-
Journal of Cachexia, Sarcopenia and... Dec 2022Water T2 (T2 ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for...
BACKGROUND
Water T2 (T2 ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2 to identify changes in muscle function over time in limb girdle muscular dystrophies.
METHODS
Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2 value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2 at baseline, age, disease duration, and baseline function.
RESULTS
A higher T2 at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2 in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2 (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2 (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems.
CONCLUSIONS
In dysferlinopathy, T2 did not correlate with current functional ability. However, T2 at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2 measure at baseline. Significant challenges remain in standardizing T2 values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2 could be used to improve prognostication, patient selection, and disease modelling for clinical trials.
Topics: Humans; Water; Muscular Dystrophies, Limb-Girdle; Muscle, Skeletal; Muscular Dystrophies
PubMed: 36058852
DOI: 10.1002/jcsm.13063 -
Human Gene Therapy Jul 2019In a previous limb-girdle muscular dystrophy type 2D (LGMD2D) clinical trial, robust alpha-sarcoglycan gene expression was confirmed following intramuscular gene ()...
In a previous limb-girdle muscular dystrophy type 2D (LGMD2D) clinical trial, robust alpha-sarcoglycan gene expression was confirmed following intramuscular gene () transfer. This paved the way for first-in-human isolated limb infusion (ILI) gene transfer trial to the lower limbs. Delivery of scAAVrh74.tMCK.hSGCA via an intravascular route through the femoral artery predicted improved ambulation. This method was initially chosen to avoid safety concerns required for large systemic vascular delivery viral loads. ILI methods were adopted from the extensive chemotherapy experience for treatment of malignancies confined to the extremities. Six LGMD2D subjects were enrolled in a dose-ascending open-label clinical trial. Safety of the procedure was initially assessed in the single limb of a non-ambulant affected adult at a dose of 1 × 10 vg/kg. Subsequently, ambulatory children (aged 8-13 years) were enrolled and dosed bilaterally with either 1 × 10 vg/kg/limb or 3 × 10 vg/kg/limb. The six-minute walk test (6MWT) served as the primary clinical outcome; secondary outcomes included muscle strength (maximum voluntary isometric force testing) and expression at 6 months. All ambulatory participants except one had pre- and post-treatment muscle biopsies. All four subjects biopsied had confirmed gene delivery by immunofluorescence, Western blot analysis (14-25% of normal), and vector genome copies (5.4 × 10-7.7 × 10 vg/μg). Muscle strength in the knee extensors (assessed by force generation in kilograms) showed improvement in two subjects that correlated with an increase in fiber diameter post gene delivery. Six-minute walk times decreased or remained the same. Vascular delivery of AAVrh74.tMCK. was effective at producing SGCA protein at low doses that correlated with vector copies and local functional improvement restricted to targeted muscles. Future trials will focus on systemic administration to enable targeting of proximal muscles to maximize clinical benefit.
Topics: Animals; Biomarkers; Child; Disease Models, Animal; Female; Gene Expression; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Injections, Intramuscular; Male; Middle Aged; Muscular Dystrophies, Limb-Girdle; Sarcoglycanopathies; Transduction, Genetic; Transgenes; Treatment Outcome
PubMed: 30838895
DOI: 10.1089/hum.2019.006 -
Cells Sep 2021Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes,... (Review)
Review
Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes, organelles, and inner membrane systems. In addition, it interacts with actomyosin structures and microtubules. As a multifunctional protein, plectin has been implicated in several multisystemic diseases, the most common of which is epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). A great part of our knowledge about plectin's functional diversity has been gained through the analysis of a unique collection of transgenic mice that includes a full (null) knockout (KO), several tissue-restricted and isoform-specific KOs, three double KOs, and two knock-in lines. The key molecular features and pathological phenotypes of these mice will be discussed in this review. In summary, the analysis of the different genetic models indicated that a functional plectin is required for the proper function of striated and simple epithelia, cardiac and skeletal muscle, the neuromuscular junction, and the vascular endothelium, recapitulating the symptoms of humans carrying plectin mutations. The plectin-null line showed severe skin and muscle phenotypes reflecting the importance of plectin for hemidesmosome and sarcomere integrity; whereas the ablation of individual isoforms caused a specific phenotype in myofibers, basal keratinocytes, or neurons. Tissue-restricted ablation of plectin rendered the targeted cells less resilient to mechanical stress. Studies based on animal models other than the mouse, such as zebrafish and , will be discussed as well.
Topics: Animals; Disease Models, Animal; Epidermolysis Bullosa Simplex; Humans; Muscular Dystrophies, Limb-Girdle; Mutation; Plectin; Protein Isoforms
PubMed: 34572100
DOI: 10.3390/cells10092453 -
Orphanet Journal of Rare Diseases Aug 2018Limb-girdle muscular dystrophy (LGMD) is a commonly diagnosed hereditary muscular disorder, characterized by the progressive weakness of the limb-girdle muscles....
BACKGROUND
Limb-girdle muscular dystrophy (LGMD) is a commonly diagnosed hereditary muscular disorder, characterized by the progressive weakness of the limb-girdle muscles. Although the condition has been well-characterized, clinical and genetic heterogeneity can be observed in patients with LGMD. Here, we aimed to describe the clinical manifestations and genetic variability among a cohort of patients with LGMD in South China.
RESULTS
We analyzed the clinical information, muscle magnetic resonance imaging (MRI) findings, and genetic results obtained from 30 patients (24 families) with clinically suspected LGMD. In 24 probands, 38 variants were found in total, of which 18 were shown to be novel. Among the 30 patients, the most common subtypes were dysferlinopathy in eight (26.67%), sarcoglycanopathies in eight [26.67%; LGMD 2C in three (10.00%), LGMD 2D in three (10.00%), and LGMD 2F in two (6.67%)], LGMD 2A in seven (23.33%), followed by LGMD 1B in three (10.00%), LGMD 2I in three (10.00%), and early onset recessive Emery-Dreifuss-like phenotype without cardiomyopathy in one (3.33%). Furthermore, we also observed novel clinical presentations for LGMD 1B, 2F, and 2I patients with hypermobility of the joints in the upper limbs, a LGMD 2F patient with delayed language development, and other manifestations. Moreover, distinct distributions of fatty infiltration in patients with LGMD 2A, dysferlinopathy, and the early onset recessive Emery-Dreifuss-like phenotype without cardiomyopathy were also observed based on muscle MRI results.
CONCLUSIONS
In this study, we expanded the clinical spectrum and genetic variability found in patients with LGMD, which provided additional insights into genotype and phenotype correlations in this disease.
Topics: Adolescent; Adult; Age of Onset; Asian People; China; Female; Genetic Variation; Humans; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Young Adult
PubMed: 30107846
DOI: 10.1186/s13023-018-0859-6 -
Molecular Medicine Reports May 2014Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders, which has led to certain investigators disputing its rationality. The mutual feature of... (Review)
Review
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders, which has led to certain investigators disputing its rationality. The mutual feature of LGMD is limb-girdle affection. Magnetic resonance imaging (MRI), perioral skin biopsies, blood-based assays, reverse‑protein arrays, proteomic analyses, gene chips and next generation sequencing are the leading diagnostic techniques for LGMD and gene, cell and pharmaceutical treatments are the mainstay therapies for these genetic disorders. Recently, more highlights have been shed on disease biomarkers to follow up disease progression and to monitor therapeutic responsiveness in future trials. In this study, we review LGMD from a variety of aspects, paying specific attention to newly evolving research, with the purpose of bringing this information into the clinical setting to aid the development of novel therapeutic strategies for this hereditary disease. In conclusion, substantial progress in our ability to diagnose and treat LGMD has been made in recent decades, however enhancing our understanding of the detailed pathophysiology of LGMD may enhance our ability to improve disease outcome in subsequent years.
Topics: Animals; Biomarkers; Genetic Association Studies; Humans; Muscular Dystrophies, Limb-Girdle; Prevalence
PubMed: 24626787
DOI: 10.3892/mmr.2014.2048 -
The British Journal of Radiology Sep 2022To investigate the prevalence, describe the radiological features, and consider the clinical sequelae of COVID-19- associated shoulder girdle calcific myositis.
OBJECTIVE
To investigate the prevalence, describe the radiological features, and consider the clinical sequelae of COVID-19- associated shoulder girdle calcific myositis.
METHODS
All patients who underwent a CT pulmonary angiogram study at our institution (Queen Alexandra Hospital, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom) in April and May 2020, January 2021, and July 2021 were included. A total of 1239 CT pulmonary angiogram studies for 1201 patients were reviewed. Patients with COVID-19 and associated shoulder girdle calcific myositis were identified. Their electronic patient records were reviewed. The patients' demographics, serum inflammatory markers, and proning history were recorded.
RESULTS
Of the 364 patients in Wave 1, 71 patients (19.5%) had COVID-19, and of those, 2 patients (2.8%) had shoulder girdle calcific myositis. Of the 521 patients in Wave 2, 354 patients (67.9%) had COVID-19, and of those, 3 patients (0.8%) had shoulder girdle calcific myositis. Of the 316 patients in Wave 3, 37 patients (11.7%) had COVID-19, and of those, 1 patient (2.7%) had shoulder girdle calcific myositis. The overall prevalence was 1.3%. The most common site of calcific myositis was within the subscapularis muscle.
CONCLUSION
COVID-19-associated shoulder girdle calcific myositis is a rare extrapulmonary musculoskeletal manifestation of COVID-19. Early recognition and increased awareness of this disease entity, in our experience, aids in reducing patient morbidity and improving long-term functional outcome.
ADVANCES IN KNOWLEDGE
We have reported a novel disease entity associated with COVID-19, in the form of shoulder girdle calcific myositis. We have described the common imaging features and discussed our experience of management and clinical sequelae.
Topics: COVID-19; Calcinosis; Humans; Myositis; Rotator Cuff; Shoulder; Tendinopathy
PubMed: 35867893
DOI: 10.1259/bjr.20220411 -
Biochimica Et Biophysica Acta Feb 2007Limb girdle muscular dystrophy type 2A results from mutations in the gene encoding the calpain 3 protease. Mutations in this disease are inherited in an autosomal... (Review)
Review
Limb girdle muscular dystrophy type 2A results from mutations in the gene encoding the calpain 3 protease. Mutations in this disease are inherited in an autosomal recessive fashion and result in progressive proximal skeletal muscle wasting but no cardiac abnormalities. Calpain 3 has been shown to proteolytically cleave a wide variety of cytoskeletal and myofibrillar proteins and to act upstream of the ubiquitin-proteasome pathway. In this review, we summarize the known biochemical and physiological features of calpain 3 and hypothesize why mutations result in disease.
Topics: Animals; Calpain; Humans; Muscle Proteins; Muscular Dystrophies, Limb-Girdle; Mutation, Missense
PubMed: 16934440
DOI: 10.1016/j.bbadis.2006.07.002 -
Neurology India 2010
Topics: Calpain; Humans; Muscle Proteins; Muscular Dystrophies, Limb-Girdle; Mutation
PubMed: 20739783
DOI: 10.4103/0028-3886.68658 -
Advances in Therapy May 2023Limb girdle muscular dystrophies (LGMDs) are a group of rare and heterogeneous disorders involving progressive wasting of shoulder and pelvic girdle musculature. This...
INTRODUCTION
Limb girdle muscular dystrophies (LGMDs) are a group of rare and heterogeneous disorders involving progressive wasting of shoulder and pelvic girdle musculature. This study aimed to generate qualitative evidence on patient and caregiver experiences with symptoms and impacts of LGMD on overall function and daily life for sarcoglycanopathy subtypes 2C/R5, 2D/R3, and 2E/R4.
METHODS
Twenty-three individuals with LGMD with (n = 5) or without (n = 18) a caregiver participated in 60-minute semi-structured video interviews. Interview transcripts were analyzed using thematic analysis. Differences in patient experience by ambulation status and LGMD subtype were examined.
RESULTS
Participants were ambulatory (n = 14) and non-ambulatory (n = 9), representing three subtypes: 2C/R5 (n = 4), 2D/R3 (n = 12), and 2E/R4 (n = 7), with mean age of 34.8 years (SD = 16.08). 56.5% identified as female. Conceptual saturation was achieved within 18/23 interviews. Ambulatory participants identified difficulty with complex physical activities, e.g., running (n = 11, 78.6%), physical strength (n = 14, 100%), and difficulty with transfers, e.g., difficulty getting off the floor (n = 10, 71.4%). All non-ambulatory participants discussed problems with activities of daily living (ADLs) and transfers, e.g., getting in/out of bed and upper extremity function, particularly reaching (n = 8, 88.9%) and fine motor skills (n = 6, 66.7%). Fatigue and pain were reported by the majority of participants (n = 16, 69.6% and n = 19, 82.6%, respectively). A conceptual disease model was developed illustrating symptoms and impacts and their relationships to disease stage, capturing the patient experience across LGMD disease trajectory.
CONCLUSIONS
This study contributes to the limited evidence describing the patient experience of living with LGMD. The conceptual model can inform patient-centered assessment in future LGMD clinical trials.
Topics: Humans; Female; Adult; Activities of Daily Living; Muscular Dystrophies, Limb-Girdle; Upper Extremity; Patient Outcome Assessment
PubMed: 36917428
DOI: 10.1007/s12325-023-02463-8 -
Cancer Sep 2014Soft tissue tumors are rare and can arise from a variety of soft tissues and viscera in a variety of body sites. Their management requires a thorough understanding of... (Review)
Review
Soft tissue tumors are rare and can arise from a variety of soft tissues and viscera in a variety of body sites. Their management requires a thorough understanding of the biology of the different histologies and molecular subtypes as well as the constraints of specific anatomic sites. The surgical approach has undergone significant changes thanks to a better understanding of the natural history of the different histologic subtypes, the importance of site, and the different sensitivity to available drugs. The soft tissue tumor family includes 3 major, distinct categories: desmoid-type fibromatosis, soft tissue sarcoma, and gastrointestinal stromal tumor. In general, limb-sparing and function-sparing approaches should be used when feasible for tumors located in the extremities and girdles. Resections of adherent structures/viscera, which may be close but not invaded, may be needed in tumors arising in the retroperitoneum/abdomen to minimize microscopic intralesional margins, maximize local tumor control, and possibly improve survival. Margins of resection and the use of adjuvant/neadjuvant radiation therapy and/or chemotherapy are contingent on an accurate histologic diagnosis. Treatment planning should include multidisciplinary consultation to determine optimal therapy, taking into consideration tumor histology, site and extent of the disease, its natural history and sensitivity to available treatments, surgical challenges, and-of course-quality of life.
Topics: Disease Management; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Neoadjuvant Therapy; Precision Medicine; Sarcoma; Soft Tissue Neoplasms
PubMed: 24752977
DOI: 10.1002/cncr.28715