Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Congenital Merosin-deficient Muscular Dystrophy 1A. Core disease mechanism...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Immobilization of Dystrophin and Laminin α2-Chain Deficient Zebrafish Larvae In Vivo Prevents the Development of Muscular Dystrophy

• Authors: Mei Li, A. Arner
• Year: 2015
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/ec9ff6ad9f18b3ab8e0bdb4589031d529fc2c828
• DOI: 10.1371/journal.pone.0139483
• PMID: 26536238
• PMCID: 4633184
• Citations: 17
• Influential citations: 1
• Summary: The immobilization also significantly reduced the structural damage in the mutated strains, showing that muscle activity is an important pathological mechanism.
• Evidence snippets:
• Snippet 1 (score: 0.652) > Muscular dystrophy is a heterogeneous group of inherited disorders, manifested by progressive skeletal muscle wasting and degeneration [1]. The primary cause of these disorders is often a lack of functional membrane-associated structural proteins in muscle due to genetic defects. > The most common and severe form is Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. This protein is an intracellular component of the dystrophin-glycoprotein complex (DGC), a membrane-associated structure providing attachments between the cellular cytoskeleton and the extracellular matrix [2]. Laminin α2-chain (merosin) is an extracellular component, binding to the DGC via α-dystroglycan and attaching to the matrix. In addition, laminin α2-chain has other interactions via integrins (α7β1) in the cell membrane [3]. Mutations in the laminin α2 gene have been shown to cause merosin-deficient congenital muscular dystrophy type 1A, also known as MDC1A [4]. > The pathogenesis of muscular dystrophy has been extensively investigated; mechanical stress, oxidative challenge, growth factors and stretch-activated ion channels have been shown to be involved. The DGC complex and the laminin α2-chain binding integrins have major signalling functions in muscle, and alterations in these structures influence several cellular processes affecting muscle development and structure [5,6], and thus potentially the disease development in muscular dystrophy. The precise mechanism initiating the onset of the dystrophy is still not clear. Given the position of the proteins, both dystrophin and laminin α2-chain are essential for the maintenance of muscle sarcolemmal integrity. It has been established that mechanical damage to the cell membrane is a key pathological mechanism in DMD and it might also play an important role in MDC1A pathogenesis [7][8][9]. To examine this in an in vivo context, different immobilization procedures have been applied to the dystrophin-deficient mdx mouse model.

[2] Wasting Mechanisms in Muscular Dystrophy

• Authors: Jonghyun Shin, M. Tajrishi, Y. Ogura, Ashok Kumar
• Year: 2013
• Venue: The international journal of biochemistry & cell biology
• URL: https://www.semanticscholar.org/paper/a4de726eec1b28151758e90b3b2bcc6ab5a101ca
• DOI: 10.1016/j.biocel.2013.05.001
• PMID: 23669245
• PMCID: 3759654
• Citations: 146
• Influential citations: 6
• Summary: Major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy are reviewed and it is suggested that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle.
• Evidence snippets:
• Snippet 1 (score: 0.651) > Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy.

[3] Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

• Authors: A. Gonzalez-Jamett, Walter Vásquez, Gabriela Cifuentes-Riveros, Rafaela Martínez-Pando, J. Sáez et al.
• Year: 2022
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/25df4981216f0fc24aa18398b9f70f7f7147790b
• DOI: 10.3390/biomedicines10020507
• PMID: 35203715
• PMCID: 8962419
• Citations: 28
• Summary: The interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.647) > Merosin/laminin-congenital muscular dystrophies, EDMD, and LGMD constitute other examples of inflammatory diseases. The merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene [60] that lead to the partial or complete absence of α2laminin. This protein, also called merosin, is a component of the extracellular matrix (ECM) that links the ECM to the DGC and to the sarcolemma-associated integrin complex [46]. Consequently, merosin plays a critical role in the maintenance of the sarcolemma integrity and muscle function. Mutations in other genes that code components of the ECM, such as the collagen type VI, are associated with other MDs, including Bethlem myopathy and Ullrich-scleroatonic muscular dystrophy [88]. The expression of merosine in satellite cells is associated with the proliferation and differentiation of myogenic cells [46]. Consequently, MDC1A-causing mutations in the LAMA2 gene lead to a defective muscle repair associated with chronic inflammation, fibrosis, and muscle atrophy [89]. Clinical symptoms of MDC1A include severe muscle atrophy, progressive muscle weakness, joint contractures, breathing and feeding difficulties [60]. Most patients lose their ambulation in infancy and exhibit a drastic shortening of their lifespan [89]. In skeletal muscle of patients and mouse models of MDC1A, an early onset of chronic inflammation occurs, leading to cycles of degeneration/regeneration and accumulation of fibrotic lesions [60]. In DyW mice, a murine model of laminin-deficient muscular dystrophy, merosin-deficient skeletal muscles exhibit high macrophage infiltration from early ages to adulthood. This infiltration is accompanied by an increase in the NF-κB signaling and over-expression of pro-inflammatory cytokines, which favors inflammation and causes inhibition of myogenesis [89]. > EDMD is an early onset dystrophy characterized by slowly progressive muscle atrophy and weakness, spinal stiffness and heart disease.

[4] Becker Muscular Dystrophy Due to an Inversion of Exons 23 and 24 of the DMD Gene

• Authors: D. Brožková, R. Mazanec, Zdeněk Rychlý, J. Haberlova, J. Böhm et al.
• Year: 2011
• Venue: Muscle & nerve
• URL: https://www.semanticscholar.org/paper/3b074c47b74f4edbc5bf0cd1d8a5189ad8fdad63
• DOI: 10.1002/mus.22189
• PMID: 22006696
• PMCID: 3404890
• Citations: 50
• Influential citations: 1
• Summary: It is shown that point mutations in PMP22 may be more likely in HNPP patients than in CMT1 patients after exclusion of C MT1A/HNPP.
• Evidence snippets:
• Snippet 1 (score: 0.645) > present with a mild form of congenital muscular dystrophy or a limb-girdle-like muscular dystrophy. To our knowledge, cardiac impairment has never been reported in such patients. A longitudinal study of a patient with partial laminin-a2 deficiency secondary to mutations in the LAMA2 gene revealed dilated cardiomyopathy with ventricular arrhythmias. Is this a chance association or a novel phenotype? Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is the most common form of congenital muscular dystrophy (CMD). 1,2 It is characterized by the complete absence of laminin-achain expression in skeletal muscles. A more rare allelic form of muscular dystrophy is characterized by partially reduced expression of the laminin-a2 chain. Patients with this less severe form of CMD frequently present with a limb-girdle syndrome 3,4 ; to date, there are no reports of cardiac compromise in these patients.

[5] Phenotype Genotype Characterization of FKRP-related Muscular Dystrophy among Indian Patients

• Authors: G. Unnikrishnan, K. Polavarapu, Mainak Bardhan, S. Nashi, S. Vengalil et al.
• Year: 2023
• Venue: Journal of Neuromuscular Diseases
• URL: https://www.semanticscholar.org/paper/16f78cb92f1950a5e9d2154105f20ae585107c1d
• DOI: 10.3233/JND-221618
• PMID: 37154180
• PMCID: 10357142
• Citations: 6
• Summary: A Duchenne-like phenotype was the most commonly encountered pattern in Indian patients with FKRP gene mutations, with c.1343C>T being the most common mutation.
• Evidence snippets:
• Snippet 1 (score: 0.618) > Fukutin-related protein (FKRP) is a ribitol phosphate transferase involved in the glycosylation of dystroglycans on the sarcolemma, which is an impor-616 G. Unnikrishnan et al. / FKRP-related Muscular Dystrophy tant step that helps in its attachment to the laminin proteins in the extracellular matrix [1]. The gene encoding FKRP is located at chromosome 19q13.3 and spans about 12.5kb [2]. Mutations in the FKRP gene result in highly variable phenotypes and comprise of autosomal recessive LGMD 2I [3], currently renamed as LMGD R9-FKRP related [4], autosomal recessive FKRP related congenital muscular dystrophy, also called merosin-deficient congenital muscular dystrophy type 1C (MDC1C) [2], and the severe phenotype of Walker-Warburg syndrome and Muscle-Eye-Brain disease [5,6]. Here we describe the clinical, genetic, and laboratory findings in nine patients with FKRP gene mutations from India. For this study patients who have not attained the ability to walk independently till 2 years of age and till the last available follow-up have been classified as having a congenital muscular dystrophy phenotype and others as having a LGMD phenotype in accordance to the 229th ENMC international workshop proposal for Limb girdle muscular dystrophies [4].

[6] Merosin-deficient muscular dystrophy: pathogenesis, clinical manifestations and therapeutic strategies

• Authors: A. Monakhova, D. Vlodavets, N. Zavadenko, E. Belousova, D. Kazakov et al.
• Year: 2020
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/011f6cb4af5b57758d3249fd0d7b2db17831d59b
• DOI: 10.17816/2686-8997-2020-1-3-159-168
• Summary: CMD type 1A is characterized by a delay in motor development from the first months of the life, facial muscles weakness, ptosis, ophthalmoplegia, spine rigidity, early occurrence of contractures in the shoulder, elbow, hip and knee joints, and some children suffer from mental retardation and epilepsy.
• Evidence snippets:
• Snippet 1 (score: 0.612) > Merosin-deficient muscular dystrophy is the most common form of congenital muscular dystrophies (СMD), characterized by genetic heterogeneity and a severe course in most cases. CMD pathogenesis is associated with a partial or complete absence of laminin α2 chains in the basal membrane of muscle fiber caused by a mutation in the  LAMA2  gene. The clinical manifestations of LAMA2-associated muscular dystrophy vary from severe СMD (СMD 1A) with an early onset to a relatively mild course with a late onset and phenotype of limb-girdle muscular dystrophy. CMD type 1A is characterized by a delay in motor development from the first months of the life (while the vast majority of children do not master the ability to walk independently), facial muscles weakness, ptosis, ophthalmoplegia, spine rigidity, early occurrence of contractures in the shoulder, elbow, hip and knee joints, restrictive respiratory disorders, nutritional problems, such as disorders of swallowing and chewing, gastroesophageal reflux, low body weight; some children suffer from mental retardation and epilepsy.

[7] Merosin and laminin in myogenesis; specific requirement for merosin in myotube stability and survival

• Authors: P. Vachon, F. Loechel, Hong Xu, U. Wewer, E. Engvall
• Year: 1996
• Venue: The Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/94f66aeb34b6c4648e063be03aaefcf32fee109d
• DOI: 10.1083/jcb.134.6.1483
• PMID: 8830776
• PMCID: 2121009
• Citations: 217
• Influential citations: 3
• Summary: These studies identify novel biological functions for merosin in myoblast fusion and muscle cell survival and explain some of the pathogenic events observed in congenital muscular dystrophy caused by merosIn deficiency and provide in vitro models to further investigate the molecular mechanisms of this disease.
• Evidence snippets:
• Snippet 1 (score: 0.611) > Laminin (laminin-1; alpha 1-beta 1-gamma 1) is known to promote myoblast proliferation, fusion, and myotube formation. Merosin (laminin- 2 and -4; alpha 2-beta 1/beta 2-gamma 1) is the predominant laminin variant in skeletal muscle basement membranes; genetic defects affecting its structure or expression are the causes of some types of congenital muscular dystrophy. However, the precise nature of the functions of merosin in muscle remain unknown. We have developed an in vitro system that exploits human RD and mouse C2C12 myoblastic cell lines and their clonal variants to study the roles of merosin and laminin in myogenesis. In the parental cells, which fuse efficiently to multinucleated myotubes, merosin expression is upregulated as a function of differentiation while laminin expression is downregulated. Cells from fusion-deficient clones do not express either protein, but laminin or merosin added to the culture medium induced their fusion. Clonal variants which fuse, but form unstable myotubes, express laminin but not merosin. Exogenous merosin converted these myotubes to a stable phenotype, while laminin had no effect. Myotube instability was corrected most efficiently by transfection of the merosin-deficient cells with the merosin alpha 2 chain cDNA. Finally, merosin appears to promote myotube stability by preventing apoptosis. Hence, these studies identify novel biological functions for merosin in myoblast fusion and muscle cell survival; furthermore, these explain some of the pathogenic events observed in congenital muscular dystrophy caused by merosin deficiency and provide in vitro models to further investigate the molecular mechanisms of this disease.

[8] The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy.

• Authors: F. Rahimov, L. Kunkel
• Year: 2013
• Venue: The Journal of cell biology
• URL: https://www.semanticscholar.org/paper/f40d5c11c05bfed36ed352efec2330b6b6ade1ba
• DOI: 10.1083/jcb.201212142
• PMID: 23671309
• Citations: 237
• Influential citations: 12
• Summary: The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle and distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes are revealed.
• Evidence snippets:
• Snippet 1 (score: 0.607) > The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. > contracting myofiber to withstand the mechanical stress generated by sarcomeres and to prevent its fragile sarcolemma from contraction-induced injuries (Petrof et al., 1993). Disruption of the DAPC, as a result of structural or posttranslational defects in one of the components building this protein complex, weakens the sarcolemma and causes different types of muscular dystrophy depending on the altered protein. The subcomplex of integral proteins sarcoglycans and sarcospan within the DAPC provides additional mechanical support to the DAPC and thereby to the sarcolemma (Yoshida et al., 1994). Mutations in genes encoding the , , , and  subunits of the sarcoglycan complex cause sarcoglycanopathies, a subtype of recessively inherited limb-girdle muscular dystrophies (LGMDs; Table 1). In general, structural defects in one sarcoglycan subunit lead to reduction or complete loss of the other subunits, destabilizing the entire protein complex, which consequently weakens the sarcolemma. > LGMDs are the most heterogeneous subgroup of muscular dystrophies that predominantly involve the proximal limb-girdle musculature, mainly those around hips and shoulders. Besides sarcoglycanopathies, there are several additional LGMDs with distinct molecular underpinnings that can arise as a result of mutations in proteins unrelated to the DAPC, each type categorized based on the mode of inheritance and altered gene product. > Aberrant glycosylation of -dystroglycan.

[9] Identification of hub genes related to Duchenne muscular dystrophy by weighted gene co-expression network analysis

• Authors: Yan-li Wei, Qisheng Su, Xiao-Hua Li
• Year: 2022
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/270eedbe2a86196967455d575878a3326f57e676
• DOI: 10.1097/MD.0000000000032603
• PMID: 36596079
• PMCID: 9803489
• Citations: 5
• Summary: SerPING1, F13A1, C1S, C 1R, and HLA-DPA1 may participate in the development of DMD by regulating innate immunity and inflammation, and they are expected to be a potential biomarker and novel therapeutic targets for DMD.
• Evidence snippets:
• Snippet 1 (score: 0.599) > Muscular dystrophy (MD) is a genetic disorder in which genetic abnormalities lead to abnormalities in a group of proteins that maintain stability of skeletal muscle cell structure and function. Chronic and progressive muscle weakness or muscle atrophy is the main clinical manifestation of MD. Common muscular dystrophy are Duchenne muscular dystrophy (DMD), Bekerer muscular dystrophy (BMD), myotonic muscular dystrophy (MD), congenital muscular dystrophy (CMD), limb girdle type Muscular dystrophy (LGMD), facial scapulohumeral muscular dystrophy (FSMD), distal muscular dystrophy, ophthalmopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), etc. Among them, DMD is an X-recessive genetic disease caused by mutations in the anti-atropin gene. It is the most common type of progressive muscular dystrophy and the most severe type in childhood. [1] Most of the patients with DMD were found to have disease at the age of 3 to 5 years, often accompanied by delayed motor development, progressive skeletal muscle atrophy, scoliosis, joint spasm, respiratory muscle weakness, and dilated heart disease. Most patients with DMD died of respiratory failure and heart failure around the age of 20. [2,3] At present, there are a lot of studies on DMD. Gene substitution with adenovirus and CRISPR gene editing are considered as potential therapeutic methods for DMD. [4] Some targets have been found to delay the development of DMD. p. 5] Although great progress has been made in the treatment of DMD, there is still much room for exploration. [7] We believe that exploring the molecular and mechanism involved in the occurrence and development of DMD may help to find new therapeutic targets for DMD, and may provide help for the treatment of DMD. > Weighted gene co-expression network analysis (WGCNA) is 1 way to identify gene modules and key genes related to phenotypic traits. [8]

[10] Corrections

• Authors: Brian F. Corbett, S. Leiser
• Year: 1917
• Venue: The Lancet. Infectious Diseases
• URL: https://www.semanticscholar.org/paper/6e15b554df61f7df5b5152d8502ea6562b443c16
• DOI: 10.1016/S1473-3099(18)30236-6
• PMID: 29695353
• PMCID: 6988428
• Summary: The data deposition code for this article was incorrectly set as 1HVs instead of 1HV8, and the online version of this article has been corrected.
• Evidence snippets:
• Snippet 1 (score: 0.595) > Facioscapulohumeral muscular dystrophy (FSHD), a progressive muscle disease affecting mainly the muscles of the face and upper arms caused by deletions of a 3.3-kb repeat region located on 4q35.2 (6), is an additional common type of muscular dystrophy. > Among the group of congenital myopathies, nemaline myopathy (NM) is the most common nondystrophic congenital myopathy and is characterized by relatively nonprogressive proximal weakness of often, but not always, congenital onset and the presence of nemaline rod structures in the affected myofibers (7). Mutations in six different genes encoding the thin filament proteins and other skeletal muscle proteins account for the majority of disease cases. > Clinical and histopathologic overlap between the inherited muscular disorders, and the distinct idiopathic inflammatory myopathies is also being increasingly recognized (8). Polymyositis (PM), the most common of the inflammatory myopathies, is a T cellmediated pathology in which a cellular immune response is a key feature in promoting muscle damage. Inclusion body myositis (IBM) is suspected to be a primary inflammatory myopathy, like dermatomyositis (DM) and PM, or a primary degenerative myopathic disorder, such as a dystrophy with secondary inflammation (9). The general distinction between immune-mediated and nonimmune-mediated muscle diseases becomes less defined as more is learned of the complex, underlying pathogenic mechanisms in both inflammatory myopathies and muscular dystrophies. > Currently, although the number of genes identified increases every year, adding to our understanding and revealing the overall complexity of the pathogenesis of the various muscular disorders, and despite the well documented histological pathology of dystrophic tissue, the underlying molecular pathways remain poorly understood, and the decisive secondary factors responsible for the variability in the clinical phenotypes are still mainly unknown. Gene expression profiling of human and mouse normal and diseased skeletal muscle has generated more detailed insight in the molecular process underlying the different conditions (10)(11)(12)(13)(14).

[11] Muscle transcriptome profiling reveals novel molecular pathways and biomarkers in laminin-α2 deficient patients

• Authors: V. Pini, Francesco Catapano, R. Bonaccorso, B. Weisburd, S. Previtali et al.
• Year: 2025
• Venue: Acta Neuropathologica Communications
• URL: https://www.semanticscholar.org/paper/366466a754f8138ec85ed531b98aedb877ccb41e
• DOI: 10.1186/s40478-026-02227-9
• PMID: 41630090
• PMCID: 12955283
• Summary: This work characterizes the main contributors of human LAMA2-RD pathology, providing insight into molecular pathways that could be used as disease biomarkers or as targets for therapeutic approaches.
• Evidence snippets:
• Snippet 1 (score: 0.595) > Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is caused by LAMA2 gene mutations, coding for laminin-211 (merosin) α2 subunit. LAMA2 mutations leading to complete laminin-211 absence result in an invariably severe clinical phenotype, with profound muscle weakness and respiratory insufficiency. Milder phenotypes are often associated with mutations allowing the production of a partially functional protein. While several dysregulated genes/pathways linked to LAMA2-RD muscle loss are known, an in-depth characterization of LAMA2-RD muscle gene expression profile in patients with mutations differentially affecting LAMA2 expression is lacking. We generated muscle transcriptomic data from patients with either complete or partial laminin-211 deficiency, and identified pathways linked to the most dysregulated processes. Genes related to fibrosis, inflammation and metabolism were similarly expressed in both patient cohorts. However, a subset of novel pro-fibrotic and pro-inflammatory genes were exclusively expressed in patients (and mice) completely lacking laminin-211, indicating aspects exacerbated in this cohort. Our work characterizes the main contributors of human LAMA2-RD pathology, providing insight into molecular pathways that could be used as disease biomarkers or as targets for therapeutic approaches.

[12] A Novel LAMA2 Mutation (c.7412G>A) Was Found in a Chinese Patient With Congenital Muscular Dystrophy

• Authors: Mei-Fang Zhao, Yu-Xing Liu, L. Fan, Zhaochuan Liu, Yao Deng et al.
• Year: 2025
• Venue: Journal of Cellular and Molecular Medicine
• URL: https://www.semanticscholar.org/paper/0f98519ef15447555f80d10f1421b631318ffd76
• DOI: 10.1111/jcmm.70667
• PMID: 40751275
• PMCID: 12316597
• Summary: A novel LAMA2 mutation was identified in a Chinese family with CMD and it is indicated that the amino acid residue is highly conserved and has low tolerance to variation, suggesting a high pathogenic potential of the mutation.
• Evidence snippets:
• Snippet 1 (score: 0.591) > as follows: merosin-deficient CMD type 1A (MDC1A), merosin-deficient CMD type 1B (with muscle hypertrophy and respiratory failure) (MDC1B), merosin-deficient congenital muscular dystrophy type 1C (with muscle hypertrophy) (MDC1C), merosin-deficient congenital muscular dystrophy type 1D (with intellectual disability and abnormal glycosylation) (MDC1D) and CMD with cardiomyopathy, etc. [10][11][12][13]. > CMD is a genetically diverse muscle disorder with multiple causative genes, each of which plays a distinct role in the pathogenesis of CMD [14]. Different genes contribute to disease development in various ways. The laminin protein encoded by the LAMA2 gene plays a crucial role in maintaining the connection between muscle fibres and the surrounding matrix [15]. Mutations in the LAMA2 gene can lead to impaired connections between muscle fibres and the matrix, affecting muscle function [16]. Collagen VI, encoded by the COL6A1, COL6A2 and COL6A3 genes, is an essential component of muscle and other connective tissues [17]. Mutations in these genes can impair collagen function, affecting the stability and strength of muscles. Alpha-dystroglycan (α-DG) maintains the integrity and stability of muscle cells by connecting to the extracellular matrix and the intracellular cytoskeleton, and its function depends on its glycosylation status [18]. Proteins responsible for the glycosylation of α-DG, such as those encoded by FKRP, FKTN, POMT1, POMT2, LARGE1, POMGNT1 and ISPD, are essential for this process [19]. Mutations in these genes can lead to defects in α-DG glycosylation, affecting its connection function with the extracellular matrix and causing impaired stability of the muscle cell membrane [20].

[13] Role of Perinatal Stem Cell Secretome as Potential Therapy for Muscular Dystrophies

• Authors: S. Pacilio, S. Lombardi, R. Costa, F. Paris, Giovannamaria Petrocelli et al.
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/a499f87c78412b9098a4c1b2d4a45acce323cfbf
• DOI: 10.3390/biomedicines13020458
• PMID: 40002871
• PMCID: 11852414
• Citations: 1
• Summary: The challenging points related to the inflammation condition characterizing MD pathology are discussed and a concise summary of the literature supporting the potential of perinatal stem cells in targeting and modulating the MD inflammation is provided.
• Evidence snippets:
• Snippet 1 (score: 0.591) > In LGMD, R5 and R9 inflammation is a prominent feature, and patients often respond to corticosteroid treatment, suggesting that immune cells such as B-cells, CD4 + , and CD8 + T-cells contribute to disease pathology [16,17]. Dysferlinopathies, that feature inflammatory infiltrates, myonecrosis, and regeneration, including Miyoshi myopathy and LGMD type 2R are marked by defective membrane repair mechanisms, leading to immune cell infiltration, particularly macrophages [18]. Inflammatory cytokines such as TNF-α and iNOS are elevated, and NF-κB signaling is implicated in disease progression [19]. Notably, the complement system plays a distinct role in dysferlinopathies, with the Membrane Attack Complex (MAC) localizing to muscle fibers, an absent feature in DMD, indicating disease-specific immune mechanisms [20]. Congenital Muscular Dystrophies (CMDs) exhibit inflammation like in DMD, with macrophages dominating the inflammatory infiltrates [21] and marked dystrophic changes with striking fatty infiltration. Lamininopathies, such as Merosin-Deficient Congenital Muscular Dystrophy (MDC1A), are associated with early immune cell invasion and activation of TLR and NF-κB signaling pathways [22]. Laminin α-2-deficient dystrophy shows fatty infiltration, with complete absence or patchy reduction in laminin α-2. In Facioscapulohumeral Muscular Dystrophy (FSHD), around 30-40% of patients exhibit muscle inflammation, with macrophages and T-cells accumulating in the muscle tissue [23]. Other MDs, such as Emery-Dreifuss Muscular Dystrophy (EDMD) and Oculopharyngeal Muscular Dystrophy (OPMD), also involve immune responses, though to varying degrees [24].

[14] Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin‐deficient congenital muscular dystrophy type 1A

• Authors: A. Khorrami, Pouya Goleij, Vahidreza Karamad, E. Taheri, B. Shadman et al.
• Year: 2021
• Venue: Journal of Clinical Laboratory Analysis
• URL: https://www.semanticscholar.org/paper/72c26a5b0cb380fb4388c7abb52aac65259fe903
• DOI: 10.1002/jcla.23930
• PMID: 34528292
• PMCID: 8605159
• Citations: 4
• Summary: Two missense mutations in LAMA2 gene in compound heterozygous status in an Iranian patient with MDC1A are identified using whole‐exome sequencing (WES) for Merosin‐deficient congenital muscular dystrophy.
• Evidence snippets:
• Snippet 1 (score: 0.583) > The merosin-deficient congenital muscular dystrophy type 1A (MDC1A) with autosomal recessive inheritance affects the peripheral and central nervous system in children. 1 This disorder is characterized by increased levels of creatine kinase (CK) in serum, hypotonia, abnormalities of white matter, poor cry and suck, failure to thrive, and muscle weakness. 2,3 The prevalence of MDC1A is 1-9 per 1,000,000 children and constitutes 1-6% of all congenital muscular dystrophy cases. 4,5 Furthermore, this disorder is rarer in Asian population and more common in European countries and Caucasians race. 5,6 The various mutations in the LAMA2 gene (with 65 exons) are the main cause of MDC1A. 7 Other major factors involved in congenital muscular dystrophies are presented in Figure 1. > LAMA2 gene, on chromosome 6q22, encodes the laminin-α2 chain, which connects with laminin-γ1 and laminin-β1 chains and forms the heterotrimeric laminin-211 protein. The laminin-211 protein is a main component of the extracellular matrix and the skeletal muscle membrane. 8,9 The interaction of this protein with various matrix macromolecules plays an important role in tissue phenotypes, cell movement, and cell differentiation. 9 Previous studies reported that the genetic variations of MDC1A are compound heterozygous or homozygous mutations. 6,10 Moreover, de novo mutations are the rare events and a few have been reported in MDC1A patients. 11,12 e early diagnosis of MDC1A is based on high serum concentrations of CK, deficiency of merosin in skin or muscle biopsy, alterations in white matter on brain, and clinical examination. 11 Previous studies reported the efficiency of whole-exome sequencing (WES) for the molecular diagnosis of the congenital muscular dystrophy. 13,14 However, use of WES method is not cost-effective in patients with clinical overlap. A previous study on an Iranian patient with congenital muscular dystrophy revealed an improved diagnostic yield of WES method. 15

[15] MR imaging of pelvic and thigh muscles in congenital muscular dystrophy.

• Authors: A. Oto, Ü. Aydıngöz, Nuri Başgün, Beril Talim, E. Karaağaoğlu et al.
• Year: 2001
• Venue: The Turkish journal of pediatrics
• URL: https://www.semanticscholar.org/paper/6661c7d799b6eb160bd9c6cb9367f6a3655fbcb6
• DOI: 10.24953/turkjpediatr.2001.3015
• PMID: 11297158
• Citations: 6
• Summary: Intensity score of the anterior thigh muscles was found to be the best differentiating variable and the regression analysis model formed was able to differentiate the two forms with a sensitivity of 80 percent and specificity of 83 percent.
• Evidence snippets:
• Snippet 1 (score: 0.582) > Congenital muscular dystrophy (CMD) is a heterogeneous group of diseases characterized by muscle weakness at birth or within the first few months of life, dystrophic changes in muscle, early onset hypotonia, joint contractures, delayed motor milestones and a relatively slow progression1. At least three different types can be identified within CMD nosology: Type I (classical form) with a normal intelligence and no apparent central nervous system (CNS) involvement, Type II (Fukuyama CMD) presenting with severe CNS manifestations, and uncommon forms such as muscle-eye-brain disease and Walker-Walburg syndrome2. The discovery of merosin deficiency in some CMD patients has led to subclassification of the classical form to the merosin-positive CMD and merosin-deficient CMD forms3. Merosin-deficient CMD is a clinically homogeneous disorder caused by mutations of the LAMA 2 gene4. Three genes responsible for merosin-positive CMD have been mapped so far: Fukuyama CMD on 9q31, CMD with early rigidity of the spine (CMD-RSS) on lp35-36, and muscle-eye-brain disease on lp32-345'7. When compared to the merosinpositive form, merosin-deficient CMD is more uniform in its clinical and pathological features and tends to be more severe, with marked motor disability and associated severe respiratory problems8. Merosin-deficient CMD and merosin-positive CMD have been further distinguished by the demonstration of CNS anomalies and white matter changes in magnetic resonance (MR) imaging studies of merosin-deficient CMD patients9»10. However, there is no study in the literature comparing the muscle involvement patterns of the two groups. In this study our purpose was to define and compare the MR imaging findings of pelvic and thigh muscles in merosin-deficient and merosin-positive CMD patients.

[16] Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

• Authors: A. Rawls, Bridget K. Diviak, Cameron I. Smith, Grant W. Severson, Sofia A. Acosta et al.
• Year: 2023
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/2d7f023c19774543c7e0bfca5c0dfb0b1aab2b39
• DOI: 10.3390/biom13101536
• PMID: 37892218
• PMCID: 10605463
• Citations: 10
• Summary: The pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies are examined to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair.
• Evidence snippets:
• Snippet 1 (score: 0.581) > Muscular dystrophies (MDs) are genetic degenerative neuromuscular diseases characterized by progressive muscle weakness that results in significant morbidity.To date, mutations in 57 genes have been identified that cause nine specific classes of muscular dystrophy [1].Dystrophies are classified based on the specific gene involved and clinical features such as muscles affected, rate of disease progression, histopathology, and age of diagnosis.Inflammation is a common factor in the pathogenesis and progression of many types of MD.Chronic inflammation exacerbates muscle damage, induces fibrotic deposition and fatty replacement of myofibers, and impedes the regenerative process of skeletal muscle. > There are no curative treatments for any dystrophies currently, but new AAV and base editing approaches to provide the missing proteins or fix the genetic lesion provide hope.Though there is tremendous curative potential, these genetic approaches will not treat all dystrophies or even all versions of a single dystrophy.For example, there are more than 7000 known mutations in dystrophin that result in Duchenne muscular dystrophy (DMD) [2].Therefore, understanding the mechanisms underlying inflammation and other pathogenic processes will aid in identifying therapeutic approaches that can ameliorate the progression of these diseases.Preclinical and clinical treatments that specifically target inflammation and fibrosis are the subject of this review.

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

• Authors: L. Liang, Qigang Zhang, Xuefan Gu
• Year: 2017
• Venue: Iranian Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/6e2264a141c0a1dad90ba3ea495a23b00a8dc308
• DOI: 10.5812/IJP.1884
• Summary: This Chinese case with a genetic diagnosis exposing a novel point mutation and a novel exonic deletion in the causative gene LAMA2 expands the mutation spectrum of MDC1A and highlights that the diagnosis of M DC1A should be suspected in the presence of an elevated CK white.
• Evidence snippets:
• Snippet 1 (score: 0.580) > Congenital muscular dystrophy (CMD) is a collection of rare and greatly heterogeneous neuromuscular disorders. The clinical characteristics consist of congenital hypotonia, progressive muscle weakness, muscle contractures, and delayed motor milestones. Merosin deficient congenital muscular dystrophy type 1A (MDC1A) is a kind of CMD with the protein merosin (also known as laminin 2) deficient in the muscle tissue due to mutations in LAMA2 gene located at 6q22 -23 spanning 65 exons (NM-000426.3). MDC1A holds a predominantly autosomal recessive mode of inheritance. Besides classical features such as muscle weakness, elevated serum creatine kinase (CK), white matter abnormalities on the cranial Magnetic Resonance Imaging (MRI) and specific pattern on muscle biopsy are, also, key characteristics (1). > MDC1A was first described by Tomé FM in 1994 (2). The overall prevalence of CMDs and the percentage of each disorder among CMDs vary markedly in different areas of the world. As for MDC1A, it accounts for about 30% patients with CMD in Europe, 10% in the USA, and only 6% in Japan (3)(4)(5)(6). There is no such data in China yet, for it is extremely rare in China with only a few reported cases to date (7,8). In the present study, we report a case with MDC1A. > We have confirmed the diagnosis by clinical presentation, char-acteristic white matter abnormalities, muscle biopsy, and so on as the molecular genetic testing.

[18] The Notch signaling pathway in skeletal muscle health and disease

• Authors: D. Vargas-Franco, R. Kalra, Isabelle Draper, Christina A. Pacak, A. Asakura et al.
• Year: 2022
• Venue: Muscle & Nerve
• URL: https://www.semanticscholar.org/paper/2bc32ef6a1acc95f1c31b7e3ef5a268aadda4024
• DOI: 10.1002/mus.27684
• PMID: 35968817
• PMCID: 9804383
• Citations: 43
• Summary: The clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.580) > Since the landmark discovery in 1986 of DMD (dystrophin), 1 the causative gene for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), dozens of additional genes have been associated with various phenotypic subtypes of muscular dystrophy. > Common disease mechanisms across multiple subtypes have, however, been more difficult to identify, with only a few major clusters such as the dystroglycanopathies identified to date. Given the common phenotypic features within muscular dystrophy categories, such as limb-girdle muscular dystrophy (LGMD), there is a high likelihood that convergent disease mechanisms exist across more muscular dystrophy subtypes than is currently recognized. > There are therapeutic implications of identifying deeper biological ties between muscular dystrophy subtypes. In recent years, the US Food and Drug Administration (FDA) has approved several molecular and genetic therapies for neuromuscular disorders that target specific genes and even specific mutation types within those genes. These approaches are being applied to ever rarer forms of muscular dystrophies. However, proceeding through the preclinical and clinical research studies needed to attain FDA approval for a new therapy is lengthy and costly, and on the current trajectory it will be decades before molecular and genetic therapies are available for all known subtypes of muscular dystrophy. > The identification and characterization of disease mechanisms that are shared by multiple muscular dystrophy subtypes could pave the way for new pathway-based treatments that have therapeutic effects for multiple disease subtypes. 2 This has the potential to accelerate the timeline for broader therapeutic coverage of patients with muscular dystrophy, with a greater impact on the entire muscular dystrophy population. > One disease mechanism that bears further analysis is the Notch signaling pathway, which is known to maintain muscle stem cell (MuSC, also known as satellite cell) quiescence. Recently, three different muscle disease genes that are known to interact with the Notch signaling pathway have been identified: MEGF10, POGLUT1, and most recently JAG2.

[19] Congenital muscular dystrophy type 1A with residual merosin expression

• Authors: Hyo Jeong Kim, Young-Chul Choi, H. Park, Young-Mock Lee, H. Kim et al.
• Year: 2014
• Venue: Korean Journal of Pediatrics
• URL: https://www.semanticscholar.org/paper/63933b734999bb2de63362c1c3a694fe43f996b9
• DOI: 10.3345/kjp.2014.57.3.149
• PMID: 24778697
• PMCID: 4000761
• Citations: 5
• Influential citations: 1
• Summary: Clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement, and Immunohistochemical staining of muscle fibers including merosin, is important to evaluate patients with hypotonia, delayed motor development, and abnormal white matter changes.
• Evidence snippets:
• Snippet 1 (score: 0.577) > Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin α2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin α2)-deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency. We observed a Korean girl with MDC1A with residual merosin expression. Clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement. Immunohistochemical staining of muscle fibers including merosin, is important to evaluate patients with hypotonia, delayed motor development, and abnormal white matter changes.

[20] Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

• Authors: Erika M. Hissong, S. Salvatore, K. Tanji, E. Lavi
• Year: 2016
• Venue: Human Pathology: Case Reports
• URL: https://www.semanticscholar.org/paper/9789128fd73be46a294c8200bc355049d1b53672
• DOI: 10.1016/J.EHPC.2015.06.003
• Citations: 3
• Influential citations: 1
• Summary: Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demYelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.
• Evidence snippets:
• Snippet 1 (score: 0.575) > Abstract Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.

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