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Genetic Basis and Epidemiology of Myopathies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 56267

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Dr. Efthimios Dardiotis

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Guest Editor

1. Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, 41110 Larissa, Greece
2. School of Medicine, University of Thessaly, 41110 Larissa, Greece
Interests: neurosciences; neurology; neurogenetics; molecular neurology; cognitive impairment; neurorehabilitation
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Dr. Eleni Peristeri

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Guest Editor

Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Greece
Interests: cognitive decline in neurodegenerative disorders and normal ageing
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Dear Colleagues,

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually appearing from birth, and a static or slowly progressive cognitive decline. Though different candidate genes have now been identified as associated with the various phenotypic and histological expressions of myopathies, the unexpectedly wide genetic and clinical heterogeneity of these disorders calls for more extensive research on the genetic factors influencing their pathogenesis. Furthermore, because of the paucity of neuropsychological data on myopathies, further studies are required to determine the cognitive (sub)domains that are mostly negatively affected, as well as the consistency of cognitive deficits in patients with different types of myopathies. This Special Issue aims at reducing these gaps by collecting studies on the role of genetic factors in the pathogenesis of myopathies as well as on the cognitive impairments that determine the classification of the many forms of myopathies.

Dr. Dardiotis Efthimios
Dr. Eleni Peristeri
Guest Editors

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 181 KiB

Open AccessEditorial

Editorial for Special Issue “Genetic Basis and Epidemiology of Myopathies”

by Eleni Peristeri and Efthimios Dardiotis

Int. J. Mol. Sci. 2021, 22(4), 2152; https://doi.org/10.3390/ijms22042152 - 22 Feb 2021

Viewed by 1563

Abstract

We are pleased to announce a Special Issue on the Genetic Basis and Epidemiology of Myopathies. This Special Issue is collecting papers pertaining to various lines of research focusing on the genetic basis and the epidemiology of myopathies. The Guest Editors’ note combines the contributing authors’ reviews and findings of relevant research, and we hope that future studies on myopathies will attempt to confirm these findings and, additionally, evaluate supplementary phenotypic and histological expressions of myopathies, as well as genetic factors in their pathogenesis. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

Research

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15 pages, 4344 KiB

Open AccessArticle

Description of a Novel Mechanism Possibly Explaining the Antiproliferative Properties of Glucocorticoids in Duchenne Muscular Dystrophy Fibroblasts Based on Glucocorticoid Receptor GR and NFAT5

by Sandrine Herbelet, Boel De Paepe and Jan L. De Bleecker

Int. J. Mol. Sci. 2020, 21(23), 9225; https://doi.org/10.3390/ijms21239225 - 3 Dec 2020

Cited by 6 | Viewed by 2626

Abstract

Glucocorticoids are drugs of choice in Duchenne muscular dystrophy (DMD), prolonging patients’ ambulation. Their mode of action at the protein level is not completely understood. In DMD, muscle tissue is replaced by fibrotic tissue produced by fibroblasts, reducing mobility. Nuclear factor of activated T-cells 5 (NFAT5) is involved in fibroblast proliferation. By treating one DMD fibroblast cell culture and one of unaffected skeletal muscle fibroblasts with methylprednisolone (MP) or hydrocortisone (HC) for 24 h or 12 d, the antiproliferative properties of glucocorticoids could be unraveled. NFAT5 localization and expression was explored by immunocytochemistry (ICC), Western blotting (WB) and RT-qPCR. NFAT5 and glucocorticoid receptor (GR) colocalization was measured by ImageJ. GR siRNA was used, evaluating GR’s influence on NFAT5 expression during MP and HC treatment. Cell proliferation was monitored by IncuCyte ZOOM. In DMD fibroblasts, treatment with MP for 24 h induced dots (ICC) positive for NFAT5 and colocalizing with GR. After 12 d of MP or HC in DMD fibroblasts, NFAT5 expression was decreased (RT-qPCR and WB) and growth arrest was observed (Incucyte ZOOM), whereas NFAT5 expression and cell growth remained unchanged in unaffected skeletal muscle fibroblasts. This study may help understand the antiproliferative properties of glucocorticoids in DMD fibroblasts. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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11 pages, 1400 KiB

Open AccessArticle

Abnormal NFAT5 Physiology in Duchenne Muscular Dystrophy Fibroblasts as a Putative Explanation for the Permanent Fibrosis Formation in Duchenne Muscular Dystrophy

by Sandrine Herbelet, Boel De Paepe and Jan L. De Bleecker

Int. J. Mol. Sci. 2020, 21(21), 7888; https://doi.org/10.3390/ijms21217888 - 24 Oct 2020

Cited by 5 | Viewed by 2884

Abstract

Duchenne muscular dystrophy (DMD) is characterized by chronic inflammation and fibrotic tissue production by fibroblasts. The promyogenic factor nuclear factor of activated T-cells 5 (NFAT5) is virtually present in all cells, responding to hyperosmolar or pro-inflammatory stress. In embryogenic fibroblasts, absence of NFAT5 results in cell cycle arrest. Here, unaffected skeletal muscle fibroblasts from one healthy donor showed NFAT5 nuclear translocation upon hyperosmolar stress and normal cell viability. Absence of NFAT5 translocation under pro-inflammatory conditions resulted in decreased cell growth (Incucyte ZOOM). In DMD skeletal muscle fibroblasts from one DMD patient, NFAT5 was merely located in the nucleus. Exposure to hyperosmolar conditions or pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α had no influence on NFAT5 physiology (immunofluorescence, western blotting, RT-qPCR). Hyperosmolarity resulted in decreased cell viability and pro-inflammatory stress in unaltered cell growth. These findings suggest that NFAT5 is vital to DMD fibroblast survival. Exposure to pro-inflammatory or hyperosmolar stress in DMD fibroblasts results in an unexpected NFAT5 response, where fibroblasts are not triggered by inflammatory cytokines and do not withstand hyperosmolarity. Chronic inflammation could be viewed as a non-restrictive factor in the formation of fibrosis in DMD. Abnormal NFAT5 physiology could provide a molecular explanation for permanent fibrotic matrix production by DMD fibroblasts. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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19 pages, 3531 KiB

Open AccessArticle

Looking for Targets to Restore the Contractile Function in Congenital Myopathy Caused by Gln¹⁴⁷Pro Tropomyosin

by Olga E. Karpicheva, Armen O. Simonyan, Nikita A. Rysev, Charles S. Redwood and Yurii S. Borovikov

Int. J. Mol. Sci. 2020, 21(20), 7590; https://doi.org/10.3390/ijms21207590 - 14 Oct 2020

Cited by 4 | Viewed by 2039

Abstract

We have used the technique of polarized microfluorimetry to obtain new insight into the pathogenesis of skeletal muscle disease caused by the Gln¹⁴⁷Pro substitution in β-tropomyosin (Tpm2.2). The spatial rearrangements of actin, myosin and tropomyosin in the single muscle fiber containing reconstituted thin filaments were studied during simulation of several stages of ATP hydrolysis cycle. The angular orientation of the fluorescence probes bound to tropomyosin was found to be changed by the substitution and was characteristic for a shift of tropomyosin strands closer to the inner actin domains. It was observed both in the absence and in the presence of troponin, Ca²⁺ and myosin heads at all simulated stages of the ATPase cycle. The mutant showed higher flexibility. Moreover, the Gln¹⁴⁷Pro substitution disrupted the myosin-induced displacement of tropomyosin over actin. The irregular positioning of the mutant tropomyosin caused premature activation of actin monomers and a tendency to increase the number of myosin cross-bridges in a state of strong binding with actin at low Ca²⁺. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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Review

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48 pages, 682 KiB

Open AccessReview

Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models

by Aitana Almodóvar-Payá, Mónica Villarreal-Salazar, Noemí de Luna, Gisela Nogales-Gadea, Alberto Real-Martínez, Antoni L. Andreu, Miguel Angel Martín, Joaquin Arenas, Alejandro Lucia, John Vissing, Thomas Krag and Tomàs Pinós

Int. J. Mol. Sci. 2020, 21(24), 9621; https://doi.org/10.3390/ijms21249621 - 17 Dec 2020

Cited by 14 | Viewed by 6231

Abstract

GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

27 pages, 1950 KiB

Open AccessReview

Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

by Wei Chiu, Ya-Hsin Hsun, Kao-Jung Chang, Aliaksandr A. Yarmishyn, Yu-Jer Hsiao, Yueh Chien, Chian-Shiu Chien, Chun Ma, Yi-Ping Yang, Ping-Hsing Tsai, Shih-Hwa Chiou, Ting-Yi Lin and Hao-Min Cheng

Int. J. Mol. Sci. 2020, 21(24), 9589; https://doi.org/10.3390/ijms21249589 - 16 Dec 2020

Cited by 10 | Viewed by 4874

Abstract

Neuromuscular diseases (NMDs) belong to a class of functional impairments that cause dysfunctions of the motor neuron-muscle functional axis components. Inherited monogenic neuromuscular disorders encompass both muscular dystrophies and motor neuron diseases. Understanding of their causative genetic defects and pathological genetic mechanisms has led to the unprecedented clinical translation of genetic therapies. Challenged by a broad range of gene defect types, researchers have developed different approaches to tackle mutations by hijacking the cellular gene expression machinery to minimize the mutational damage and produce the functional target proteins. Such manipulations may be directed to any point of the gene expression axis, such as classical gene augmentation, modulating premature termination codon ribosomal bypass, splicing modification of pre-mRNA, etc. With the soar of the CRISPR-based gene editing systems, researchers now gravitate toward genome surgery in tackling NMDs by directly correcting the mutational defects at the genome level and expanding the scope of targetable NMDs. In this article, we will review the current development of gene therapy and focus on NMDs that are available in published reports, including Duchenne Muscular Dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked myotubular myopathy (XLMTM), Spinal Muscular Atrophy (SMA), and Limb-girdle muscular dystrophy Type 2C (LGMD2C). Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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17 pages, 15319 KiB

Open AccessReview

Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

by Tai-Heng Chen, Yan-Zhang Wu and Yung-Hao Tseng

Int. J. Mol. Sci. 2020, 21(20), 7783; https://doi.org/10.3390/ijms21207783 - 21 Oct 2020

Cited by 8 | Viewed by 7669

Abstract

Facioscapulohumeral muscular dystrophy (FSHD)—the worldwide third most common inherited muscular dystrophy caused by the heterozygous contraction of a 3.3 kb tandem repeat (D4Z4) on a chromosome with a 4q35 haplotype—is a progressive genetic myopathy with variable onset of symptoms, distribution of muscle weakness, and clinical severity. While much is known about the clinical course of adult FSHD, data on the early-onset infantile phenotype, especially on the progression of the disease, are relatively scarce. Contrary to the classical form, patients with infantile FSHD more often have a rapid decline in muscle wasting and systemic features with multiple extramuscular involvements. A rough correlation between the phenotypic severity of FSHD and the D4Z4 repeat size has been reported, and the majority of patients with infantile FSHD obtain a very short D4Z4 repeat length (one to three copies, EcoRI size 10–14 kb), in contrast to the classical, slowly progressive, form of FSHD (15–38 kb). With the increasing identifications of case reports and the advance in genetic diagnostics, recent studies have suggested that the infantile variant of FSHD is not a genetically separate entity but a part of the FSHD spectrum. Nevertheless, many questions about the clinical phenotype and natural history of infantile FSHD remain unanswered, limiting evidence-based clinical management. In this review, we summarize the updated research to gain insight into the clinical spectrum of infantile FSHD and raise views to improve recognition and understanding of its underlying pathomechanism, and further, to advance novel treatments and standard care methods. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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29 pages, 1273 KiB

Open AccessReview

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

by Sandrine Herbelet, Arthur Rodenbach, Boel De Paepe and Jan L. De Bleecker

Int. J. Mol. Sci. 2020, 21(13), 4596; https://doi.org/10.3390/ijms21134596 - 28 Jun 2020

Cited by 22 | Viewed by 5384

Abstract

In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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11 pages, 256 KiB

Open AccessReview

Cognitive Deficits in Myopathies

by Eleni Peristeri, Athina-Maria Aloizou, Paraskevi Keramida, Zisis Tsouris, Vasileios Siokas, Alexios-Fotios A. Mentis and Efthimios Dardiotis

Int. J. Mol. Sci. 2020, 21(11), 3795; https://doi.org/10.3390/ijms21113795 - 27 May 2020

Cited by 9 | Viewed by 2930

Abstract

Myopathies represent a wide spectrum of heterogeneous diseases mainly characterized by the abnormal structure or functioning of skeletal muscle. The current paper provides a comprehensive overview of cognitive deficits observed in various myopathies by consulting the main libraries (Pubmed, Scopus and Google Scholar). This review focuses on the causal classification of myopathies and concomitant cognitive deficits. In most studies, cognitive deficits have been found after clinical observations while lesions were also present in brain imaging. Most studies refer to hereditary myopathies, mainly Duchenne muscular dystrophy (DMD), and myotonic dystrophies (MDs); therefore, most of the overview will focus on these subtypes of myopathies. Most recent bibliographical sources have been preferred. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

27 pages, 991 KiB

Open AccessReview

Update on Congenital Myopathies in Adulthood

by George Konstantinos Papadimas, Sophia Xirou, Evangelia Kararizou and Constantinos Papadopoulos

Int. J. Mol. Sci. 2020, 21(10), 3694; https://doi.org/10.3390/ijms21103694 - 24 May 2020

Cited by 10 | Viewed by 5264

Abstract

Congenital myopathies (CMs) constitute a group of heterogenous rare inherited muscle diseases with different incidences. They are traditionally grouped based on characteristic histopathological findings revealed on muscle biopsy. In recent decades, the ever-increasing application of modern genetic technologies has not just improved our understanding of their pathophysiology, but also expanded their phenotypic spectrum and contributed to a more genetically based approach for their classification. Later onset forms of CMs are increasingly recognised. They are often considered milder with slower progression, variable clinical presentations and different modes of inheritance. We reviewed the key features and genetic basis of late onset CMs with a special emphasis on those forms that may first manifest in adulthood. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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20 pages, 1341 KiB

Open AccessReview

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

by Tai-Heng Chen

Int. J. Mol. Sci. 2020, 21(9), 3297; https://doi.org/10.3390/ijms21093297 - 7 May 2020

Cited by 91 | Viewed by 13776

Abstract

Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics. Full article

(This article belongs to the Special Issue Genetic Basis and Epidemiology of Myopathies)

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