Decoding Neuromuscular Disorders: The Complex Role of Genetic and Epigenetic Regulators

Genes, Год журнала: 2025, Номер 16(6), С. 622 - 622

Опубликована: Май 23, 2025

Neuromuscular disorders (NMDs), such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and dystrophies (e.g., Duchenne dystrophy, DMD), are primarily driven by genetic mutations but critically modulated epigenetic mechanisms DNA methylation, histone modifications, noncoding RNA activity. These processes contribute to phenotypic variability disease progression, emerging evidence suggests that environmental factors, particularly nutrition exercise, may further influence the molecular pathways modulate these diseases. Dietary bioactive compounds polyphenols omega-3 fatty acids) exhibit modulatory properties, which could mitigate oxidative stress, inflammation, muscle degeneration in NMDs. For example, inhibition of DNMTs HDACs curcumin ALS models promyogenic effects green tea catechins DMD suggest plausible, though still requiring investigation, therapeutic avenues. However, clinical application nutriepigenetic interventions is preliminary requires validation. This review examines interaction factors ALS, SMA, dystrophies, highlighting their combined role heterogeneity Integrative strategies combining gene therapies, modulators, lifestyle offer a multidimensional approach management NMD. A deeper understanding interactions will be essential for advancing precision medicine improving patient outcomes.

Язык: Английский

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Translating Muscle RNAseq Into the Clinic for the Diagnosis of Muscle Diseases

Annals of Clinical and Translational Neurology, Год журнала: 2025, Номер unknown

Опубликована: Май 25, 2025

ABSTRACT Objective Approximately half of patients with hereditary myopathies remain without a definitive genetic diagnosis after DNA next‐generation sequencing (NGS). Here, we implemented transcriptome analysis muscle biopsies as complementary diagnostic tool for disease but no exome sequencing. Methods In total, 70 undiagnosed cases suspected muscular dystrophies or congenital were included in the study. Muscle RNAseq comprised aberrant splicing, expression, and monoallelic expression. addition, existing NGS data variant calling from reanalyzed, genome was performed selected cases. Four splicing open‐source tools compared assessed. Results established 10/70 (14.3%) by identifying transcripts produced single nucleotide variants (7/10) copy number (3/10). Reanalysis allowed 9/70 individuals (12.9%). Based on this cohort, FRASER that reported more outlier events per sample while showing highest accuracy (81.26%). Conclusions We demonstrate utility causative diseases. Evaluation four efficient identification most pathogenic events, obtaining manageable candidate manual inspection, demonstrating feasibility translation into clinical setting. also show how integration omic technologies reduces turnaround time to identify variants.

Язык: Английский

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Phenotype-driven genomics enhance diagnosis in children with unresolved neuromuscular diseases

European Journal of Human Genetics, Год журнала: 2024, Номер unknown

Опубликована: Сен. 27, 2024

Язык: Английский

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Neuromuscular diseases: genomics-driven advances

Genomics & Informatics, Год журнала: 2024, Номер 22(1)

Опубликована: Ноя. 26, 2024

Abstract Neuromuscular diseases (NMDs) are a group of rare disorders characterized by significant genetic and clinical complexity. Advances in genomics have revolutionized both the diagnosis treatment NMDs. While fewer than 30 NMDs had known causes before 1990s, more 600 now been identified, largely due to adoption next-generation sequencing (NGS) technologies such as whole-exome (WES) whole-genome (WGS). These enabled precise earlier diagnoses, although complexity many continues pose challenges. Gene therapy has transformative breakthrough In spinal muscular atrophy (SMA), therapies like nusinersen, onasemnogene abeparvovec, risdiplam dramatically improved patient outcomes. Similarly, Duchenne dystrophy (DMD) seen progress, most notably with FDA approval delandistrogene moxeparvovec, first micro-dystrophin gene therapy. Despite these advancements, challenges remain, including rarity NMDs, heterogeneity, high costs associated genomic therapies. Continued progress therapy, RNA-based therapeutics, personalized medicine holds promise for further breakthroughs management debilitating diseases.

Язык: Английский

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A novel homozygous nonsense variant in COL12A1 causes myopathic Ehlers‐Danlos syndrome: A case report and literature review

Neuropathology and Applied Neurobiology, Год журнала: 2024, Номер 50(4)

Опубликована: Авг. 1, 2024

The authors declare that they have no known competing financial interests or personal relationships could appeared to influence the work reported in this paper. data support findings of study are available on request from corresponding author. not publicly due privacy ethical restrictions. Figure S1 Characteristic features myopathic Ehlers-Danlos syndrome (mEDS) (A) Patient showing narrow high arch palate. (B) Sole finely wrinkled skin characteristic EDS. (C) patient a supine position frog sign denoting muscle hypotonia and funnel chest deformity. (D) Hyper laxity toes. (E) Coronal T2WI MRI severe scoliosis kyphosis with convexity left. S2 Genetic analysis collagen XII schematic diagram structure Family tree parents consanguineous marriages proband. electropherogram shows homozygous variant, c.4240C > T (p.R1414*) COL12A1. variant was heterozygous both asymptomatic Sanger sequencing data, A collagen-XII (long isoform short isoform) sites found current previously patients. Please note: publisher is responsible for content functionality any supporting information supplied by authors. Any queries (other than missing content) should be directed author article.

Язык: Английский

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Muscle ultrastructure and histopathological findings in a Brazilian single-centre series of genetically classified telethoninopathy patients

Surgical and Experimental Pathology, Год журнала: 2024, Номер 7(1)

Опубликована: Авг. 9, 2024

Abstract Background Telethoninopathy or TCAP -gene related Limb Girdle Muscular Dystrophy is a rare genetic disease that was first described in Brazil. There are around 100 families reported worldwide. Due to its rarity, detailed information on muscle biopsy light and electron microscopic features lacking. Cases presentation Retrospective study of consecutive biopsies performed patients from Neuromuscular Outpatient Clinic between 2011 2023. Inclusion criteria: telethoninopathy diagnosed by both immunohistochemistry molecular studies. Seven (0.7% 7/953) were found: five male two female, admitted 6 54 years old. Detailed microscopy findings illustrated. Muscle imaging presented. A dystrophic pattern found 57% (4/7) the patients. Other 43% (3/7) presented myopathic such as variation fibre calibre, nuclear internalization, rimmed vacuoles, oxidative irregularities. Morphometry disclosed type 1 lobulated fibres 34%, 52%, smaller than 2 fibres, respectively, three patients, without predominance. Electron demonstrated pseudoinclusions, pyknosis, multifocal loss sarcolemma, 17 nm intrasarcoplasmic filamentous inclusions. All presented: (1) complete absence immunohistochemical expression telethonin, (2) homozygous c.157C > T, p.(Gln53*) pathogenic variant exon gene. Conclusion Anti-telethonin may be helpful unsolved cases with nonspecific abnormalities, specially small fibres. Appropriate diagnosis important for adequate counselling.

Язык: Английский

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Essential neuromuscular advice for pathologists (first of two parts)

Surgical and Experimental Pathology, Год журнала: 2024, Номер 7(1)

Опубликована: Дек. 4, 2024

Abstract Background Neuromuscular disorders are characterized by disturbances in any part of the neurologic pathways, including: Central Nervous System, motor neuron anterior horn spinal cord; peripheral nerve, neuromuscular junction, and muscle. considered rare affections but when prevalences all subtypes analysed together they may be encountered general neurologists pathologists. Therefore, basic knowledge this field is necessary to timely guide serologic, molecular, or muscle biopsy investigation for appropriate treatment and/or genetic counselling. Main body The aims review are: (1) briefly describe prevalence common disorders; (2) present concepts topographic diagnosis; (3) provide essential information pathologists about diagnostic approach (4) imaging myopathologists; (5) imaging, examples disorders. Conclusion A multiprofessional integrated precise diagnosis. Detailed clinical examination with formulation phenotypic hypothesis basis diagnosis Surgical-Molecular Pathology era. Clinical, epidemiological, neurophysiological, laboratorial, physiopathologic aspects adequate

Язык: Английский

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2024 update of the National French consensus on gene lists for the diagnosis of muscle diseases using high-throughput sequencing

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 22, 2024

Diagnosing rare muscle diseases can be challenging due to their genetic heterogeneity. In order coordinate the diagnosis by a gene panel approach, French National Network for Rare Neuromuscular Diseases (FILNEMUS) has previously established pioneering nationwide strategy based on lists organized in 13 phenotype-specific panels. We now provide revised guidelines that add 47 recently described muscle-disease causing genes and update gene-disease relationships initially included genes. Using data collected from all FILNEMUS molecular laboratories, we also establish "Major Muscle Genes Panel" includes responsible most frequent diseases, providing first-tier test if choice of is not clear. The updated diagnostic network will help avoiding unnecessary analysis variants uncertain significance, reduce turn-around time results facilitate rapid access national genome sequencing platforms.

Язык: Английский

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Detection of gene variants associated with recessive limb–girdle muscular weakness and Pompe disease in a global cohort of patients through the application of next-generation sequencing analysis

Frontiers in Genetics, Год журнала: 2024, Номер 15

Опубликована: Ноя. 29, 2024

Hereditary myopathies arise due to numerous pathogenic variants occurring in distinct genes, which amount several hundred. Limb-girdle muscular dystrophies (LGMDs) constitute a heterogeneous group of neuromuscular disorders involving more than 30 genes. Clinically, LGMD is characterized by limb-girdle weakness (LGMW). Late-onset Pompe disease an important disorder with differential diagnosis for LGMD, where next-generation sequencing (NGS) plays crucial role accurate and prompt diagnosis. The sensitivity specificity 10-gene NGS panel have been previously evaluated the prevalent forms recessive (LGMD-R) Latin American patients LGMW unknown cause. This project aims identify regional relative prevalence frequent LGMD-R subtypes larger geographic area diagnose identifying genetic disease.

Язык: Английский

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Next-Generation Sequencing in Myopathies

Elsevier eBooks, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Язык: Английский

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