Muscle Disease

Therapeutic Potential of Proteasome Inhibition in Duchenne and Becker Muscular Dystrophies

Objective To investigate the clinical manifestations and laboratory examinations of Duchenne muscular dystrophy (DMD) patients and evaluate the principle of intermittent intravenous combined with oral glucocorticoid therapy. Methods The clinical features, laboratory examinations andfollow-up data of 155 DMD patients were collected. These patients were given dexamethasone 5-10 mg/d by intravenous infusion for 10-15 d and oral prednisone acetate 0.50-0.75 mg/(kg·d) for one month. After treatment, the motor ability of lower limbs, the level of serum creatine kinase (CK) and 99mTc-MIBI gated myocardial perfusion imaging (GMPI) findings were compared with those before glucocorticoid therapy by statistical analysis. Results 1) The motor ability was improved in 70 follow-up cases of DMD patients with long-term oral prednisone (squat and rise: Z = 207.000, P = 0.034; climbing stairs: Z = 237.000, P =0.008). 2) The level of serum CK of 155 first diagnosed patients reached the peak at 3 years old, and declined after the age of 8 (P < 0.05, for all). The serum CK of 70 follow-up cases was significantly decreased after 10-15 d dexamethasone intravenous infusion (P = 0.000), and increased again after one-month oral administration of prednisone acetate (P = 0.000), but was still lower than that before treatment (P = 0.008). 3) The 99mTc-MIBI GMPI of 77 patients showed different degrees of myocardial involvement and significantly uneven left ventricular radionuclide distribution, especially in apex cordis (55 cases), inferior wall (45 cases) and anterior wall (30 cases) of apex. Conclusions There exists increased level of serum CK in the sub⁃clinical stage of DMD. The level of serum CK declined year by year after the age of 8. Intermittent intravenous combined with oral glucocorticoid therapy has an important effect on protecting motor and cardiac functions, extending walking time and reducing serum CK level and muscle cell damage. Early glucocorticoid therapy is recommended. DOI : 10.3969/j.issn.1672-6731.2015.05.008

Muscular dystrophy.

Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis

Efficacy of Multi-exon Skipping Treatment in Duchenne Muscular Dystrophy Dog Model Neonates

D.P.15 Quantitative T2 relaxation times in lower leg of Duchenne and Becker muscular dystrophy patients

Background: Serum creatine kinase (CK) level is increased muscular dystrophy (MD) and may be used as a clue to identify MDs. Objective: The objective is to compare CK levels between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), to correlate value of serum CK with number of deletions, duration of illness and to establish a cut off value of CK for screening. Materials and Methods: A cross-sectional survey was carried out in a tertiary care institute of Kolkata. Clinically diagnosed patients of 139 DMDs and 50 BMDs along with 69 age-matched individuals suffering from diseases other than MDs was included. Estimation of serum CK levels and gene analysis were done for all. Results: DMD victims were found to be younger with low age of onset and lesser disease duration but higher serum CK level compared to those having BMD. Most of the genetic deletions were happened in distal region of dystrophin gene and a significant difference was revealed to exist between DMD and BMD neither in regard to proportion of overall deletion nor deletions in proximal and distal region. However, gene deletion was found absent in 31% and 42% of DMD and BMD cases. Serum CK level of 511.5 unit/L was seemed to be a reliable cut-off for detection of DMD and BMD with 97.3% sensitivity, 100% specificity, and area under the curve 0.989 with a P = 0.000. Conclusion: In case of nonavailability of genetic test facility as well as negative genetic test serum CK may be tried for identifying MD.

Background Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive diseases caused by mutations in the dystrophin (DMD) gene. To our knowledge, molecular analysis to differentiate between DMD and BMD has never been performed in Indonesia.&#x0D; Objective To elaborate the clinicopathologic and molecular profiles of DMD/BMD patients in Yogyakarta, Indonesia.&#x0D; Methods Eighteen muscle biopsy specimens of patients clinically suspected to have DMD/BMD were collected. Possible associations of clinical manifestations, histopathological grading, and immunohistochemistry (IHC) results were analyzed. Polymerase chain reaction (PCR) was performed to identify mutations in exon 52.&#x0D; Results. Positive Gower’s sign and high serum creatine kinase (CK) were observed in most patients. The IHC of dystrophin in two female patients suggested that they were manifesting carriers. Of the 16 male patients, 12 showed negative IHC staining, indicating DMD, while 4 patients demonstrated weak expression of dystrophin, indicating BMD. There was a significant association between high CK level and IHC results (P=0.005), indicating higher CK level in DMD patients. Histopathological grading of muscle biopsy was significantly associated with diagnosis of DMD/BMD using IHC (P=0.01), showing more severe tissue damage in DMD patients. None of the subjects had the single exon 52 deletion.&#x0D; Conclusion This is the first report of a clinicopathologic and molecular profile of DMD/BMD in an Indonesian population. Serum CK level and histopathological grading of muscle biopsy are useful in distinguishing DMD from BMD in settings where an IHC assay is not available.

Transduction of Full-length Dystrophin to Multiple Skeletal Muscles Improves Motor Performance and Life Span in Utrophin/Dystrophin Double Knockout Mice

Serum carbonic anhydrase III in progressive muscular dystrophy

Muscle Memory

Objective To analyze the characteristics of fat infiltration into the muscles of patients with Becker and Duchenne muscular dystrophy (DMD) so as to provide a guide for rehabilitation therapy. Methods Twenty-three children with Becker muscular dystrophy (BMD) and 47 with DMD who had never been treated with glucocorticoids were enrolled. MRI was performed on both of their thigh muscles. T1 weighted images were used to assess the fat infiltration of their thigh muscles using a 0-5 modified version of Mercuri′s scale. The progression of fatty infiltration of the thigh muscles in BMD was analyzed using descriptive statistics. The differences in fat infiltration between BMD and DMD were analyzed using rank sum tests. Results In patients with BMD the adductor magnus most often showed severe fat infiltration, followed by the biceps femoris, quadriceps, semimembranosus and semitendinosus, while the sartorius, gracilis and adductor longus had the lowest percentages of severe fat infiltration. Among the BMD patients the adductor magnus, biceps femoris and quadriceps showed moderate to severe involvement at the age of 8 to 9. The semimembranosus and semitendinosus showed moderate to severe involvement at the age of 10 to 11, and the sartorius, gracilis and adductor longus showed mild to moderate involvement after 15 years of age. Among the age groups of 8, 9, 10 and 11 years old, the median total fat infiltration scores were 10, 22, 28 and 25 respectively among the BMD patients, and 29, 34, 34 and 30 respectively among the DMD patients. At age 8 significant differences between the BMD and DMD patients were observed in the infiltration scores of the adductor magnus, biceps femoris, vastus lateralis, rectus femoris, vastus medialis, vastus intermedius and in the total scores. At age 9 significant differences persisted in the scores of the adductor magnus, rectus femoris, vastus medialis, vastus intermedius and the total scores. Conclusions The muscle MRIs showed significant differences in the degree of fatty infiltration between BMD and DMD patients. These findings may be useful when designing therapeutic regimens and rehabilitation programs for patients with BMD and DMD. Key words: Muscular dystrophy; Muscles, Skeletal; Fatty infiltration

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: In vitro, high-resolution NMR spectroscopy based observation in early phase of the disease

We aimed to identify novel biomarkers of muscle pathological changes via a large-scale histopathology-based multi-omics study of dystrophinopathies. We performed a comparative pathological analysis of 121 Duchenne muscular dystrophy (DMD) and 114 Becker muscular dystrophy (BMD) patients to determine muscle pathological similarities and differences between DMD and BMD that have not been systematically investigated. Customized bioinformatic analyses of bulk muscle RNA-sequencing data derived from 35 DMD patients, 39 BMD patients, and 21 controls were performed to identify gene signatures associated with pathological changes. Validation experiments, including single-nucleus RNA-sequencing, RNAscope in situ hybridization, and immunofluorescence staining, were performed in a subset of DMD and BMD patients, as well as 27 patients with other acquired and inherited myopathies. Systematic pathological analyses revealed that the percentages of necrotic, regenerating, and hypercontractive myofibers and the degree of muscle fibrosis were greater in DMD patients than in BMD patients. In both DMD and BMD patients, the percentages of necrotic, regenerating, and hypercontractive myofibers respectively increased in the early-stage and decreased in later disease stages, whereas muscle fibrosis progressively worsened with disease progression. Comparative transcriptomic analysis indicated that inflammatory responses were significantly activated in DMD patients compared to BMD patients, which was confirmed by immunohistochemistry analyses. Our customized bioinformatic analyses identified the gene set of MYH3, MYH8, IL17B, TNNT2, MYMK, and TDO2 as the most associated gene signature for muscle necrosis and regeneration. Muscle quantitative reverse transcription-polymerase chain reaction analyses confirmed significantly increased levels of IL17B and TNNT2 mRNA expression in both DMD and BMD patients compared to controls. Muscle IL17B mRNA expression was significantly correlated with histological muscle regeneration and negatively correlated with the age of patients with dystrophinopathy. Single-nucleus RNA-sequencing and RNAscope in situ hybridization demonstrated that IL17B mRNA was expressed in regenerating myofibers of patients with DMD and BMD, as well as in various acquired and inherited myopathies. Immunofluorescence staining further confirmed that interleukin-17B was expressed in regenerating myofibers of DMD and BMD patients. Our study provides evidence that interleukin-17B is a new biomarker of muscle regeneration in dystrophinopathies.