Congenital Muscular Dystrophy 1A Research Articles

Autophagy increase in Merosin-Deficient Congenital Muscular Dystrophy type 1A.

The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.

Micro-laminin gene therapy can function as an inhibitor of muscle disease in the dyW mouse model of MDC1A

Gene replacement for laminin-α2-deficient congenital muscular dystrophy 1A (MDC1A) is currently not possible using a single adeno-associated virus (AAV) vector due to the large size of the LAMA2 gene. LAMA2 encodes laminin-α2, a subunit of the trimeric laminin-211 extracellular matrix (ECM) protein that is the predominant laminin expressed in skeletal muscle. LAMA2 expression stabilizes skeletal muscle, in part by binding membrane receptors via its five globular (G) domains. We created a small, AAV-deliverable, micro-laminin gene therapy that expresses these G1–5 domains, LAMA2(G1–5), to test their therapeutic efficacy in the dyW mouse model for MDC1A. We also fused the heparin-binding (HB) domain from HB epidermal growth factor-like growth factor (HB-EGF) to LAMA2(G1–5) to test whether this would increase muscle ECM expression. dyW mice treated intravenously with rAAV9.CMV.HB-LAMA2(G1–5) showed increased muscle ECM expression of transgenic protein relative to mice treated with rAAV9.CMV.LAMA2(G1–5) and showed improved weight-normalized forelimb grip strength relative to untreated dyW mice. Additionally, dyW muscle fibers expressing either micro-laminin protein showed some measures of reduced pathology, although levels of muscle cell apoptosis and inflammation were not decreased. Although systemic expression of rAAV9.CMV.HB-LAMA2(G1–5) did not inhibit all disease phenotypes, these studies demonstrate the feasibility of using a micro-laminin gene therapy strategy to deliver gene replacement for MDC1A.

Natural disease history of the dy2J mouse model of laminin α2 (merosin)-deficient congenital muscular dystrophy.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice.

Exon Skipping Using Antisense Oligonucleotides for Laminin-Alpha2-Deficient Muscular Dystrophy.

Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is among the more promising approaches available for the treatment of several neuromuscular disorders, including Duchenne muscular dystrophy. The main weakness of this treatment arises from the low efficiency and sporadic nature of delivery of the neutrally charged PMO into muscle fibers, the mechanism of which is unknown.Recently, using wild-type and dystrophic mdx52 mice, we showed that muscle fibers took up PMO more efficiently during myotube formation. Interestingly, through in situ hybridization, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibers. Next, we tested the therapeutic potential of PMO in laminin-alpha2 (laminin-α2) chain-null dy 3K/dy 3K mice, a model of merosin-deficient congenital muscular dystrophy 1A (MDC1A) with active muscle regeneration. We confirmed the recovery of the laminin-α2 chain following skipping of the mutated exon 4 in dy 3K/dy 3K mice, which prolonged the life span of the animals slightly. These findings support the theory that PMO entry into fibers is dependent on the developmental stage in myogenesis rather than on dystrophinless muscle membranes, and provide a platform for the future development of PMO-mediated therapies for a variety of muscular disorders, such as MDC1A, that involve active muscle regeneration. Herein, we describe the methods for PMO transfection/injection and evaluation of the efficacy of exon skipping in the laminin-α2-deficient dy 3K/dy 3K mouse model both in vitro and in vivo.

Novel Gene LAMA2 Mutation and Exonic Deletion Underline Merosin-Deficient Congenital Muscular Dystrophy 1A in a Chinese Family

Introduction: Merosin Deficient Congenital muscular dystrophy type 1A (MDC1A) is a rare kind of congenital muscular dystrophy. Case Presentation: Here we report a Chinese case with a genetic diagnosis exposing a novel point mutation and a novel exonic deletion in the causative gene LAMA2. We collected the medical history and did physical examination for the case. A set of auxiliary examination was performed for the diagnosis. The patient exhibited notable proximal weakness and was severely hypotonic. The CK increased slightly. The brain MRI exposed leukodystrophy. The electromyogram suggested myogenic muscle damage. Merosin was completely absent in the visual field of muscle biopsy. Gene testing exposed that the proband was a compound heterozygote with a heterozygous nonsense mutation c.817A > T in exon 5 and a deletion involved exon 4 of LAMA2 gene. The point mutation derived from the mother while the exonic deletion derived from the father. The asymptomatic sister carried the point mutation c.817A > T. Conclusions: This case expands the mutation spectrum of MDC1A and highlights that the diagnosis of MDC1A should be suspected in the presence of an elevated CK and abnormal white matter.

Correlation between thigh muscle magnetic resonance imaging findings and clinical features of congenital muscular dystrophies: a preliminary study

Objective: To analyze the clinical and magnetic resonance imaging (MRI) features of congenital muscular dystrophy (CMD) to improve the diagnostic level. Method: Clinical manifestations and thigh muscle MRI results of 8 cases of CMD diagnosed on genetic level from April 2013 to November 2015 were investigated. MRI was performed on the thigh muscles of all cases. Fatty infiltration of different muscles described in T1WI was graded to evaluate. Clinical symptoms and signs, as well as muscle MRI features were analyzed by statistical description. Result: Among these 8 cases, 2 cases were diagnosed with Ullrich congenital muscular dystrophy (UCMD), 1 case had rigid spine with muscular dystrophy type 1 (RSMD1), 1 case had LMNA related muscular dystrophy (L-CMD), 1 case had congenital muscular dystrophy 1C (MDC1C) and 3 cases had congenital muscular dystrophy 1A (MDC1A), with 4 were males and 4 females, aged from 0.9 year to 4.8 years (median age was 2.2 years). All of these 8 cases presented with muscle weakness and hypotonia from birth to within the first six months, together with delayed motor development and joint contractures. Some cases had spinal deformity or skin changes. Various degrees of fatty infiltration in gluteus maximus and thigh muscles were shown in all of the cases, and differences among CMD subtypes in the form of fatty infiltration were detected; muscle edema was present in 5 cases, and muscle atrophy in 7 cases. However, none of them has muscle hypertrophy. Semimembranous muscle absence was detected in 1 case. Conclusion: The clinical manifestations and thigh muscle MRI findings of CMD have some features, and vary in certain CMD subtypes. MRI examination combined with clinical features may provide useful information to select appropriate genetic or other diagnostic techniques, which may help clinicians to make accurate diagnosis.

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo(-) muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo(-) muscles did not cause substantial glycosylation of α dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin α2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression.

Application of targeted capture technology and next generation sequencing in molecular diagnosis of inherited myopathy

To elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy. Related genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed. Seventy-seven of 134 patients (89 males and 45 females, visiting ages from 6-month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery-Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (α-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients. Next generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy.

Deletion of Galgt2 (B4Galnt2) Reduces Muscle Growth in Response to Acute Injury and Increases Muscle Inflammation and Pathology in Dystrophin-Deficient Mice

Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx). Galgt2(-/-) mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdxmice.

Hypercontractile Airway Smooth Muscle is a Potential Driver of Respiratory Pathophysiology in Congenital Muscular Dystrophy 1A

Merosin deficient congenital muscular dystrophy (MDC1A) is a fatal, autosomal recessive disease caused by laminin α2 chain deficiency, preventing formation of the extracellular matrix protein laminin 211. Afflicted children experience profound muscle weakness and degeneration and often die prematurely from failure to thrive or acute respiratory failure resulting from weak respiratory muscles and progressive scoliosis. While diseased skeletal muscle has been well characterized, airway smooth muscle (ASM) has not been investigated and respiratory failure has been attributed solely to diaphragmatic weakness. Therefore, as a first step we investigated the contractile properties of ASM isolated from DyW mice, an animal model of MDC1A.Primary bronchial rings from 7wk WT and DyW mice were harvested and cleaned. Rings were mounted on wire triangles in a bath with oxygenated Krebs solution and connected to a force transducer to measure contractile responses to depolarizing 51mM KCl Krebs solution and 10‐5 M carbachol to activate G‐protein coupled muscarinic receptors. Rings were quick frozen and saved for histological analysis. Transverse sections (7 µm thick) were stained with Gomori Trichrome to differentiate ASM. Bronchial ASM cross sectional area (CSA) was calculated using NIS Basic Research software. Contractile forces were normalized to ASM CSA to determine ASM stress.The stress responses of DyW bronchi are significantly higher than WT in response to both 51 mM KCl (nWT=7, nDyW=3, p<0.002) and 10‐5 M carbachol (nWT =8, nDyW =4, p<0.006). These data indicate that ASM isolated from DyW mice are significantly hypercontractile compared to their WT counterpart, and could potentially contribute to respiratory insufficiency in MDC1A.

M.I.4 Progress in gene therapy for muscular dystrophy using vascular delivery of GALGT2

The myomatrix present at the neuromuscular junction, as well as the transmembrane receptor complexes linking it to the F-actin cytoskeleton, are distinct from those present along the rest of the skeletal myofiber sarcolemmal membrane. Covalent protein modifications, including glycosylation, also differ between these two muscle regions. We have shown that overexpression of GALGT2, a glycosyltransferase normally confined to the neuromuscular synapse, in mouse or macaque skeletal muscle leads to ectopic glycosylation of alpha dystroglycan and the overexpression of normally synaptic dystroglycan-binding proteins, including utrophin, laminin alpha5 and agrin. As a likely result of these and related changes, GALGT2 overexpression can inhibit the development of muscle disease in the mdx model of Duchenne muscular dystrophy, the dyW model of Congenital Muscular Dystrophy 1A, and the Sgca−/− model of Limb Girdle Muscular Dystrophy 2D. In addition, GALGT2 overexpression can increase binding of myomatrix proteins to alpha dystroglycan and prevent muscle damage induced by eccentric contractions. Moreover, elimination of endogenous GALGT2 upregulation in mdx muscles leads to more severe disease. These proof of concept studies suggest that GALGT2 is a surrogate gene therapy with potentially broad applications in muscle disease. With help from a team of investigators in the Center for Gene Therapy at Nationwide Children's Hospital, we are developing methods for vascular delivery of gene therapies, using both gene replacement and surrogate gene strategies, with the goal of performing clinical trials in multiple forms of muscular dystrophy. This work was supported by grants from the NIH U54 NS055958 and R01 AR060949.

P.8.6 Genotype/phenotype analysis in Chinese laminin-α2 deficient congenital muscular dystrophy patients

Laminin-α2 (merosin) deficiency is an autosomal recessive disorder characterized by severe muscular dystrophy associated with typical abnormal white matter signal on brain MRI. It contributes to approximately half of the congenital muscular dystrophy (CMD) cases in the western world, but there are only a few clinical cases report in China. To determine the clinical and molecular genetic characteristics of merosin deficient congenital muscular dystrophy 1A (MDC1A), we studied 40 CMD patients with typical white matter abnormality and complete or partial deficiency of laminin-α2 diagnosed by immunohistochemistry staining. Genomic DNA was extracted using standard procedures from the peripheral blood leukocytes, and multiplex ligation-dependent probe amplification (MLPA) was applied to detect LAMA2 gene to identify genetic mutation. For those patients whose deletion/duplication mutation was not identified, LAMA2 gene mutation analysis were performed using PCR-DNA directly sequence. And then the relationships between genotype and phenotype were analyzed. We identified 71 mutations in LAMA2 gene of all 40 patients (88.75). Among these mutations, Most of them are compound heterozygous. We found 14 known and 31 previously undescribed mutations spanning all protein domains. Most of them were nonsense or splicing site or frame shift mutation causing laminin-α2 absence (73.4%). According to our research we further define the clinical manifestation and molecular genetic characteristics of a cohort of 40 Chinese pediatric patients with laminin-α2 deficient CMD, and our data suggest that the majority of laminin-α2 deficient patients in China showed LAMA2 gene mutations. Genetic characterization of affected families is valuable in prenatal diagnosis.

The Expanding Spectrum of LAMA2 Gene Mutations: From Congenital Muscular Dystrophy 1A to Limb Girdle Muscular Dystrophy 2R (P07.036)

The Expanding Spectrum of LAMA2 Gene Mutations: From Congenital Muscular Dystrophy 1A to Limb Girdle Muscular Dystrophy 2R (P07.036)

G.P.7 Effects of overexpression of LARGE on a mouse model of congenital muscular dystrophy

Dystroglycan (DG) is a central component of dystrophin–glycoprotein complex that links extracellular matrix and cytoskeleton. α-Dystroglycanopathy is a disorder characterized by muscular dystrophy often associated with brain anomaly and eye abnormalities. Mutations of known or putative glycosyltransferases, POMGnT1, POMT1, POMT2, fukutin, FKRP and LARGE, were identified and defective glycosylation of α-DG was implicated in the pathogenesis of this disorder. Interestingly, it has been reported that overexpression of LARGE strongly increase a function of α-DG and bypasses the defective glycosylation of α-DG in cultured cells deficient in fukutin or POMGnT1. Most recently, it has been demonstrated that LARGE acts on α-DG as a bifunctional glycosyltransferase which produces repeating units of xylose and glucuronic acid. In the previous study, we have generated transgenic mice that overexpresses LARGE (LARGE Tg mice) and characterized them. LARGE Tg mice were born according to the Mendelian ratio and grew normally. The mice exhibited no obvious abnormal behavior. In the mice, α-DG was hyperglycosylated and its laminin binding activity was greatly increased ubiquitously. Because the enhanced binding of α-DG with laminin should increase the stability of sarcolemma and facilitate signal transductions through α-DG, it is conceivable that the overexpression of LARGE could ameliorate the degeneration of muscle cells even in other types of muscular dystrophy than α-dystroglycanopathy. In this study, we crossed LARGE Tg mice with dy2J mice, one of a model mouse of congenital muscular dystrophy 1A in which laminin α2 chain is deficient. The dy2J mice overexpressing LARGE (dy2J/LARGE mice) have been born and we are currently characterizing them. In this meeting, we will present the detailed phenotype of dy2J/LARGE mice particularly focusing on its muscle pathology.

Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2

BackgroundCongenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.MethodsWe investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.ResultsA previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.ConclusionsOur data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.

Non-redundant function of dystroglycan and β1 integrins in radial sorting of axons

Radial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during peripheral nerve development. Radial sorting is impaired in models of human diseases, congenital muscular dystrophy (MDC) 1A, MDC1D and Fukuyama, owing to loss-of-function mutations in the genes coding for laminin α2, Large or fukutin glycosyltransferases, respectively. It is not clear which receptor(s) are activated by laminin 211, or glycosylated by Large and fukutin during sorting. Candidates are αβ1 integrins, because their absence phenocopies laminin and glycosyltransferase deficiency, but the topography of the phenotypes is different and β1 integrins are not substrates for Large and fukutin. By contrast, deletion of the Large and fukutin substrate dystroglycan does not result in radial sorting defects. Here, we show that absence of dystroglycan in a specific genetic background causes sorting defects with topography identical to that of laminin 211 mutants, and recapitulating the MDC1A, MDC1D and Fukuyama phenotypes. By epistasis studies in mice lacking one or both receptors in SCs, we show that only absence of β1 integrins impairs proliferation and survival, and arrests radial sorting at early stages, that β1 integrins and dystroglycan activate different pathways, and that the absence of both molecules is synergistic. Thus, the function of dystroglycan and β1 integrins is not redundant, but is sequential. These data identify dystroglycan as a functional laminin 211 receptor during axonal sorting and the key substrate relevant to the pathogenesis of glycosyltransferase congenital muscular dystrophies.

Transgenic overexpression of the α7 integrin reduces muscle pathology and improves viability in the dyW mouse model of merosin-deficient congenital muscular dystrophy type 1A

Merosin-deficient congenital muscular dystrophy 1A (MDC1A) is a devastating neuromuscular disease that results in children being confined to a wheelchair, requiring ventilator assistance to breathe and premature death. MDC1A is caused by mutations in the LAMA2 gene, which results in the partial or complete loss of laminin-211 and laminin-221, the major laminin isoforms found in the basal lamina of skeletal muscle. MDC1A patients exhibit reduced α7β1 integrin; however, it is unclear how the secondary loss of α7β1 integrin contributes to MDC1A disease progression. To investigate whether restoring α7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the α7 integrin in the skeletal muscle of the dy(W⁻/⁻) mouse model of MDC1A. Enhanced expression of the α7 integrin restored sarcolemmal localization of the α7β1 integrin to laminin-α2-deficient myofibers, changed the composition of the muscle extracellular matrix, reduced muscle pathology, maintained muscle strength and function and improved the life expectancy of dy(W⁻/⁻) mice. Taken together, these results indicate that enhanced expression of α7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin-α2-deficient mice, and strategies that increase α7 integrin in muscle might provide an innovative approach for the treatment of MDC1A.

P03.9 Muscular hypotonia, joint contractures and elevated creatin kinase level as main symptoms for Congenital muscular dystrophy 1A (with laminin alpha-2-deficiency)

P03.9 Muscular hypotonia, joint contractures and elevated creatin kinase level as main symptoms for Congenital muscular dystrophy 1A (with laminin alpha-2-deficiency)

CNS findings in congenital muscular dystrophy 1A (with laminin alpha-2-deficiency)

AbstractCongenital muscular dystrophy (MDC) is a group of rare hereditary myopathies with an early onset of progressive muscle weakness and dystrophic changes as evidenced by muscle biopsy. Some forms are associated with severe malformations of the brain. This study presented 2 pediatric patients with genetically diagnosed congenital muscular dystrophy 1A. The patients exhibited a typical combination of muscular hypotonia, joint contractures and elevated creatine kinase levels. Characteristic white matter lesions were not present in an early MRI scan of one patient, but could be detected at the age of 18 months. The second patient showed both severe white and grey matter abnormalities (pachy microgyria) in the MRI scan. In both cases, MRI findings did not correlate with the mental development of the patients.

Muscular hypotonia, joint contractures and elevated creatin kinase level as main symptoms for Congenital muscular dystrophy 1A (MDC 1A/congenital muscular dystrophy with laminin α 2 (merosin) deficiency)

Introduction: congenital muscular dystrophies (MDC) are hereditary myopathies characterized by congenital muscular hypotonia, delayed motor development and early onset of progressive muscle weakness. Dystrophic patterns are found in muscular biopsy. Some forms are associated with affections of the brain or eyes. Incidental rate is ca. 2.5–4.5×(10–5). The congenital muscular dystrophy with laminin α 2 -deficiency (MDC1A) counts ca. 30 to 40% of all MDC in Europe. A defect of laminin α 2 affects primarily the basement membrane of the muscular cell.