Treating neuromuscular diseases: unveiling gene therapy breakthroughs and pioneering future applications

Journal of Biomedical Science, Год журнала: 2025, Номер 32(1)

Опубликована: Фев. 21, 2025

Abstract In this review, we highlight recent advancements in adeno-associated virus (AAV)-based gene therapy for genetic neuromuscular diseases (NMDs), focusing on spinal muscular atrophy (SMA) and Duchenne dystrophy (DMD). We discuss the current FDA-approved therapies NMDs provide updates preclinical studies that demonstrate potential of various AAV-based to reduce SMA severity serve as effective treatments DMD. Additionally, explore transformative impact CRISPR/Cas9 technology future NMDs. Despite these encouraging developments, further research is required identify robust biomarkers can guide treatment decisions predict outcomes. Overall, pioneering lay groundwork efforts aimed at curing offer a roadmap developing other neurodegenerative diseases.

Язык: Английский

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Proteomic Profiling Towards a Better Understanding of Genetic Based Muscular Diseases: The Current Picture and a Look to the Future

Biomolecules, Год журнала: 2025, Номер 15(1), С. 130 - 130

Опубликована: Янв. 15, 2025

Proteomics accelerates diagnosis and research of muscular diseases by enabling the robust analysis proteins relevant for manifestation neuromuscular in following aspects: (i) evaluation effect genetic variants on corresponding protein, (ii) prediction underlying defect based proteomic signature muscle biopsies, (iii) pathophysiologies different entities diseases, key definition new intervention concepts, (iv) patient stratification according to biochemical fingerprints as well (v) monitoring success therapeutic interventions. This review presents—also through exemplary case studies—the various advantages mass proteomics investigation discusses technical limitations, provides an outlook possible future application concepts. Hence, is excellent large-scale analytical tool diagnostic workup (hereditary) warrants systematic profiling pathophysiological processes. The steady development may allow overcome existing limitations including a quenched dynamic range quantification protein isoforms. Future directions include targeted settings using not only biopsies but also liquid address need minimally invasive procedures.

Язык: Английский

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Disease Trajectories of a Large French Cohort of 142 Congenital Myopathy Patients in Adult Age

European Journal of Neurology, Год журнала: 2025, Номер 32(4)

Опубликована: Март 30, 2025

ABSTRACT Background Congenital myopathies (CMyo) are a group of rare inherited muscle disorders classified to date according myopathological features on biopsy. They usually present with an early onset, slow or non‐progressive weakness. The phenotypic spectrum is wide, ranging from severe onset forms milder and later conditions. Data regarding the disease trajectory CMyo in adult patients lacking. Here, we describe clinical, myopathological, genetic large cohort facilitate their management adulthood. Methods Global data 142 myopathologically genetically defined patients, 76 women 66 men, followed at Institute Myology Pitié‐Salpêtrière Hospital, were retrospectively analyzed focusing muscular phenotype, cardiac, respiratory assessment. Results RYR1 ‐ related was most represented entity ( N = 65, 45%), by DNM2‐related 26, 18%). Eighty‐two percent presented prenatal, infancy childhood including delayed motor milestones. An as > 18 years (median age 43 years), identified 15% 18). Fifteen wheelchair‐bound. poorest outcome found SELENON‐related patients. Conclusions This observational study provides long‐term progression CMyo. Adult generally mild disability follow‐up. Nevertheless, subset experienced loss gait failure. should be considered differential diagnosis adult‐onset due but possible late‐onset forms.

Язык: Английский

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Lipid storage myopathy associated with sertraline treatment is an acquired mitochondrial disorder with respiratory chain deficiency

Acta Neuropathologica, Год журнала: 2024, Номер 148(1)

Опубликована: Ноя. 26, 2024

Lipid storage myopathies are considered inborn errors of metabolism affecting the fatty acid and leading to accumulation lipid droplets in cytoplasm muscle fibers. Specific diagnosis is based on investigation organic aids urine, acylcarnitines blood genetic testing. An acquired myopathy patients treated with antidepressant drug sertraline, a serotonin reuptake inhibitor, has recently emerged as new tentative differential diagnosis. We analyzed biopsy tissue group 11 adult weakness which developed at time when they were sertraline treatment. This comprise most western Sweden during recent nine-year period. By enzyme histochemistry, electron microscopy, quantitative proteomics, immunofluorescence respiratory chain subunits, blot analyses we demonstrate that this exhibit characteristic morphological proteomic profile. The also showed an acylcarnitine profile suggestive multiple acyl-coenzyme A dehydrogenase deficiency, but no explanation was found by whole genome or exome sequencing. analysis revealed profound loss Complex I subunits from some extent deficiency II IV. Most other components well oxidation citric cycle upregulated accordance massive mitochondrial proliferation. verified analysis, histochemistry. typical ultrastructural changes mitochondria included pleomorphism, dark matrix frequent round osmiophilic inclusions. Our results show associated treatment disorder important features.

Язык: Английский

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Estimating the Prevalence of Autosomal Recessive Neuromuscular Diseases in the Korean Population

Journal of Korean Medical Science, Год журнала: 2025, Номер 40

Опубликована: Янв. 1, 2025

Genetic neuromuscular diseases (NMDs) are a heterogeneous group of conditions that primarily affect the peripheral nerves, muscles, and junctions. This study was performed to identify pathogenic or likely variants (PLPVs), calculate carrier frequencies, predict genetic prevalence autosomal recessive-NMDs (AR-NMDs) in Korean population. In total, 267 genes were associated with AR-NMDs. We analyzed from 984 whole genomes identified PLPVs assess frequency variants. 165 PLPVs, including 75 literature verified 90 manually Most AR-NMD frameshifts (61, 37.0%), followed by nonsense (36, 21.8%), missense (35, 21.2%), splice (28, 17.0%). The AR-NMDs 27.1%. DYSF exhibited highest (1.63%), GAA (1.55%), HEXB (1.53%), PREPL (0.76%), NEB (0.66%), ADSS1 (0.65%), ALPK3 CHRNG (0.65%). predicted population 38.0 cases per 100,000 individuals. (6.7 individuals) showed prevalence. variant allele c.1250C>T at 0.00764, c.[752T>C; c.761C>T] 0.00505, c.2055+2T>G 0.00437. Our suggests 27.1% healthy carriers least one causing PLPV, revealing NMDs

Язык: Английский

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Essential neuromuscular advice for pathologists: Limb Girdle Muscular Dystrophy (second of two parts)

Surgical and Experimental Pathology, Год журнала: 2025, Номер 8(1)

Опубликована: Фев. 20, 2025

Abstract Background Limb Girdle Muscular Dystrophy is defined as a group of progressive autosomal recessive (85%, 28 genes) and dominant (15%, 5 muscular dystrophies described in at least two unrelated families, affecting individuals that achieve independent walking, with predominant proximal muscles weakness presentation, elevated serum creatine kinase activity, dystrophic changes on muscle biopsy, degeneration imaging over the course disease. Main body The aims this review are: (1) to show recent (LGMD) genetic classification illustrated clinical physiopathological characteristics, cellular localization main gene products; (2) present radiophenotypes an algorithm for differential diagnosis; (3) role biopsy phenotypic characterization, pathogenicity confirmation era surgical-molecular pathology. Conclusion Pathologists may be aware clinical, neurophysiological, laboratorial, imaging, molecular, modalities provide precise phenotypic-genotypic diagnosis adequate rehabilitation care, counselling.

Язык: Английский

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NEUROMYODredger: Whole Exome Sequencing for the Diagnosis of Neurodevelopmental and Neuromuscular Disorders in Seven Countries

Clinical Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Although substantial advancements have been made in genetic testing, several barriers continue to limit patient access, leading delays diagnosis, effective treatments, and preventative measures. The NEUROMYODredger-3billion Megaproject End the Diagnostic Odyssey grant offered free whole exome sequencing (WES) 245 patients with undiagnosed neurodevelopmental or neuromuscular disorders seven countries: Algeria, Chile, Egypt, France, Mexico, Peru, Romania. We found pathogenic variants 79 (diagnostic yield 32.24%)-36 (43.90%) 43 (26.38%). Fifty harboured of uncertain significance (VUS, 20.40%)-14 (17.07%) 36 (22.08%), 116 had negative results (47.34%). NEUROMYODredger helped end diagnostic odyssey around 30% patients, while ongoing functional studies reanalysis strategies are used order reach more diagnoses. In conclusion, a singleton WES approach is valuable determining diagnosis diseases, especially low middle-income countries.

Язык: Английский

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Limb Girdle Muscular Dystrophies

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

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Myofibrillar Myopathies

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Congenital Myopathies

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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