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TTN-Related Myopathy, Dominant-Negative TTNsv

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of TTN-Related Myopathy, Dominant-Negative TTNsv. Core disease mechanisms, mo...

2026-04-16
Asta MONDO:0100494 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of TTN-Related Myopathy, Dominant-Negative TTNsv. Core disease mechanisms, mo...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease

  • Authors: J. Gohlke, J. Lindqvist, Z. Hourani, S. Heintzman, Paola Tonino et al.
  • Year: 2024
  • Venue: Human Molecular Genetics
  • URL: https://www.semanticscholar.org/paper/f89b0318494bf64f55360b276bb15b4efe186b51
  • DOI: 10.1093/hmg/ddae136
  • PMID: 39277846
  • PMCID: 11578113
  • Citations: 2
  • Summary: Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs, and that GDF11, a member of the TGF-β superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.488) > Our results suggest that a range of pathogenic variants in TTN may cause a mild skeletal myopathy or muscular dystrophy in the monoallelic state. We have identified a dominant negative mechanism in an in-frame deletion which produces a shortened protein that impairs sarcomeric structure. Truncating variants lead to nonsense mediated decay, which may serve as a protective mechanism against potential harmful effects of truncated proteins. Splice variants and out-of-frame deletions induce exon skipping and may impact functional domains. Although further study is necessary to fully elucidate the dominant mode of action for the latter variant types, family and genetic studies demonstrate clear autosomal dominant segregation of these variants with skeletal muscle disease. Our work adds to the growing evidence for a new class of dominant skeletal muscle titinopathies [7][8][9]63], a category historically restricted to only HMERF and LGMD2J. > Incomplete understanding of genotype-phenotype relationships has been a barrier to accurate diagnosis and care of patients with TTN variants, particularly those with neuromuscular presentations [63]. Our findings indicate that monoallelic truncating, splice, and deletion TTN variants may cause both skeletal and cardiac disease, with reproductive risks associated with both dominant transmission (in the monoallelic state) and recessive transmission (in the biallelic state). Recognition of the spectrum of potential clinical manifestations and reproductive implications associated with different variants in both the biallelic and monoallelic state is necessary for appropriate medical management and genetic counseling of persons identified with TTN variants. With the recent addition of TTN to the American College of Medical Genetics and Genomics list of 'secondary findings' genes for clinical testing disclosure [64], carriers of TTN variants will be increasingly identified across all medical settings. > No truncated titin was detected for TTNtvs included in this study, in contrast to studies on cardiac muscle of TTNtv patients , where a poison peptide effect has been proposed as a mechanism of disease.

[2] Molecular pathomechanisms and cell-type-specific disease phenotypes of MELAS caused by mutant mitochondrial tRNATrp

  • Authors: Hideyuki Hatakeyama, A. Katayama, H. Komaki, I. Nishino, Yu-ichi Goto
  • Year: 2015
  • Venue: Acta Neuropathologica Communications
  • URL: https://www.semanticscholar.org/paper/45cbf95ed89374114a4618cf2c82cfae95ccae8c
  • DOI: 10.1186/s40478-015-0227-x
  • Summary: iPSC-based disease models would be widely available for understanding the "definite" genotype-phenotype relationship of affected tissues and organs in various mitochondrial diseases caused by heteroplasmic mtDNA mutations, as well as for further drug discovery applications.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Numerous pathogenic mutations responsible for mitochondrial diseases have been identified in mitochondrial DNA (mtDNA)-encoded tRNA genes. In most cases, however, the detailed molecular pathomechanisms and cellular pathophysiology of these mtDNA mutations —how such genetic defects determine the variation and the severity of clinical symptoms in affected individuals— remain unclear. To investigate the molecular pathomechanisms and to realize in vitro recapitulation of mitochondrial diseases, intracellular mutant mtDNA proportions must always be considered. We found a disease-causative mutation, m.5541C>T heteroplasmy in MT-TW gene, in a patient exhibiting mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with multiple organ involvement. We identified the intrinsic molecular pathomechanisms of m.5541C>T. This mutation firstly disturbed the translation machinery of mitochondrial tRNATrp and induced mitochondrial respiratory dysfunction, followed by severely injured mitochondrial homeostasis. We also demonstrated cell-type-specific disease phenotypes using patient-derived induced pluripotent stem cells (iPSCs) carrying ~100 % mutant m.5541C>T. Significant loss of terminally differentiated iPSC-derived neurons, but not their stem/progenitor cells, was detected most likely due to serious mitochondrial dysfunction triggered by m.5541C>T; in contrast, m.5541C>T did not apparently affect skeletal muscle development. Our iPSC-based disease models would be widely available for understanding the "definite" genotype-phenotype relationship of affected tissues and organs in various mitochondrial diseases caused by heteroplasmic mtDNA mutations, as well as for further drug discovery applications.

[3] Cored in the act: the use of models to understand core myopathies

  • Authors: Aurora Fusto, L. Moyle, P. Gilbert, E. Pegoraro
  • Year: 2019
  • Venue: Disease Models & Mechanisms
  • URL: https://www.semanticscholar.org/paper/b77140bd6761dabd23c1570227944173a798440e
  • DOI: 10.1242/dmm.041368
  • PMID: 31874912
  • PMCID: 6955215
  • Citations: 21
  • Influential citations: 1
  • Summary: The current landscape of core myopathy models is summarized, the advantages and limitations of available models are outlined, and the hurdles and opportunities of future modeling strategies are assessed.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > ABSTRACT The core myopathies are a group of congenital myopathies with variable clinical expression – ranging from early-onset skeletal-muscle weakness to later-onset disease of variable severity – that are identified by characteristic ‘core-like’ lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies. Summary: The core myopathies are neuromuscular disorders with no cure. In this Review, we outline our current understanding of pathomechanisms, the advantages and limitations of available models, and discuss emerging modeling technologies.

[4] PROCEEDINGS OF THE XVII CONGRESS OF THE ITALIAN ASSOCIATION OF MYOLOGY Siracusa, Italy May 31 - June 3, 2017

  • Authors: San Zosimo, C. Amici
  • Year: 2017
  • Venue: Acta Myologica
  • URL: https://www.semanticscholar.org/paper/cd7eef1b6bba3b4e0eeff8d53d57493eb314c70d
  • PMID: 28781516
  • PMCID: 5530601
  • Summary: The phenotypic breakdown in a large Italian cohort of patients presenting with hypoglycosylation of alpha-dystroglycan (a-DG) in muscle biopsy and a molecular definition is presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.424) > (in alphabetical order of the first Author) a further, peculiar, morphological-phenotype leading to schedule genetic testing in myopathy patients. > Core myopathy with early respiratory failure and titin gene mutation Cassandrini D. 2 Core myopathies are related to different genetic mutations and respiratory failure may be part of the clinical spectrum. > We describe a woman who developed respiratory insufficiency at age 49 years; symptoms were progressive, requiring non-invasive ventilation one year later; she also complained of generalized fatigue. Her medical history included scoliosis since childhood and family history was negative for neurological diseases. Neurological examination showed mild neck flexor and proximal lower limb weakness, with diffuse muscle hypotrophy. Routine laboratory analyses and thyroid hormones were in normal range except for a mild hyperCKemia. Cardiac function was normal. Standard nerve conduction studies were normal, while EMG showed a diffuse myopathic pattern. > A biopsy of the biceps brachialis muscle showed diffuse core-like lesions, with preferential eccentric distribution within muscle fibers, along with type 2 fiber atrophy. Cytoplasmic bodies and rimmed vacuoles were absent. > DNA analysis failed to show mutations in the RYR1 gene. A targeted next generation sequencing platform, MotorPlex, revealed a previously reported mutation (c.95195C > T p.P31732L), in heterozygosity, in the exon 344 of titin gene (TTN), associated with an hereditary myopathy with early respiratory failure (HMERF). > The clinical picture slowly deteriorated until 55 years of age, when the patient died of pneumonia complications. > At variance with the two previously described families with the same mutation, defined as semi-dominant, our patient presents a severe phenotype in the heterozygous condition. She also displays a unique histopathological pattern, not observed in other patients with HMERF linked to TTN mutations. > These findings expand the genotype-phenotype correlation in HMERF. > Muscle pathological features of a hyperkalemic paralysis/dermatomyositis "double trouble" Rota S. 1 Here we report muscle pathological findings of a 66-yearold woman which presented with hand and face erythematous rashes, progressive proxi

[5] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.416) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[6] Early clinical and pre-clinical therapy development in Nemaline myopathy

  • Authors: G. Fisher, L. Mackels, Theodora Markati, A. Sarkozy, Julien Ochala et al.
  • Year: 2022
  • Venue: Expert Opinion on Therapeutic Targets
  • URL: https://www.semanticscholar.org/paper/1b091b1660fbf0f6a4fd765c0994c2c632b302e5
  • DOI: 10.1080/14728222.2022.2157258
  • PMID: 36524401
  • Citations: 9
  • Influential citations: 1
  • Summary: Experimental treatments for NM were explored, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells that target either the causative gene or associated genes implicated in the same pathway or other therapies that improve or optimize muscle function more generally.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > ABSTRACT Introduction Nemaline myopathies (NM) represent a group of clinically and genetically heterogeneous congenital muscle disorders with the common denominator of nemaline rods on muscle biopsy. NEB and ACTA1 are the most common causative genes. Currently, available treatments are supportive. Areas covered We explored experimental treatments for NM, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells. These approaches target either i) the causative gene or associated genes implicated in the same pathway; ii) pathophysiologically relevant biochemical mechanisms such as calcium/myosin regulation of muscle contraction; iii) myogenesis; iv) other therapies that improve or optimize muscle function more generally; v) and/or combinations of the above. The scope and efficiency of these attempts is diverse, ranging from gene-specific effects to those widely applicable to all NM-associated genes. Expert Opinion The wide range of experimental therapies currently under consideration for NM is promising. Potential translation into clinical use requires consideration of additional factors such as the potential muscle type specificity as well as the possibility of gene expression remodeling. Challenges in clinical translation include the rarity and heterogeneity of genotypes, phenotypes, and disease trajectories, as well as the lack of longitudinal natural history data and validated outcomes and biomarkers.

[7] Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism

  • Authors: G. Meola, R. Cardani
  • Year: 2015
  • Venue: Journal of Neuromuscular Diseases
  • URL: https://www.semanticscholar.org/paper/d1cef90e69961480ac8901cf04d4d320989a6103
  • DOI: 10.3233/JND-150088
  • PMID: 27858759
  • PMCID: 5240594
  • Citations: 61
  • Influential citations: 4
  • Summary: This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Abstract Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert’s disease) is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in CNBP. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders. The pathogenesis of DM is explained by a common RNA gain-of-function mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. However additional pathogenic mechanism like changes in gene expression, modifier genes, protein translation and micro-RNA metabolism may also contribute to disease pathology and to clarify the phenotypic differences between these two types of myotonic dystrophies. This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies.

[8] Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction

  • Authors: Xueqi Dong, Di Zhang, Yi Qu, Yu-Xiao Hu, Chun Yang et al.
  • Year: 2022
  • Venue: Journal of Geriatric Cardiology : JGC
  • URL: https://www.semanticscholar.org/paper/0d916551748d4c5ad6632a165a6aba5e3a7efab1
  • DOI: 10.11909/j.issn.1671-5411.2022.04.001
  • PMID: 35572216
  • PMCID: 9068586
  • Citations: 3
  • Summary: The TTN p.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > In contrast to the recent broad TTNtv mutation research, our finding of TTN p. R2021X as a genetic cause in a LVNC family expands the spectrum of titinopathies. > Haploinsufficiency is now generally accepted to be the molecular mechanism for TTNtv. This means that transcripts of TTNtv may undergo nonsensemediated decay, so that the abnormal protein is never expressed, leading to a reduced protein dose. > More recent work showed that DCM causing TTNtv is enriched in the sarcomeric A-band region; however, I-band TTNtv has been identified in healthy individuals and the general population without DCM. [13] n previous studies of cardiomyocytes derived from induced pluripotent stem cells from DCM patients with TTNtv, or created using CRISPR/Cas9 gene-editing technology, functional and RNAseq data suggest alternative exon splicing as the predominant mechanism for reduced penetrance of I-band TTNtv. [22] TNtv have also been associated with various other clinical phenotypes, including peripartum cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and a range of skeletal myopathies, [12,[23][24][25] In this study, RT-PCR and cell immunofluorescence data supported a haploinsufficient disease mechanism in TTN p. R2021X mutation. However, it is still unclear how this mutation leads to this distinct phenotype; more insight into the genetic susceptibilities or an environmental modifier of TTN gene expression is needed to understand the underlying signaling pathways in LVNC. Here, we provided several lines of evidence that demonstrated mitochondrial dysfunction in the presence of TTN p. R2021X mutation. Remarkable reduction of OCR, ATP level, and ETCs activity indicated impaired mitochondrial respiratory activity in the mutant cells. Indeed, abnormal mitochondrial structures were identified in the mutant cells under electron microscopy. Our findings are in line with the metabolic remodelling results found in both TTNtv-positive DCM patients and TTNtv mutated rat hearts model.

[9] Skeletal muscle CaV1.1 channelopathies

  • Authors: B. Flucher
  • Year: 2020
  • Venue: Pflugers Archiv
  • URL: https://www.semanticscholar.org/paper/e392714f9f8db3666dc9b8b16e918aa68febc706
  • DOI: 10.1007/s00424-020-02368-3
  • PMID: 32222817
  • PMCID: 7351834
  • Citations: 42
  • Influential citations: 5
  • Summary: General considerations concerning the possible roles of CaV1.1 in disease are addressed and the state of the art regarding the pathophysiology of the CaV 1.1-related skeletal muscle diseases are discussed with an emphasis on molecular disease mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.393) > CaV1.1 is specifically expressed in skeletal muscle where it functions as voltage sensor of skeletal muscle excitation-contraction (EC) coupling independently of its functions as L-type calcium channel. Consequently, all known CaV1.1-related diseases are muscle diseases and the molecular and cellular disease mechanisms relate to the dual functions of CaV1.1 in this tissue. To date, four types of muscle diseases are known that can be linked to mutations in the CACNA1S gene or to splicing defects. These are hypo- and normokalemic periodic paralysis, malignant hyperthermia susceptibility, CaV1.1-related myopathies, and myotonic dystrophy type 1. In addition, the CaV1.1 function in EC coupling is perturbed in Native American myopathy, arising from mutations in the CaV1.1-associated protein STAC3. Here, we first address general considerations concerning the possible roles of CaV1.1 in disease and then discuss the state of the art regarding the pathophysiology of the CaV1.1-related skeletal muscle diseases with an emphasis on molecular disease mechanisms.

[10] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 3
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[11] Recommendations for the Management of Cardiomyopathy Mutation Carriers: Evidence, Doubts, and Intentions

  • Authors: José F. Couto, Elisabete Martins
  • Year: 2023
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/f6c2aee42bc675ff8b32aeb310f7b46feaead751
  • DOI: 10.3390/jcm12144706
  • PMID: 37510821
  • PMCID: 10380898
  • Citations: 3
  • Summary: Regular follow-ups are advised, even in those with negative phenotypes, because these disorders are often age dependent, and during pregnancy and in the case of athletes, special consideration should be made as well.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > DCM has been associated with nearly 40 different genes. Mutations related to the cytoskeletal complex, proteins of the nuclear envelope, sarcomere, ion channels, and transcription factors have been reported; however, up to 25% of all cases involve titin (TTN). Regarding the cytoskeletal complex proteins, the dystrophin gene is commonly impaired. This gene is, simultaneously, the cause of Duchenne muscular dystrophy (DMD). Desmin (DES) is related to the myocardium's cytoskeleton architecture but also to the skeleton and smooth muscle. DES mutations have been reported in patients with skeletal or myocardial myopathies [26]. Furthermore, lamin A/C (LMNA) proteins of the nuclear envelope are implicated, having been found in individuals that develop earlier conduction system disease and have higher sudden cardiac death risk. Mutations in ion channels such as sodium channel gene SCN5A, also in Brugada syndrome or in familial Long QT Syndrome, have been reported as well [12,19]. > RBM20 is an RNA binding protein. Autosomal dominant mutations have been described, typically associated with early onset disease and with a more severe clinical presentation [27]. > Of all cases of FDM, up to 10% will carry a heterozygous mutation of a sarcomere gene, such as an MYH7 chain or ACTC. This means that FDM and HCM share some genetic causes. Currently, it has been proposed that in HCM, force generation is impaired, affecting the movement of contractile proteins, whereas in FDM, the mechanisms for relaying contractile force to the z-disks/cell membrane are altered [12]. > Lastly, the interplay of multiple genes, for example due to digenetic inheritance, could significantly impact the severity of the phenotype. Recently it has been reported that a patient carrying both TTN and RBM20 mutations had an earlier and more severe onset of disease [28].

[12] Clinical spectrum of manifestations in symptomatic female with Duchenne muscular dystrophy: A concise review

  • Authors: Emily Stefhani Keil, Milena Luisa Schulze, I. Kitzberger, Vítor Henrique Schulze, Carolina Helena Haveroth Lara et al.
  • Year: 2023
  • Venue: Translational Science of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/6760c769bf2d709871db749e6046e1545058a1e5
  • DOI: 10.3233/TRD-220056
  • Summary: The aim of this article is to present the main findings described in literature about these unusual dystrophinopathies clinical manifestations in females, in order to ease the practical approach to these conditions.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > Myopathic disorders describe a wide group of diseases that share disturbance in the skeletal muscle's structure and/or function that can be classified as acquired or genetic but not necessarily hereditary. The latter reaches muscular dystrophies, congenital myopathies, channelopathies, and metabolic myopathies (including mitochondrial disorders), and the former encloses inflammatory, systemicdisease related and toxic myopathies [12,14]. > Even though a diverse range of pathophysiological mechanisms alter the muscular anatomy and physiology, some clinical manifestations are common amongst most of the myopathies, such as diffuse muscular weakness proximal, muscular fatigue, muscle pain, or atrophy, cramps, hypertonia or even myoglobinuria [12,21]. It is also noted that in severe cases or advanced stages of certain myopathies, muscular dysfunction may lead to death related to diaphragmatic weakness or overlap with muscular and cardiac disorders. [7,12,17] Further, due to the morbimortality related to such conditions, an early diagnosis and management are imperative, exceptionally in those linked to genetic mechanisms, since several start developing early in life, shortening the carrier's lifespan, e.g., Duchenne and Becker syndromes [25]. Both pathologies are caused by mutations in the dystrophin gene located in the X chromosome, causing primary degeneration of muscle fibers associated with fibrosis and lipo-substitution of the muscle tissue. Clinical work in recent years showed that Becker and Duchenne muscular dystrophies are part of a larger spectrum, where Becker constitutes the mild clinical endpoint and Duchenne the more severe and of the spectrum [21]. > Therefore, as it has an X-linked hereditary pattern, Duchenne Muscular Dystrophy (DMD) diagnosis is exclusive to male patients, with well-defined clinical progression and pathophysiology. Female hereditary pattern carriers are quite common in many other diseases that are inherited X linked recessively [25].

[13] Autoimmune Neuromuscular Disorders at a Molecular Crossroad: Linking Pathogenesis to Targeted Immunotherapy

  • Authors: Anca-Maria Florea, Dimela-Gabriela Luca, E. Davidescu, B. Popescu
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/bdfab881665ca5af76de4ec1417182f3871c8545
  • DOI: 10.3390/ijms262311736
  • PMID: 41373880
  • PMCID: 12693520
  • Summary: Current knowledge regarding pathogenic mechanisms and their link to immunotherapy is analyzed, extensively outlining both similarities and distinctions.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > More than 600 distinct neuromuscular disorders have been identified and are typically classified by anatomical site of involvement, such as motor neurons, peripheral nerves, neuromuscular junctions, or muscle fibers, or by their underlying pathophysiology [1]. Autoimmune-mediated conditions constitute a major subgroup and are the primary focus of this review. The incidence and prevalence have increased over the past decade, a trend attributed to improved diagnostic methods, advances in therapy, heightened clinical awareness, and demographic changes associated with an aging population [2][3][4][5]. > Despite clinical heterogeneity, autoimmune neuromuscular disorders share common immunological mechanisms. These convergent pathways establish a molecular framework for understanding disorders such as myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and idiopathic inflammatory myopathies, which are the primary focus of this review. > Therapeutic advances have paralleled mechanistic insights in this field. Molecularly targeted therapies, including complement inhibitors, neonatal Fc receptor (FcRn) antagonists, and B-cell-directed agents, are reshaping management strategies. Concurrently, technological innovations such as machine learning and advanced imaging are enhancing diagnostic precision and patient stratification. > This review aims not only to summarize disease-specific mechanisms but also to highlight the intersection between pathogenesis and targeted immunotherapy. By examining overlapping immune pathways and their therapeutic implications, the review clarifies how mechanistic insights have informed treatment advances and where further progress is needed. > A comprehensive literature search was performed using Google Scholar, PubMed, and Scopus. The search was limited to English-language publications, primarily from 2018 to 2025. Both studies addressing these disorders collectively and those examining each entity in detail were included. Additionally, the reference lists of selected articles were reviewed to identify further relevant sources.

[14] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

  • Authors: M. Saporta
  • Year: 2015
  • Venue: Neural Regeneration Research
  • URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
  • DOI: 10.4103/1673-5374.158345
  • PMID: 26199602
  • PMCID: 4498347
  • Citations: 4
  • Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[15] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

  • Authors: Christine Péladeau, J. Sandhu
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
  • DOI: 10.3390/ijms22116068
  • PMID: 34199845
  • PMCID: 8200055
  • Citations: 18
  • Influential citations: 1
  • Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[16] Panorama of the distal myopathies

  • Authors: M. Savarese, J. Sarparanta, A. Vihola, P. Jonson, M. Johari et al.
  • Year: 2020
  • Venue: Acta Myologica
  • URL: https://www.semanticscholar.org/paper/bf45b4ee57352994fe4e33f3a8a7452f933a0355
  • DOI: 10.36185/2532-1900-028
  • PMID: 33458580
  • PMCID: 7783427
  • Citations: 53
  • Influential citations: 2
  • Summary: The present review aims at describing the genetic basis of distal myopathy and at summarizing the clinical features of the different forms described so far, including a digenic mechanism, underlying a Welander-like form of Distal Myopathy.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > The term distal myopathy refers to a long list of genetic muscle diseases presenting at the onset with weakness of distal extremities, usually combined with progressive atrophy of the corresponding distal muscles. Other muscles, including proximal muscles and/or cardiac and respiratory muscles, can be affected at a later stage of the disease. The clinical phenotype is extremely variable, ranging from severe forms with earlier onset and loss of ambulation to very mild late adult onset forms. Other muscle diseases (genetically determined or acquired) may present with a distal phenotype, making the diagnostic process more complex. > Although two patients with weakness in hands and in legs or feet were first described as distal myopathy by Gowers over 100 years ago 1 , only in 1998 the first genetic defect underlying a distal myopathy was identified 2 . Ten years ago, in 2010, only fourteen causative genes were known. In the last years, massive parallel sequencing has contributed to identify disease-causing variants in novel genes and to elucidate the first example of a digenic mechanism causing a distal myopathy (Tab. I). At the same time, the number of causative variants, identified in large resequencing projects, has exponentially increased [3][4][5][6][7] . Interestingly, most currently known genes are also responsible for separate different clinical entities, confirming the extreme phenotypic divergence observed in the field of genetic myopathies 8 . > More advanced histopathological techniques and refined cell and molecular biology studies have resulted in a better understanding of the pathophysiology of distal myopathies. Clinical, histopathological, and imaging features of each form have been partly clarified, addressing the diagnosis, and supporting a proper interpretation in case of novel variants identified in previously known genes.

[17] Proteomic analysis of nemaline myopathy in infants reveals distinct common dysregulated proteins and cellular pathways

  • Authors: C. Hedberg-Oldfors, A. Bedir, K. Visuttijai, E. Michael, Anders Oldfors
  • Year: 2025
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/870b6061aa1438faff4570dec1d4b015934ef0d2
  • DOI: 10.3389/fneur.2025.1661747
  • PMID: 41111967
  • PMCID: 12531377
  • Summary: Proteomic profiling study has identified key dysregulated proteins and pathways in infantile nemaline myopathy that advance the understanding of the disease’s molecular basis and highlight candidate targets for future therapeutic intervention.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Nemaline myopathy is one of the most common forms of congenital myopathy and is characterized by the presence of numerous small protein aggregates named nemaline rods in the muscle fibers (1). Nemaline myopathies have traditionally been classified into different types based on their clinical presentation (2, 3). At least 12 different genes have been associated with nemaline myopathy, NEB encoding nebulin and ACTA1 encoding alpha-actin are the most prevalent (4). Nemaline myopathy caused by pathogenic NEB variants usually show recessive inheritance while ACTA1 associated nemaline myopathy is usually caused by dominant, mostly de novo, variants (3). All nemaline myopathies seem to be associated with proteins involved in the structure and function of the thin filaments of the sarcomere (3). In spite of the many genes involved there are morphological similarities with regard to the common pathological hallmark, the nemaline rods, but there are also differences with regard to fiber type composition, severity of morphological changes as well as age-related changes (5,6). Currently, there are no therapies available for nemaline myopathy. Proteomic analysis of affected muscle tissue is an emerging research field that may, together with genomics, help identify dysregulated proteins and protein networks to reveal pathobiological mechanisms, novel biomarkers, and identify potential therapeutic interventions in neuromuscular disorders (7). In this study, we used a proteomic approach to identify dysregulated proteins and altered cellular pathways in muscle at infancy of the two major genetic forms of nemaline myopathy with similar clinical phenotype and muscle biopsy histopathology. This work identified several dysregulated proteins, which are potential targets to treat nemaline myopathy.

[18] Navigating gastrointestinal challenges in genetic myopathies: Diagnostic insights and future directions

  • Authors: Mohammed Al-Beltagi, N. Saeed, A. Bediwy, Reem Elbeltagi
  • Year: 2025
  • Venue: World Journal of Methodology
  • URL: https://www.semanticscholar.org/paper/a5abc3a3a7e2f39d81ddbd4fc70620cdfaab5e38
  • DOI: 10.5662/wjm.v15.i4.102408
  • PMID: 40900856
  • PMCID: 12400393
  • Summary: This review underscores the complexity of GI manifestations in genetic myopathies and the need for a comprehensive, multidisciplinary management approach and has implications for both clinical practice and public health.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > These disruptions are usually caused by mutations in genes crucial for muscle structure, repair, and contraction [43]. These mutations can affect genes that encode important proteins like dystrophin, sarcoglycans, DYSF, calpain, or laminin, leading to compromised muscle fiber stability, impaired muscle membrane integrity, and abnormal calcium homeostasis [83]. > LGMD2A is caused by mutations in the CAPN3 gene, impacting a crucial protein in maintaining muscle structure. LGMD2B, on the other hand, is caused by mutations in the DYSF gene, which affects a protein involved in membrane repair and signaling pathways in muscle cells [84]. Finally, LGMD1B results from mutations in LMNA genes, which affect muscle cell gene expression and function by affecting proteins essential for maintaining the nuclear envelope. These disruptions increase the likelihood of muscle damage, impaired muscle regeneration, and, ultimately, progressive muscle wasting and weakness [85]. Inflammatory processes and oxidative stress also contribute to developing LGMD, worsening muscle damage. The specific molecular mechanisms that cause the different subtypes of LGMD can vary, reflecting the diverse genetic causes and underlying pathways involved [86]. Understanding these molecular changes is crucial for developing targeted therapies and interventions to halt or slow the progression of LGMD. > Congenital myopathies arise from mutations affecting genes encoding proteins crucial for skeletal muscle structure, function, and regulation. Mutations in genes such as ACTA1, RYR1, MTM1, and selenoprotein N have been implicated in various forms of congenital myopathies, including nemaline myopathy, central core disease, myotubular myopathy, and congenital fiber-type disproportion [87]. Molecular studies have revealed diverse mechanisms contributing to muscle dysfunction, including disruption of sarcomere organization, impaired calcium handling, defective protein synthesis, and altered oxidative metabolism [88]. Dysregulation of signaling pathways involved in muscle development, such as the RhoA-ROCK pathway, has also been implicated in the pathogenesis of congenital myopathies [2].

[19] Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery

  • Authors: K. Llewellyn, A. Nalbandian, Lan Weiss, I. Chang, Howard Yu et al.
  • Year: 2017
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/8f47d29199964591678cb84f32e4991cd50e833a
  • DOI: 10.1371/journal.pone.0176919
  • PMID: 28575052
  • PMCID: 5456028
  • Citations: 14
  • Influential citations: 1
  • Summary: The differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2) illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Human induced pluripotent stem cells (hiPSCs) represent a versatile model system for studying diseases that affect a number of organs. When given the proper stimuli, hiPSCs can be differentiated into a number of desired cell types and tissues. Moreover, the consistency, expandability, and purity of the hiPSCs provide a valuable tool to screen and test drugs in vitro. Therefore, developing robust iPSC models of both rare and common disorders is an excellent option for those diseases requiring poorly accessible and/or limited availability tissue samples. Due to the pleiotropic nature of VCP disease, we recently established iPSC lines to elucidate the pathobiology and cellular and molecular mechanisms underlying this disease [55]. In the present study, we report the differentiation of VCP disease-specific hiPSCs into a myogenic lineage for the discovery of the underlying molecular mechanisms and the development of a drug-screening assay offering the significant possibility to intervene in the early stages of the disease. Ultimately, knowledge of the cellular and molecular signaling pathways affected by VCP mutations provides future promise in the development, assessment, and clinical application of pharmacological and gene therapies to prevent or slow down the progression of VCP disease. > We previously reported differentiation and characterization of VCP patient hiPSCs into a neural lineage [55]. These differentiated neural cells showed all the typical hallmarks of VCP pathology, including increased p62/SQSTM1, LC3-I/II and TDP-43. Inclusion body myopathy (IBM) is the most common feature present in 80-90% of affected VCP patients [5,31]. Typically, the progressive muscle weakness rapidly advances resulting in patient mortality from cardiomyopathy or respiratory failure between approximately 40-60 years of age. The differentiation of human iPSCs into skeletal muscle cells has been challenging with methods ranging from serial media changes to viral infection of myogenic genes such as Pax7 [47,64,68]. Of note, an interesting observation we made was that staining with early myogenic precursor markers such as MYF-5, desmin, and Pax7 illustrated increased expression from Day 21, and they are still expressed at Day 50.

[20] Protein Structure-Function Relationship at Work: Learning from Myopathy Mutations of the Slow Skeletal Muscle Isoform of Troponin T

  • Authors: A. Mondal, J.-P. Jin
  • Year: 2016
  • Venue: Frontiers in Physiology
  • URL: https://www.semanticscholar.org/paper/fc0c4b1c4d10098b517e3d7c94a53c93e6a7b272
  • DOI: 10.3389/fphys.2016.00449
  • PMID: 27790152
  • PMCID: 5062619
  • Citations: 21
  • Influential citations: 2
  • Summary: This focused review summarizes the current knowledge of TnT isoform regulation, structure-function relationship of TNT and how various ssTnT mutations cause recessive NM, in order to promote in depth studies for further understanding the pathogenesis and pathophysiology of TNNT1 myopathies toward the development of effective treatments.
  • Evidence snippets:
  • Snippet 1 (score: 0.380) > The truncated ANM slow TnT fragment is not detectable in the patient muscle (Jin et al., 2003), indicating a rapid degradation of non-myofilament associated TnT protein and fragments in muscle cells (Wang et al., 2005). This effective removal of mutant or damaged TnT from the myocytes when they are not integrated in the myofibrils is an important protective mechanism to avoid cytotoxic effect (Jeong et al., 2009). This mechanism also explains how the various TNNT1 mutations reported to date all present as recessively inherited diseases (Johnston et al., 2000;van der Pol et al., 2014;Marra et al., 2015;Abdulhaq et al., 2016). On the other hand, this mechanism converts a potentially dominant negative mutation into a recessive mutation, which calls for more extensive genetic screening of TnT mutations in the clinical diagnosis of recessive myopathies. > Based on the structural and functional defect of ANM slow TnT mutant, the molecular basis of the pathogenesis and pathophysiology of ANM is the complete loss of slow TnT protein in slow muscle fibers (Jin et al., 2003;Wang et al., 2005). The loss of slow TnT causes atrophy and degeneration of slow twitch muscle fibers that are essential for many vital physiological activities (Jin et al., 2003). In a transgenic mouse models of ANM, slow TnT deficiency caused significant decreases in the contents of type I slow fibers in diaphragm and soleus muscles (Feng et al., 2009;Wei et al., 2014). Although, the slow TnT deficient slow fibers had active regeneration and hypertrophic growth of type II fast fibers, the muscles showed significantly decreased fatigue resistance (Feng et al., 2009;Wei et al., 2014), consistent with the pathophysiological phenotype of posture muscle weakness and respiratory muscle failure in ANM patients (Johnston et al., 2000). > The identification of ANM and subsequent mechanistic studies have promoted clinical awareness of TNNT1 myopathy and its testing in the clinical diagnosis of myopathies.

Notes

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