Limb-girdle Research Articles

Comorbidity of bathing suit ichthyosis and limb-girdle muscular dystrophy type 2 A in a Tunisian patient revealed by Whole Exome Sequencing

Elevated rates of consanguinity and inbreeding are responsible for the high prevalence of recessively inherited diseases among inbred populations including Tunisia. In addition, the co-occurrence of two of these conditions, called also comorbidity, within the same individual or in members of the same family are often described in Tunisia which is challenging for diagnosis. The high throughput sequencing has improved the diagnosis of inherited diseases. We report here on a 32-year-old woman born to consanguineous parents. She presented with congenital ichthyosis and muscular dystrophy. She was primarily suspected as suffering from Chanarin-Dorfman syndrome (CDS) with unusual form. Screening of founder mutations allowed only the elucidation of the molecular etiology of Ichthyosis. As the result was inconclusive, Whole Exome Sequencing (WES) was conducted. WES data analysis led to the identification of a mutation in the CAPN3 gene underlying limb-girdle muscular dystrophy type 2A (LGMD2A). Sanger sequencing confirmed the familial segregation of mutations. This work presents the first case worldwide of individual comorbidity of bathing suit ichthyosis and LGMD2A. The co-occurrence of two diseases should be systematically considered when establishing a diagnosis especially in consanguineous populations. WES is a powerful tool for molecular diagnosis in particular for revealing comorbidities and rectifying the diagnosis.

Health-Related Quality of Life in FKRP-Related Limb-Girdle Muscular Dystrophy R9.

Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care. To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality. Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i.e., Individualized Neuromuscular Quality of Life questionnaire (INQoL) and the 36-item Short Form (SF-36) at baseline, 8, and 14 months and measures of fatigue and sleep quality at 9 months. HRQoL response rate was 84/90 (75 c.826 C > A homozygotes and nine c.826 C > A compound heterozygotes). Compared to Norwegian normative data, all SF-36 domain scores were impaired (p≤0.006) except mental health in males (p = 0.05) and pain scores. During 14 months, perceived muscle weakness and the INQoL index (disease burden) worsened in c.826 C > A homozygotes. Compound heterozygotes reported more dysphagia and physical difficulties than homozygotes and showed a tendency towards worsening in weakness over time but some improvement on the INQoL index. Homozygous females reported generally poorer HRQoL and a higher burden than males. The INQoL index was related to perceived muscle weakness and fatigue, and fatigue to myalgia and mental distress. The prevalence of fatigue and poor sleep was 40% and 49%, respectively. The 14-month follow-up period shows a worsening of perceived weakness and burden in c.826 C > A homozygotes, which can then be expected. The prevalence and impact of fatigue indicate a need for awareness and treatment of fatigue. Myalgia and mental distress are potential targets in the treatment of fatigue, which future studies need to establish. Sleep issues and gender-specific care needs also require attention in LGMDR9.

Limb-girdle muscular dystrophies: An update

Limb-girdle muscular dystrophies (LGMDs) are a heterogenous group of genetically driven muscle disorders, which share the two common features of progressive, predominantly proximal girdle skeletal muscle involvement and dystrophic changes on pathology. This is a rapidly expanding landscape in neurology both in relation to diagnosis as well as evolving targeted treatment options. Thirty-one LGMD subtypes are described to date; five of autosomal dominant inheritance and 26 of autosomal recessive transmission. This article describes their pathogenesis, clinical presentation, diagnosis and recent therapeutic advances.

The Profiling of 179 miRNA Expression in Serum from Limb Girdle Muscular Dystrophy Patients and Healthy Controls.

Limb girdle muscular dystrophies (LGMDs) are a group of genetically inherited neuromuscular diseases with a very variable clinical presentation and overlapping traits. Over the last few years there has been an increasing interest in the use of non-invasive circulating biomarkers to monitor disease progression and to evaluate the efficacy of therapeutic approaches. Our aim was to identify the miRNA signature with potential value for LGMD patient screening and stratification. Using miRCURY LNA miRNA qPCR Serum/Plasma Panel, we analyzed 179 miRNAs from 16 patients, divided in four pools based on their genetic diagnosis, and from healthy controls. The miRNAs analysis showed a total of 107 dysregulated miRNAs in LGMD patients when compared to the healthy controls. After filtering via skeletal tissue expression and gene/pathways target analysis, the number of dysregulated miRNAs drastically reduced. Six selected miRNAs-let-7f-5p (in LGMDR1), miR-20a-5p (in LGMDR2), miR-130b-5p, miR-378a-5p (both in LGMDR3), miR-376c-3p and miR-382-5p (both in LGMDR4)-whose expression was significantly lower compared to controls in the different LGMD pools, were further investigated. The bioinformatic analysis of the target genes in each selected miRNA revealed ECM-receptor interaction and TGF-beta signaling as the most involved pathways. The correlation analysis showed a good correlation of let-7f-5p with fibrosis and with the cross sectional area of type I and type II fibers, while miR-130b-5p showed a good correlation with the age of onset of the disease. The receiver operating characteristic curves showed how single miRNAs were able to discriminate a specific group of LGMD patients and how the combination of six miRNAs was able to discriminate LGMD patients from controls.

Effectiveness of conservative non-pharmacological interventions in people with muscular dystrophies: a systematic review and meta-analysis

IntroductionManagement of muscular dystrophies (MD) relies on conservative non-pharmacological treatments, but evidence of their effectiveness is limited and inconclusive.ObjectiveTo investigate the effectiveness of conservative non-pharmacological interventions for MD physical management.MethodsThis...

MicroRNA as potential biomarker for severity, progression, and therapeutic monitoring in animal models of limb-girdle muscular dystrophy: a systematic review.

Limb-girdle muscular dystrophies (LGMD) constitute a heterogeneous group of neuromuscular disorders in which there are alterations in proteins responsible for the preservation of muscle architecture and function, leading to proximal and progressive muscle weakness. There is, however, significant phenotypic and genotypic variation, as well as difficulty in establishing biomarkers that help to define pathogenic mechanisms and assess disease severity and progression. In this field, there is special attention to microRNAs, small non-coding RNA molecules related to the regulation of gene expression and, consequently, the production of proteins. Thus, this research aimed to verify the correlation between the expression of microRNAs and the severity, progression, and therapeutic response of LGMD animal models. A search was carried out in the PubMed, Embase, Scopus, ScienceDirect, Cochrane, and SciELO databases, with articles in English and without a time limit. The PRISMA 2020 checklist was used, and the protocol of this review was submitted to PROSPERO. The bibliographic survey of the 434 records found that 5 original articles met the inclusion criteria. The studies explored myomicroRNAs or miRNA panels with gene expression analysis. The analysis demonstrates that miR-1, 133a, and 206 are differentially expressed in serum and muscle. They change according to the degree of inflammation, fibrosis, muscle regeneration, and progression of the dystrophic process. MicroRNAs are up-regulated in dystrophic muscles, which are reversed after treatment in a dose-dependent manner. The present study inferred that miRs are essential in severity, progression, and therapeutic response in LGMD models and may be a useful biomarker in clinical research and prognosis. However, the practical application of these findings should be further explored.

Misfolding of fukutin-related protein (FKRP) variants in congenital and limb girdle muscular dystrophies.

Fukutin-related protein (FKRP, MIM ID 606596) variants cause a range of muscular dystrophies associated with hypo-glycosylation of the matrix receptor, α-dystroglycan. These disorders are almost exclusively caused by homozygous or compound heterozygous missense variants in the FKRP gene that encodes a ribitol phosphotransferase. To understand how seemingly diverse FKRP missense mutations may contribute to disease, we examined the synthesis, intracellular dynamics, and structural consequences of a panel of missense mutations that encompass the disease spectrum. Under non-reducing electrophoresis conditions, wild type FKRP appears to be monomeric whereas disease-causing FKRP mutants migrate as high molecular weight, disulfide-bonded aggregates. These results were recapitulated using cysteine-scanning mutagenesis suggesting that abnormal disulfide bonding may perturb FKRP folding. Using fluorescence recovery after photobleaching, we found that the intracellular mobility of most FKRP mutants in ATP-depleted cells is dramatically reduced but can, in most cases, be rescued with reducing agents. Mass spectrometry showed that wild type and mutant FKRP differentially associate with several endoplasmic reticulum (ER)-resident chaperones. Finally, structural modelling revealed that disease-associated FKRP missense variants affected the local environment of the protein in small but significant ways. These data demonstrate that protein misfolding contributes to the molecular pathophysiology of FKRP-deficient muscular dystrophies and suggest that molecules that rescue this folding defect could be used to treat these disorders.

A young female with limb girdle muscle dystrophy type 2 B misdiagnosed for resistant polymyositis

A young female with limb girdle muscle dystrophy type 2 B misdiagnosed for resistant polymyositis

A rare case of anti U3 RNP scleroderma presenting as limb girdle muscle weakeness

A rare case of anti U3 RNP scleroderma presenting as limb girdle muscle weakeness

Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States. This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation. Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (EMD) and autosomal genes reported to have skewed gender ratios (ANO5, CAV3, and LMNA). The most common associated genes were FKRP, CAPN3, ANO5, and DYSF. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive. This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.

Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients

BackgroundLimb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis. The frequency of LGMD subtypes varies among regions in China and ethnic populations worldwide. Here, we analyzed the prevalence of LGMD subtypes, their corresponding clinical manifestations, and molecular data in a cohort of LGMD patients in Southeast China.MethodsA total of 81 consecutive patients with clinically suspected LGMDs from 62 unrelated families across Southeast China were recruited for targeted next-generation sequencing and whole-exome sequencing from July 2017 to February 2020.ResultsAmong 50 patients (41 families) with LGMDs, the most common subtypes were LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%). Dystroglycanopathies (including LGMD-R9/LGMD2I, LGMD-R11/LGMD2K, LGMD-R14/LGMD2N and LGMD-R20/LGMD2U) were the most common childhood-onset subtypes and were found in 12.2% of the families. A total of 14.6% of the families had the LGMD-R7/LGMD2G subtype, and the mutation c.26_33dupAGGTGTCG in TCAP was the most frequent (83.3%). The only patient with the rare subtype LGMD-R18/LGMD2S had TRAPPC11 mutations; had a later onset than those previously reported, and presented with proximal‒distal muscle weakness, walking aid dependency, fatty liver disease and diabetes at 33 years of age. A total of 22.0% of the patients had cardiac abnormalities, and one patient with LMNA-related muscular dystrophy/LGMD1B experienced sudden cardiac death at 37 years of age. A total of 15.4% of the patients had restrictive respiratory insufficiency. Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B.ConclusionWe determined the prevalence of different LGMD subtypes in Southeast China, described the detailed clinical manifestations and distinct muscle MRI patterns of these LGMD subtypes and reported the frequent mutations and the cardiorespiratory involvement frequency in our cohort, all of which might facilitate the differential diagnosis of LGMDs, allowing more timely treatment and guiding future clinical trials.

Cognitive abnormalities in Becker muscular dystrophy: a mysterious link between dystrophin deficiency and executive functions

BackgroundDistrophinopathies are a heterogeneous group of neuromuscular disorders due to mutations in the DMD gene. Different isoforms of dystrophin are also expressed in the cerebral cortex and Purkinje cells. Despite cognitive abnormalities in Duchenne muscular dystrophy subjects that have been described in the literature, little is known about a comprehensive cognitive profile in Becker muscular dystrophy patients.AimThe aim of this study was to assess cognitive functioning in Becker muscular dystrophy patients by using an extensive neuropsychological battery. Our hypothesis is that the most impaired functions are the highly intentional and conscious ones, such as working memory functions, which require a prolonged state of cellular activation.MethodsWe performed an extensive neuropsychological assessment on 28 Becker muscular dystrophy patients from 18 to 65 years old. As control subjects, we selected 20 patients with limb-girdle muscular dystrophy, whose clinical picture was similar except for cognitive integrity. The evaluation, although extended to all areas, was focused on prefrontal control skills, with a distinction between inhibitory processes of selective attention and activating processes of working memory.Results and conclusionsSignificant underperformances were found exclusively in the Dual Task and PASAT tests, to demonstrate a selective impairment of working memory that, while not causing intellectual disability, reduces the intellectual potential of patients with Becker muscular dystrophy.

Ryanodine receptor type 1 content decrease-induced endoplasmic reticulum stress is a hallmark of myopathies.

Decreased ryanodine receptor type 1 (RyR1) protein levels are a well-described feature of recessive RYR1-related myopathies. The aim of the present study was twofold: (1) to determine whether RyR1 content is also decreased in other myopathies and (2) to investigate the mechanisms by which decreased RyR1 protein triggers muscular disorders. We used publicly available datasets, muscles from human inflammatory and mitochondrial myopathies, an inducible muscle-specific RYR1 recessive mouse model and RyR1 knockdown in C2C12 muscle cells to measure RyR1 content and endoplasmic reticulum (ER) stress markers. Proteomics, lipidomics, molecular biology and transmission electron microscopy approaches were used to decipher the alterations associated with the reduction of RyR1 protein levels. RYR1 transcripts were reduced in muscle samples of patients suffering from necrotizing myopathy (P=0.026), inclusion body myopathy (P=0.003), polymyositis (P<0.001) and juvenile dermatomyositis (P<0.001) and in muscle samples of myotonic dystrophy type 2 (P<0.001), presymptomatic (P<0.001) and symptomatic (P<0.001) Duchenne muscular dystrophy, Becker muscular dystrophy (P=0.004) and limb-girdle muscular dystrophy type 2A (P=0.004). RyR1 protein content was also significantly decreased in inflammatory myopathy (-75%, P<0.001) and mitochondrial myopathy (-71%, P<0.001) muscles. Proteomics data showed that depletion of RyR1 protein in C2C12 myoblasts leads to myotubes recapitulating the common molecular alterations observed in myopathies. Mechanistically, RyR1 protein depletion reduces ER-mitochondria contact length (-26%, P<0.001), Ca2+ transfer to mitochondria (-48%, P=0.002) and the mitophagy gene Parkinson protein 2 transcripts (P=0.037) and induces mitochondrial accumulation (+99%, P=0.005) and dysfunction (P<0.001). This was associated to the accumulation of deleterious sphingolipid species. Our data showed increased levels of the ER stress marker chaperone-binding protein/glucose regulated protein 78, GRP78-Bip, in RyR1 knockdown myotubes (+45%, P=0.046), in mouse RyR1 recessive muscles (+58%, P=0.001) and in human inflammatory (+96%, P=0.006) and mitochondrial (+64%, P=0.049) myopathy muscles. This was accompanied by increased protein levels of the pro-apoptotic protein CCAAT-enhancer-binding protein homologous protein, CHOP-DDIT3, in RyR1 knockdown myotubes (+27%, P<0.001), mouse RyR1 recessive muscles (+63%, P=0.009), human inflammatory (+50%, P=0.038) and mitochondrial (+51%, P=0.035) myopathy muscles. In publicly available datasets, the decrease in RYR1 content in myopathies was also associated to increased ER stress markers and RYR1 transcript levels are inversely correlated with ER stress markers in the control population. Decreased RyR1 is commonly observed in myopathies and associated to ER stress in vitro, in mouse muscle and in human myopathy muscles, suggesting a potent role of RyR1 depletion-induced ER stress in the pathogenesis of myopathies.

Clinical and Genetic Characteristics of Limb-Girdle Muscular Dystrophy in Iranian Patients

Background: Limb-girdle muscular dystrophy (LGMD) is a bothersome muscle disease associated with weakness of the shoulder and pelvic girdle. Objectives: The study aimed to determine the genetic diversity and relative frequency of various forms of LGMD in Iranian children. Methods: In this descriptive research, 60 children referred to the neurology or emergency department of the Pediatric Medical Center were studied from April 2019 to April 2020. Additional tests (muscle biopsy and genetic testing) were performed to confirm the diagnosis of LGMDs. Quantitative data such as disease level, motor, respiratory, and cardiac functions, and molecular data underwent statistical analysis. Results: A total of 41 patients with a mean age of 11.1 were studied. Twenty-two patients were diagnosed with genetic tests and 19 with muscle biopsies. Also, there were 26.8% cases of alpha sarcoglycanopathy, 24.4% beta sarcoglycanopathy, 17.1% gamma sarcoglycanopathy, 7.3% calpainopathy, 7.3% dysferlinopathy, 7.3% dystroglycanopathy, 7.3% titinopathy, and one case of laminopathy. Among genetically confirmed individuals, 27.3% had SGCB mutation, and 18.2% had SGCA mutation. A significant relationship was seen between the mutation type and creatine phosphokinase (CPK) levels (P &lt; 0.05). Conclusions: The prevalence of alpha and beta sarcoglycanopathy phenotypes in the study population showed that the severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan expression.

CRISPR/Cas9 Genome Editing in LGMD2A/R1 Patient-Derived Induced Pluripotent Stem and Skeletal Muscle Progenitor Cells.

Large numbers of Calpain 3 (CAPN3) mutations cause recessive forms of limb-girdle muscular dystrophy (LGMD2A/LGMDR1) with selective atrophy of the proximal limb muscles. We have generated induced pluripotent stem cells (iPSC) from a patient with two mutations in exon 3 and exon 4 at the calpain 3 locus (W130C, 550delA). Two different strategies to rescue these mutations are devised: (i) on the level of LGMD2A-iPSC, we combined CRISPR/Cas9 genome targeting with a FACS and Tet transactivator-based biallelic selection strategy, which resulted in a new functional chimeric exon 3-4 without the two CAPN3 mutations. (ii) On the level of LGMD2A-iPSC-derived CD82+/Pax7+ myogenic progenitor cells, we demonstrate CRISPR/Cas9 mediated rescue of the highly prevalent exon 4 CAPN3 mutation. The first strategy specifically provides isogenic LGMD2A corrected iPSC for disease modelling, and the second strategy can be further elaborated for potential translational approaches.

A Straightforward Approach to Analyze Skeletal Muscle MRI in Limb-Girdle Muscular Dystrophy for Differential Diagnosis: A Systematic Review

Skeletal muscle MRI studies in limb-girdle muscular dystrophy (LGMD) have increased over the past decades, improving the utility of MRI as a differential diagnostic tool. Nevertheless, the relative rarity of individual genotypes limits the scope of what each study can address, making it challenging to obtain a comprehensive overview of the MRI image of this splintered group. Furthermore, MRI studies have varied in their methods for assessing fat infiltration, which is essential in skeletal muscle MRI evaluation. It stayed problematic and impeded attempts to integrate multiple studies to cover the core MRI features of a distinct LGMD. In this study, we conducted a systematic review of LGMD in adults published until April 2023; 935 references were screened in PubMed and EMBASE, searches of the gray literature, and additional records were added during the screening process. Finally, 39 studies were included in our final analysis. We attempted to quantitatively synthesize the MRI data sets from the 39 individual studies. Finally, we illustrated ideal and simple MRI muscle involvement patterns of six representative LGMD genotypes. Our summary synthesis reveals a distinct distribution pattern of affected muscles by LGMD genotypes, which may be helpful for a quick first-tier differential diagnosis guiding genetic diagnostics.

Considering the Promise of Vamorolone for Treating Duchenne Muscular Dystrophy.

This commentary provides an independent consideration of data related to the drug vamorolone (VBP15) as an alternative steroid proposed for treatment of Duchenne muscular dystrophy (DMD). Glucocorticoids such as prednisone and deflazacort have powerful anti-inflammatory benefits and are the standard of care for DMD, but their long-term use can result in severe adverse side effects; thus, vamorolone was designed as a unique dissociative steroidal anti-inflammatory drug, to retain efficacy and minimise these adverse effects. Extensive clinical trials (ongoing) have investigated the use of vamorolone for DMD, with two trials also for limb-girdle muscular dystrophies including dysferlinopathy (current), plus a variety of pre-clinical trials published. Vamorolone looks very promising, with similar efficacy and some reduced adverse effects (e.g., related to height) compared with other glucocorticoids, specifically prednisone/prednisolone, although it has not yet been directly compared with deflazacort. Of particular interest to clarify is the optimal clinical dose and other aspects of vamorolone that are proposed to provide additional benefits for membranes of dystrophic muscle: to stabilise and protect the sarcolemma from damage and enhance repair. The use of vamorolone (and other glucocorticoids) needs to be evaluated in terms of overall long-term efficacy and cost, and also in comparison with many candidate non-steroidal drugs with anti-inflammatory and other benefits for DMD.

Prognostic Utility of Cardiovascular Magnetic Resonance-Based Phenotyping in Patients With Muscular Dystrophy.

Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively investigated in adult patients with muscular dystrophy. Methods and Results We prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb-girdle muscular dystrophy, and type 1 myotonic dystrophy (median age, 36.0 [interquartile range, 23.0-50.0] years; 51 [34.5%] women) over 7.7 years in addition to an age- and sex-matched healthy control cohort (n=50). Cardiovascular magnetic resonance markers, including 3-dimensional strain and fibrosis, were assessed for their respective association with major adverse cardiac events. Our results showed that markers of contractile performance were reduced across all muscular dystrophy groups. In particular, the dystrophinopathies cohort experienced reduced left ventricular (LV) ejection fraction and high burden of replacement fibrosis. Patients with type 1 myotonic dystrophy showed a 26.8% relative reduction in LV mass with corresponding reduction in chamber volumes. Eighty-two major adverse cardiac events occurred over a median follow-up of 5.2 years. Although LV ejection fraction was significantly associated with major adverse cardiac events (adjusted hazard ratio [aHR], 3.0 [95% CI, 1.4-6.4]) after adjusting for covariates, peak 3-dimensional strain amplitude demonstrated greater predictive value (minimum principal amplitude: aHR, 5.5 [95% CI, 2.5-11.9]; maximum principal amplitude: aHR, 3.3 [95% CI, 1.6-6.8]; circumferential amplitude: aHR, 3.4 [95% CI, 1.6-7.2]; longitudinal amplitude: aHR, 3.4 [95% CI, 1.7-6.9]; and radial strain amplitude: aHR, 3.0 [95% CI, 1.4-6.1]). Minimum principal strain yielded incremental prognostic value beyond LV ejection fraction for association with major adverse cardiac events (change in χ2=13.8; P<0.001). Conclusions Cardiac dysfunction is observed across all muscular dystrophy subtypes; however, the subtypes demonstrate distinct phenotypic profiles. Myocardial deformation analysis highlights unique markers of principal strain that improve risk assessment over other strain markers, LV ejection fraction, and late gadolinium enhancement in this vulnerable patient population.

Gene therapy for primary myopathies: literature review and prospects

Gene therapy has emerged as a promising frontier in the pursuit of effective treatments for primary myopathies. This scientific review explores the application of viral vectors and more specifically of recombinant adeno-associated virus (rAAV) vectors as a potent gene delivery tool in the context of primary myopathies, highlighting its transformative potential. Focusing on primary myopathies, including Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophies (LGMDs), X-linked myotubular myopathy (XLMTM), and Pompe disease, we review the ongoing pre-clinical and clinical trials that underscore the therapeutic promise of rAAV-based gene therapies. Recent developments in gene therapy have unveiled innovative gene transfer approaches, particularly with rAAV vectors. These vectors offer a well-tolerated and efficient means of delivering corrective genetic material to diseased muscles, thereby addressing the root causes of primary myopathies. Encouraging data from pre-clinical studies and early clinical trials have demonstrated the potential to ameliorate muscle function, reduce pathological manifestations, and enhance the quality of life for patients afflicted with these devastating diseases. However, the transition from bench to bedside is not without challenges. This review emphasizes the critical need for a comprehensive risk management strategy to better handle potential side effects and immune responses associated with gene therapy. As the field of gene therapy for primary myopathies is advancing, it is imperative to refine and optimize safety measures, ensuring that the transformative potential of these therapies is realized while the risks are minimized. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

Machine learning-based radiomics to differentiate immune-mediated necrotizing myopathy from limb-girdle muscular dystrophy R2 using MRI.

This study aimed to assess the feasibility of a machine learning-based radiomics tools to discriminate between Limb-girdle muscular dystrophy R2 (LGMDR2) and immune-mediated necrotizing myopathy (IMNM) using lower-limb muscle magnetic resonance imaging (MRI) examination. After institutional review board approval, 30 patients with genetically proven LGMDR2 (12 females; age, 34.0 ± 11.3) and 45 patients with IMNM (28 females; age, 49.2 ± 16.6) who underwent lower-limb MRI examination including T1-weighted and interactive decomposition water and fat with echos asymmetric and least-squares estimation (IDEAL) sequences between July 2014 and August 2022 were included. Radiomics features of muscles were obtained, and four machine learning algorithms were conducted to select the optimal radiomics classifier for differential diagnosis. This selected algorithm was performed to construct the T1-weighted (TM), water-only (WM), or the combined model (CM) for calf-only, thigh-only, or the calf and thigh MR images, respectively. And their diagnostic performance was studied using area under the curve (AUC) and compared to the semi-quantitative model constructed by the modified Mercuri scale of calf and thigh muscles scored by two radiologists specialized in musculoskeletal imaging. The logistic regression (LR) model was the optimal radiomics model. The performance of the WM and CM for thigh-only images (AUC 0.893, 0.913) was better than those for calf-only images (AUC 0.846, 0.880) except the TM. For "calf + thigh" images, the TM, WM, and CM models always performed best (AUC 0.953, 0.907, 0.953) with excellent accuracy (92.0, 84.0, 88.0%). The AUCs of the Mercuri model of the calf, thigh, and "calf + thigh" images were 0.847, 0.900, and 0.953 with accuracy (84.0, 84.0, 88.0%). Machine learning-based radiomics models can differentiate LGMDR2 from IMNM, performing better than visual assessment. The model built by combining calf and thigh images presents excellent diagnostic efficiency.