found in a panel of informative families from French and Turkish origin with "merosin deficient" CMD. "Merosin non-deficient" families did not map on this locus. So, the "merosin-deficient" CMD can be considered as a peculiar entity within the group of Congenital Muscular Dystrophies.
Biopsy↗
[Periodic palsies and myotonias are ion channel diseases].
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Humans↗
Absence of extraocular muscle pathology in Duchenne's muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing.
Duchenne muscular dystrophy (DMD) is characterized by clinical weakness and progressive necrosis of striated muscle as a consequence of dystrophin deficiency. While all skeletal muscle groups are thought to be affected, enigmatically, the extraocular muscles (EOM) appear clinically unaffected. Here we show that dystrophin deficiency does not result in myonecrosis or pathologically elevated levels of intracellular calcium ([Ca2+]i) in EOM. At variance with a previous report, we find no evidence for dystrophin-related protein/utrophin up-regulation in EOM. In vitro experiments demonstrate that extraocular muscles are inherently more resistant to necrosis caused by pharmacologically elevated [Ca2+]i levels when compared with pectoral musculature. We believe that EOM are spared in DMD because of their intrinsic ability to maintain calcium homeostasis better than other striated muscle groups. Our results indicate that modulating levels of [Ca2+]i in muscle may be of potential therapeutic use in DMD.
Animals↗
X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers.
We describe a probable recessive X-linked myopathy characterized by the presence of vacuolated muscle fibers. Four males and their shared maternal grandfather were affected. Clinical characteristics include juvenile onset, very slow progression, and predominant proximal muscle involvement. The clinical picture and the morphological findings are compared with those previously described in a family. By immunofluorescence, all histologically abnormal muscle fibers, in particular those vacuolated, showed a strong deposition of the complement C5b-9 membrane attack complex over the whole muscle fiber surface. Weak immunostaining for membrane attack complex was also found in endomysial capillaries and perimysial vessel walls. Muscle fibers showed sarcolemmal immunolabeling with anti-major histocompatibility complex I, which was also present on the margins of many vacuoles. All vacuoles were stained by antidystrophin antibody, which colocalized in most of them with antilaminin immunostaining. Taken together, these results suggest that the deposition of membrane attack complex on the damaged cell surface membrane could be important in the pathogenesis of this muscle disorder, and that the membrane-bounded vacuoles could be a consequence of sarcolemmal invagination.
Adult↗
Immunohistochemical analysis of muscle cytochrome c oxidase deficiency in children.
Despite the demonstration of a clear biochemical defect, the genetic alterations causing childhood forms of cytochrome c oxidase (COX) deficiency remain unknown. The double genetic origin (nuclear and mitochondrial DNA), and the complexity of COX enzyme structure and regulation, indicate the need for genetic investigations of the molecular structure of individual COX subunits. In the present study a new monoclonal antibody, which reacts exclusively with heart-type human COX subunit VIIa (VIIa-H), and other monoclonal antibodies against human COX subunits, were used in the immunohistochemical analysis of skeletal muscle from children with different forms of mitochondrial myopathy with COX deficiency. By immunohistochemical investigation a normal reaction was seen with antibodies to COX subunits IV, Va+Vb, and VIa+VIc in all four cases, and in two cases with antibodies to COX VIIa-H and VIIa+VIIb. In muscle from a fatal infantile case with cardiac and skeletal muscle involvement, no immunohistochemical reaction was seen with the monoclonal antibody against the tissue-specific subunit VIIa-H. In muscle from an 11-year-old boy with exclusive muscular symptoms and signs, immunohistological reactions were absent with COX subunit VIIa-H and COX subunits VIIa+VIIb, and slightly decreased with COX subunit II, thus demonstrating a different molecular mechanism in each case. It is concluded that the molecular basis of COX deficiency in childhood may vary greatly between patients.
Animals↗
Desmin in myology. 24th European Neuromuscular Center-sponsored workshop held 5-6 November 1993, Naarden, The Netherlands.
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Animals↗
Chronic progressive external ophthalmoplegia with ragged-red fibers: clinical, morphological and genetic investigations in 43 patients.
The evaluation of the severity of progressive external ophthalmoplegia (PEO) with ragged-red fibers in muscle, at the onset of the disease, when PEO is most often the only presenting symptom, is a difficult problem in neurological practice. In order to address that issue, we have performed a comparative analysis of the clinical, morphological and molecular characteristics of 43 patients affected with that form of ocular myopathy. Quantification of mitochondrial accumulation was performed with an image analysis application on muscle sections stained with succinate dehydrogenase histochemical reaction. The proportion of muscle fibres appearing as cytochrome c oxidase deficient was used as an index of the muscle-energy defect. Muscle mitochondrial DNA deletions were detected, localized and quantitated by Southern blot analysis. Point mutations were screened in five transfer RNA genes in the mtDNA (tRNA(Leucine (UUR)), tRNA(Lysine), tRNA(Glutamine), tRNA(Isoleucine) and tRNA(Formylmethionine)) by a denaturing gradient gel electrophoresis technique. This investigation confirmed the high frequency of mtDNA deletions or point mutations in PEO. At the onset of the disease, no clinical, morphological or molecular features could predict whether PEO would remain isolated or become part of a more severe multisystem disease. However, patients with mtDNA deletions were characterized by more severe ophthalmoplegia of earlier onset. Their muscle alterations were roughly parallel in severity to the proportion of deleted mtDNA molecules in muscle. Patients with a multitissular disease and mtDNA deletions were always sporadic cases and their clinical presentation was, most often, closely related to Kearns Sayre syndrome.
Adolescent↗
Morphological and functional study of extensor digitorum longus muscle regeneration after iterative crush lesions in mdx mouse.
The regenerative capacity of mdx Extensor Digitorum Longus (EDL) muscle after iterative muscle crush injuries was examined and compared with that of age-matched control C57BL/10 mice. Muscle crush injuries were performed at 8 weeks and repeated at 12 and 16 weeks. Contralateral non-crushed EDLs from mdx and C57BL/10 mice were used as internal controls for histopathology, histoenzymology, morphometry and for the study of the contractile properties. Morphological examinations were performed at 12, 16 and 20 weeks, respectively one month after a single, a second or a third crush. Contractile properties were studied at 12 to 20 weeks. By 20 weeks, no difference in the number of fibres with internal nuclei could be observed between crushed EDL from both strains, and non-crushed mdx EDL; the area and the diameter of crushed EDL from mdx mice were, respectively, 1.5- and 1.2-fold higher than the ones from crushed EDL from C57BL/10 strain. By 20 weeks, diameter distribution of crushed EDL muscles from C57BL/10 mice were shifted towards smaller fibre diameter, whereas in mdx mice, diameter distribution of crushed EDL muscles paralleled that of non-crushed EDL muscles. By 20 weeks, crushed mdx and C57BL/10 EDL muscles produced 77 and 47% of normalized tetanus tension respectively of non-crushed mdx and C57BL/10 EDL muscles. Following crush injury, both 12- and 20-week mdx and C57BL/10 EDL exhibited a slowed time to peak (TTP) and half-relaxation time (H1/2R) of twitch. There was no difference in posttetanic potentiation between the different groups. Crushed EDL of both strains showed an increased resistance to fatigue, compared to the non-crushed controls. The present study provides morphological and functional evidence for the greater recovery of mdx muscle compared to C57BL/10 muscle following iterative crush injury; however, the recovery does not completely prevent the appearance of necrosis/regeneration features.
Animals↗
Proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy. 22-24 April 1994, The Netherlands.
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Humans↗
Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy.
Congenital muscular dystrophies (CMDs), are heterogeneous autosomal recessive disorders. Their severe manifestations consist of early hypotonia and weakness, markedly delayed motor milestones and contractures, often associated with joint deformities. Histological changes seen in muscle biopsies consist of large variations in muscle fibre size, a few necrotic and regenerating fibres and a marked increase in endomysial collagen tissue. Diagnosis is based on clinical features and on morphological changes. In several CMD cases, we have demonstrated an absence of one of the components of the extracellular matrix around muscle fibres, the merosin M chain, now referred to as the alpha 2 chain of laminin-2 (ref.3). We localized this CMD locus to chromosome 6q2 by homozygosity mapping and linkage analysis. The laminin alpha 2 chain gene (LAMA2) maps to the same region on chromosome 6q22-23 (ref. 5). We therefore investigated LAMA2 for the presence of disease-causing mutations in laminin alpha 2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminin alpha 2 protein.
Adult↗
The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy which presents typically after the age of 50 with progressive eyelid drooping and an increasing difficulty in swallowing. Though OPMD has a world-wide incidence, it is more common in the French Canadian population. We have identified a homogeneous group of families and studied 166 polymorphic markers as part of a genome search before establishing linkage to chromosome 14. We determined that the OPMD locus maps to a less than 5 cM region of chromosome 14q11.2-q13. The maximum two-point lod score in three French Canadian families of 14.73 (theta = 0.03) was obtained for an intronic cardiac beta myosin heavy chain gene (MYH7) marker. The regional localization for the OPMD locus raises the intriguing possibility that either the cardiac alpha or beta myosin heavy chain genes may play a role in this disease.
Base Sequence↗
Genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus.
Limb-girdle muscular dystrophy (LGMD) is a hereditary myopathy presenting clinical and genetic heterogeneity. In 1991, a recessive form (LGMD2A) was linked to chromosome 15q in a genetic isolate from the Isle of La Réunion. Confirmation of this localization was subsequently reported in Brazilian and northern Indiana Amish pedigrees. Here we report the exclusion of the LGMD2A locus in six Amish kindreds from southern Indiana that are related by multiple consanguineous links to the same northern Indiana families in which the involvement of the chromosome 15 locus was previously demonstrated. These findings indicate unexpected genetic heterogeneity of LGMD in an Indiana Amish isolate. Furthermore, genetic analyses also ruled out the possible involvement of the chromosome 2 locus recently described (LGMD2B), thus demonstrating that a mutation within at least one additional locus leads to this condition. Several candidate genes putatively involved in neuromuscular disorders were also excluded.
Chromosomes, Human, Pair 15↗