Assessing the Role of Aquaporin 4 in Skeletal Muscle Function.

Water transport across the biological membranes is mediated by aquaporins (AQPs). AQP4 and AQP1 are the predominantly expressed AQPs in the skeletal muscle. Since the discovery of AQP4, several studies have highlighted reduced AQP4 levels in Duchenne muscular dystrophy (DMD) patients and mouse models, and other neuromuscular disorders (NMDs) such as sarcoglycanopathies and dysferlinopathies. AQP4 loss is attributed to the destabilizing dystrophin-associated protein complex (DAPC) in DMD leading to compromised water permeability in the skeletal muscle fibers. However, AQP4 knockout (KO) mice appear phenotypically normal. AQP4 ablation does not impair physical activity in mice but limits them from achieving the performance demonstrated by wild-type mice. AQP1 levels were found to be upregulated in DMD models and are thought to compensate for AQP4 loss. Several groups investigated the expression of other AQPs in the skeletal muscle; however, these findings remain controversial. In this review, we summarize the role of AQP4 with respect to skeletal muscle function and findings in NMDs as well as the implications from a clinical perspective.

Breathing in Duchenne muscular dystrophy: translation to therapy.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a deficiency in dystrophin - a structural protein which stabilises muscle during contraction. Dystrophin deficiency adversely affects the respiratory system leading to sleep-disordered breathing, hypoventilation, and weakness of the expiratory and inspiratory musculature, which culminate in severe respiratory dysfunction. Muscle degeneration-associated respiratory impairment in neuromuscular disease is a result of disruptions at multiple sites of the respiratory control network, including sensory and motor pathways. As a result of this pathology, respiratory failure is a leading cause of premature death in DMD patients. Currently available treatments for DMD respiratory insufficiency attenuate respiratory symptoms without completely reversing the underlying pathophysiology. This underscores the need to develop curative therapies to improve quality of life and longevity of DMD patients. This review summarises research findings on the pathophysiology of respiratory insufficiencies in DMD disease in humans and animal models, the clinical interventions available to ameliorate symptoms, and gene-based therapeutic strategies uncovered by preclinical animal studies.

Duchenne muscular dystrophy newborn screening: the first 50,000 newborns screened in Taiwan.

BACKGROUND: Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked muscular disease with an overall incidence of 1:5,000 live male births. Recent availability in treatment for DMD raised the need of early diagnosis, and DMD became as a selective item of newborn screening (NBS) since Feb. 2021 in our center. MATERIALS AND METHODS: Dried blood spots (DBS) muscle-type creatine kinase (CK) isoform was measured with a commercialized kit with age-adjusted cutoffs. Subjects with an elevation of CK in the first screen were requested for a re-screen 2 weeks later. A DBS whole-exome sequencing (WES) panel for dystrophin and other neuromuscular-related genes was applied to confirm the diagnosis for subjects with persistent hyperCKemia. RESULTS: During a 1-year period, 50,572 newborns (male 26,130) received DMD screening at a mean age of 2 days (SD 1 day). Among them, 632 (1.2%) had an elevated CK value. A re-screen at a mean age of 14 days (SD 8 days) revealed 14 subjects with persistent hyperCKemia, and DMD was confirmed in 3 of them. The incidence of DMD in Taiwan was 1:8,710 (95% CI 1 in 2,963 to 1 in 25,610) live birth males. Results of DMD DBS also assisted in Pompe newborn screening. CONCLUSIONS: NBS for DMD enables earlier management of the disease. The high re-screening rate could potentially be waived by moving the DBS WES assay to a second-tier test. The long-term benefit and the impact of newborn screening on the prognosis of DMD, however, remain further elucidated.

Turner Syndrome Mosaicism 45,X/46,XY with Genital Ambiguity and Duchenne Muscular Dystrophy: Translational Approach of a Rare Italian Case.

Turner syndrome (gonadal dysgenesis with short stature and sterility) is characterized by chromosomal karyotype 45,X in 50% of cases or by mosaicism (45,X/46,XX and 45,X/46,XY) in 30-40% or X structural defects (deletions, long arm isochromosome, ring chromosome). When mosaic Turner syndrome (TS) occurs with a Y chromosome, there may be ambiguous genitalia. Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disease with an X-Linked recessive pattern of inheritance that predominantly affects males, while females are usually asymptomatic. DMD has also been observed in groups of females affected by TS, not homozygous for the mutation. Here, we report a case of an Indian neonate born with ambiguous genitalia diagnosed prenatally by ultrasound who had a karyotype of 45,X/46,XY and who also had Duchenne muscular dystrophy caused by a de novo mutation in the DMD gene. Physical examination was normal without the typical dysmorphic features of TS with the exception of the genitourinary system showing ambiguous genitalia. Gender was assigned as female. At the age of three years, she had increasing difficulty walking, running, jumping and climbing stairs, proximal upper and lower extremity muscle weakness and a positive Gowers' sign. In addition, the serum creatine kinase (CK) value was over 30X the upper limit of normal. This study shows that DMD can occur in females with TS having 45,X/46,XY mosaicism and that this coexistence should be considered in women affected by TS who start to develop potential typical symptoms such as motor or developmental delay.

CRISPR Therapeutics for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder with a prevalence of approximately 1 in 3500-5000 males. DMD manifests as childhood-onset muscle degeneration, followed by loss of ambulation, cardiomyopathy, and death in early adulthood due to a lack of functional dystrophin protein. Out-of-frame mutations in the dystrophin gene are the most common underlying cause of DMD. Gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system is a promising therapeutic for DMD, as it can permanently correct DMD mutations and thus restore the reading frame, allowing for the production of functional dystrophin. The specific mechanism of gene editing can vary based on a variety of factors such as the number of cuts generated by CRISPR, the presence of an exogenous DNA template, or the current cell cycle stage. CRISPR-mediated gene editing for DMD has been tested both in vitro and in vivo, with many of these studies discussed herein. Additionally, novel modifications to the CRISPR system such as base or prime editors allow for more precise gene editing. Despite recent advances, limitations remain including delivery efficiency, off-target mutagenesis, and long-term maintenance of dystrophin. Further studies focusing on safety and accuracy of the CRISPR system are necessary prior to clinical translation.

Dystrophin Protein Quantification as a Duchenne Muscular Dystrophy Diagnostic Biomarker in Dried Blood Spots Using Multiple Reaction Monitoring Tandem Mass Spectrometry: A Preliminary Study.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle loss, leading to difficulties in movement. Mutations in the DMD gene that code for the protein dystrophin are responsible for the development of DMD disorder, where the synthesis of this protein is completely halted. Therefore, circulating dystrophin protein could be a promising biomarker of DMD disease. Current methods for diagnosing DMD have sensitivity, specificity, and reproducibility limitations. Herein, a quantitative liquid chromatography-tandem spectrometry (LC-MS/MS) technique in multiple reaction monitoring (MRM) mode was designed and validated for accurate dystrophin protein measurement in a dried blood spot (DBS). The method was successfully validated on the basis of international guidelines regarding calibration curves, precision, and accuracy. In addition, patients and healthy controls were used to test the amount of dystrophin protein circulating in DBS samples as a potential biomarker for DMD disorders. DMD patients were found to have considerably lower levels than controls. To the best of our knowledge, this is the first study to report dystrophin levels in DBS through LC-MS/MS as a diagnostic marker for DMD to the proposed MRM method, providing a highly specific and sensitive approach to dystrophin quantification in a DBS that can be applied in DMD screening.

Evaluation of a Chair-Mounted Passive Trunk Orthosis: A Pilot Study on Able-Bodied Subjects.

Trunk stability is important for adequate arm function due to their kinematic linkage. People with Duchenne muscular dystrophy (DMD) can benefit from trunk-assistive devices for seated daily activities, but existing devices limit trunk movement to forward bending. We developed a new trunk orthosis that has spring and pulley design. This study evaluated orthosis performance with 40 able-bodied subjects under with and without orthosis condition in 20 seated tasks for trunk rotation, forward bending, and side bending movements. Subjects adopted static posture in specific trunk orientation while their muscle activity was recorded. They also rated the subjective scales of perceived exertion and usability. A percent change in muscle activity for each task, due to orthosis use, is reported. Significant muscle activity reductions up to 31% and 65% were observed in lumbar and thoracic erector spinae muscles, respectively. Using three-way ANOVA, we found these reductions to be specific to the task direction and the choice of upper limb that is used to perform the asymmetric tasks. A total of 70% participants reported acceptable usability and ~1-point increase in exertion was found for maximum voluntary reaching with the orthosis. The outcomes of this study are promising, though tested on able-bodied subjects. Hence, orthosis mounted on wheelchairs should be further evaluated on DMD patients.

Diaphragm Involvement in Duchenne Muscular Dystrophy (DMD): An MRI Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by progressive weakness and wasting of skeletal, cardiac, and respiratory muscles, with consequent cardiopulmonary failure as the main cause of death. Reliable outcome measures able to demonstrate specific trends over disease progression are essential. PURPOSE: To investigate MRI as a noninvasive imaging modality to assess diaphragm impairment in DMD. In particular, we sought to correlate MRI measurement of diaphragm structure and function with pulmonary function tests and with the abdominal volumes (VAB ) measured by optoelectronic plethysmography, being an index of the action of the diaphragm. STUDY TYPE: Cross-sectional study. POPULATION: Twenty-six DMD patients (17.9 ± 6.2 years) and 12 age-matched controls (17.8 ± 5.9 years). FIELD STRENGTH/SEQUENCE: 3-Point gradient echo Dixon sequence at 3T. ASSESSMENT: Images were acquired in breath-hold at full-expiration (EXP) and full-inspiration (INSP). INSP and EXP lung volumes were segmented and the diaphragm surface was reconstructed as the bottom surface of the left and the right lung. The inspiratory and the expiratory diaphragm surfaces were aligned by a nonrigid iterative closest point algorithm. On MRI we measured: 1) craniocaudal diaphragmatic excursion; 2) diaphragm fatty infiltration. STATISTICAL TESTS: Three-parameter sigmoid regression, one-way analysis of variance (ANOVA), Spearman's correlation. RESULTS: In patients, diaphragm excursion decreased with age (r2 = 0.68, P < 0.0001) and fat fraction increased (r2 = 0.51, P = 0.0002). In healthy subjects, diaphragm excursion and fat fraction had no relationship with age. Diaphragm excursion decreased with decreasing FEV1 %pred (r = 0.78, P < 0.0001) and FVC %pred (r = 0.76, P < 0.0001) and correlated with VAB (r = 0.60, P = 0.0002). Fatty infiltration increased with decreasing FEV1 %pred (r = -0.88, P < 0.0001) and FVC %pred (r = -0.88, P < 0.0001). DATA CONCLUSION: The progressive structural and functional diaphragm impairment is highly related to pulmonary function tests and to VAB . The results suggest that MRI might represent a new and noninvasive tool for the functional and structural assessment of the diaphragm. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:461-471.

Genetic analysis of 1051 Chinese families with Duchenne/Becker Muscular Dystrophy.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children, and there are no effective therapies for DMD or Becker Muscular Dystrophy (BMD). Currently, targeted gene therapy treatments have emerged. As a result, genetic diagnosis is the basis of treatment. In addition, genetic and prenatal diagnosis significantly reduces their incidence rates. This study combines the application of multiplex ligation-dependent probe amplification technology (MLPA) and "next-generation" sequencing technology (NGS) as the most economical and efficient method of diagnosis. Therefore, in the diagnosis of DMD/BMD, patients' MLPA data are first used to detect DMD gene deletions or duplications, and NGS and Sanger sequencing are then applied to exclude MLPA-negative samples. Meanwhile, polymerase chain reaction (PCR) is used to detect single exon deletions to exclude false-positives in MLPA caused by point mutations. METHODS: In this study, we recruited 1051 proband families of DMD from 2016 to 2018 and had access to information that could identify individual participants during or after data collection. Patients who were diagnosed with DMD were first tested by MLPA. MLPA results with single exon deletions were validated with PCR amplification and Sanger sequencing. The negative results of MLPA were further analysed with NGS and validated by Sanger sequencing. For novel missense mutations, phenotype-genotype correlations were analysed using PolyPhen2 and mutation taster. All methods were performed in accordance with the relevant guidelines and regulations. RESULTS: DMD mutations were identified in 1029 families (97.91%, 1029/1051). Large deletions, duplications, and small mutations accounted for 70.41% (740/1051), 8.28% (87/1051), and 19.12% (201/1051) of all cases, respectively. There were 205 small mutation types, 53 of which were novel. The rate of de novo mutations was 39.45% (187/474) and was higher in large duplications (49.53%, 157/317). Among 68 asymptomatic patients (< 3 years old) with unexplained persistent hyperCKaemia upon conventional physical examination, 63 were diagnosed as DMD/BMD according to genetic diagnosis. CONCLUSION: Our results expand the spectrum of DMD mutations, which could contribute to the treatment of DMD/BMD and provide an effective diagnosis method. Thus, the combination of MLPA, NGS and Sanger sequencing is of great significance for family analysis, gene diagnosis and gene therapy.

Age-dependent changes in metabolite profile and lipid saturation in dystrophic mice.

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked genetic disorder. In DMD, the absence of the dystrophin protein causes decreased sarcolemmal integrity resulting in progressive replacement of muscle with fibrofatty tissue. The effects of lacking dystrophin on muscle and systemic metabolism are still unclear. Therefore, to determine the impact of the absence of dystrophin on metabolism, we investigated the metabolic and lipid profile at two different, well-defined stages of muscle damage and stabilization in mdx mice. We measured NMR-detectable metabolite and lipid profiles in the serum and muscles of mdx mice at 6 and 24 weeks of age. Metabolites were determined in muscle in vivo using 1 H MRI/MRS, in isolated muscles using 1 H-HR-MAS NMR, and in serum using high resolution 1 H/13 C NMR. Dystrophic mice were found to have a unique lipid saturation profile compared with control mice, revealing an age-related metabolic change. In the 6-week-old mdx mice, serum lipids were increased and the degree of lipid saturation changed between 6 and 24 weeks. The serum taurine-creatine ratio increased over the life span of mdx, but not in control mice. Furthermore, the saturation index of lipids increased in the serum but decreased in the tissue over time. Finally, we demonstrated associations between MRI-T2 , a strong indicator of inflammation/edema, with tissue and serum lipid profiles. These results indicate the complex temporal changes of metabolites in the tissue and serum during repetitive bouts of muscle damage and regeneration that occur in dystrophic muscle.

Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a progressive, fatal neuromuscular disorder caused by mutations in the DMD gene. Emerging antisense oligomer based exon skipping therapy provides hope for the restoration of the reading frame. OBJECTIVES: Population-based DMD mutation database may enable exon skipping to be used for the benefit of patients. Hence, we planned this study to identify DMD gene variants in North Indian DMD cases. METHODS: A total of 100 DMD cases were recruited and Multiplex ligation-dependent probe amplification (MLPA) analysis was performed to obtain the deletion and duplication profile. RESULTS: Copy number variations (deletion/duplication) were found in 80.85% of unrelated DMD cases. Sixty-eight percent of cases were found to have variations in the distal hotspot region (Exon 45-55) of the DMD gene. Exon 44/45 variations were found to be the most prominent among single exon variations, whereas exon 49/50 was found to be the most frequently mutated locations in single/multiple exon variations. As per Leiden databases, 86.84% cases harboured out-of-frame mutations. Domain wise investigation revealed that 68% of mutations were localized in the region of spectrin repeats. Dp140 isoform was predicted to be absent in 62/76 (81.57%) cases. A total of 45/80 (56.25%) and 23/80 (28.70%) DMD subjects were predicted to be amenable to exon 51 and exon 45 skipping trials, respectively. CONCLUSION: A major proportion of DMD subjects (80%) could be diagnosed by the MLPA technique. The data generated from our study may be beneficial for strengthening of mutation database in the North Indian population.

Muscular Dystrophy Model.

Muscular dystrophy (MD) is a group of muscle weakness disease involving in inherited genetic conditions. MD is caused by mutations or alteration in the genes responsible for the structure and functioning of muscles. There are many different types of MD which have a wide range from mild symptoms to severe disability. Some types involve the muscles used for breathing which eventually affect life expectancy. This chapter provides an overview of the MD types, its gene mutations, and the Drosophila MD models. Specifically, the Duchenne muscular dystrophy (DMD), the most common form of MD, will be thoroughly discussed including Dystrophin genes, their isoforms, possible mechanisms, and signaling pathways of pathogenesis.

DMDtoolkit: a tool for visualizing the mutated dystrophin protein and predicting the clinical severity in DMD.

BACKGROUND: Dystrophinopathy is one of the most common human monogenic diseases which results in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Mutations in the dystrophin gene are responsible for both DMD and BMD. However, the clinical phenotypes and treatments are quite different in these two muscular dystrophies. Since early diagnosis and treatment results in better clinical outcome in DMD it is essential to establish accurate early diagnosis of DMD to allow efficient management. Previously, the reading-frame rule was used to predict DMD versus BMD. However, there are limitations using this traditional tool. Here, we report a novel molecular method to improve the accuracy of predicting clinical phenotypes in dystrophinopathy. We utilized several additional molecular genetic rules or patterns such as "ambush hypothesis", "hidden stop codons" and "exonic splicing enhancer (ESE)" to predict the expressed clinical phenotypes as DMD versus BMD. RESULTS: A computer software "DMDtoolkit" was developed to visualize the structure and to predict the functional changes of mutated dystrophin protein. It also assists statistical prediction for clinical phenotypes. Using the DMDtoolkit we showed that the accuracy of predicting DMD versus BMD raised about 3% in all types of dystrophin mutations when compared with previous methods. We performed statistical analyses using correlation coefficients, regression coefficients, pedigree graphs, histograms, scatter plots with trend lines, and stem and leaf plots. CONCLUSIONS: We present a novel DMDtoolkit, to improve the accuracy of clinical diagnosis for DMD/BMD. This computer program allows automatic and comprehensive identification of clinical risk and allowing them the benefit of early medication treatments. DMDtoolkit is implemented in Perl and R under the GNU license. This resource is freely available at http://github.com/zhoujp111/DMDtoolkit , and http://www.dmd-registry.com .

Rate of oral intake and effects of mechanical insufflation-exsufflation on pulmonary complications in patients with duchenne muscular dystrophy.

[Purpose] In Duchenne muscular dystrophy, it increases risks of difficulties of expectoration of secretion, asphyxia, aspiration pneumonia because of decreased cough function. The aim of this study is to prove that manually assisted coughing or mechanical insufflation-exsufflation prevents pulmonary complication and contribute to continue oral intake safely and continue rate of oral intake in Duchenne muscular dystrophy. [Subjects and Methods] We investigated the status of using ventilator, manually assisted coughing or mechanical insufflation-exsufflation, and oral intake or not. In addition, we inspected the frequency of fever (over 37 °C) needed antibiotics from medical records for index of respiratory tract infection, and compared with every period of using mechanical insufflation-exsufflation from respiratory evaluation on cough peak flow. [Results] Fifty-eight patients participated in this study. There were 45 Full-time noninvasive positive pressure ventilation patients. Forty-three in 45 Full-time noninvasive positive pressure ventilation patients (95.6%) avoided tracheostomy and continued noninvasive positive pressure ventilation because they continued oral intake without tracheal intubation due to the respiratory acute exacerbation by asphyxia or aspiration pneumonia. [Conclusion] Duchenne muscular dystrophy patients can continue oral intake safely while preventing pulmonary complication by using manually assisted coughing or mechanical insufflation-exsufflation.

Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy.

Quantitative NMRI and (31)P NMRS indices are reported in the forearms of 24 patients with Duchenne muscular dystrophy (DMD) (6-18 years, 14 non-ambulant) amenable to exon 53 skipping therapy and in 12 age-matched male controls (CONT). Examinations carried out at 3 T comprised multi-slice 17-echo measurements of muscle water T2 and heterogeneity, three-point Dixon imaging of fat fraction in flexor and extensor muscles (FLEX, EXT), and non-localised spectroscopy of phosphate metabolites. We studied four imaging indices, eight metabolic ratios combining ATP, phosphocreatine, phosphomonoesters and phosphodiesters, the cytosolic inorganic phosphate (Pia ) and an alkaline (Pib) pool present in dystrophic muscle, and average pH. All indices differed between DMD and CONT, except for muscle water T2 . Measurements were outside the 95th percentile of age-matched CONT values in over 65% of cases for percentage fat signal (%F), and in 78-100% of cases for all spectroscopic indices. T2 was elevated in one-third of FLEX measurements, whereas %pixels > 39 ms and T2 heterogeneity were abnormal in one-half of the examinations. The FLEX muscles had higher fat infiltration and T2 than EXT muscle groups. All indices, except pH, correlated with patient age, although the correlation was negative for T2 . However, in non-ambulant patients, the correlation with years since loss of ambulation was stronger than the correlation with age, and the slope of evolution per year was steeper after loss of ambulation. All indices except Pi/gATP differed between ambulant and non-ambulant patients; however, T2 and %pixels > 39 ms were highest in ambulant patients, possibly owing to the greater extent of inflammatory processes earlier in the disease. All other indices were worse in non-ambulant subjects. Quantitative measurements obtained from patients at different disease stages covered a broad range of abnormalities that evolved with the disease, and metabolic indices were up to 10-fold above normal from the onset, thus establishing a variety of potential markers for future therapy.

Musculoskeletal simulation can help explain selective muscle degeneration in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic disease that occurs due to the deficiency of the dystrophin protein. Although dystrophin is deficient in all muscles, it is unclear why degeneration progresses differently across muscles in DMD. We hypothesized that each muscle undergoes a different degree of eccentric contraction during gait, which could contribute to the selective degeneration in lower limb muscle, as indicated by various amounts of fatty infiltration. By comparing eccentric contractions quantified from a previous multibody dynamic musculoskeletal gait simulation and fat fractions quantified in a recent imaging study, our preliminary analyses show a strong correlation between eccentric contractions during gait and lower limb muscle fat fractions, supporting our hypothesis. This knowledge is critical for developing safe exercise regimens for the DMD population. This study also provides supportive evidence for using multiscale modeling and simulation of the musculoskeletal system in future DMD research.

Intellectual ability in the duchenne muscular dystrophy and dystrophin gene mutation location.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

The complex landscape of DMD mutations: moving towards personalized medicine.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.

Motor dysfunction of the gut in Duchenne muscular dystrophy: A review.

BACKGROUND: Duchenne's muscular dystrophy (DMD) is a severe type of hereditary, neuromuscular disorder caused by a mutation in the dystrophin gene resulting in the absence or production of truncated dystrophin protein. Conventionally, clinical descriptions of the disorder focus principally on striated muscle defects; however, DMD manifestations involving gastrointestinal (GI) smooth muscle have been reported, even if not rigorously studied. PURPOSE: The objective of the present review is to offer a comprehensive perspective on the existing knowledge concerning GI manifestations in DMD, focusing the attention on evidence in DMD patients and mdx mice. This includes an assessment of symptomatology, etiological pathways, and potential corrective approaches. This paper could provide helpful information about DMD gastrointestinal implications that could serve as a valuable orientation for prospective research endeavors in this field. This manuscript emphasizes the effectiveness of mdx mice, a DMD animal model, in unraveling mechanistic insights and exploring the pathological alterations in the GI tract. The gastrointestinal consequences evident in patients with DMD and the mdx mice models are a significant area of focus for researchers. The exploration of this area in depth could facilitate the development of more efficient therapeutic approaches and improve the well-being of individuals impacted by the condition.

A Voyage on the Role of Nuclear Factor Kappa B (NF-kB) Signaling Pathway in Duchenne Muscular Dystrophy: An Inherited Muscle Disorder.

A recessive X-linked illness called Duchenne muscular dystrophy (DMD) is characterized by increasing muscle weakening and degradation. It primarily affects boys and is one of the most prevalent and severe forms of muscular dystrophy. Mutations in the DMD gene, which codes for the essential protein dystrophin, which aids in maintaining the stability of muscle cell membranes during contraction, are the cause of the illness. Dystrophin deficiency or malfunction damages muscle cells, resulting in persistent inflammation and progressive loss of muscular mass. The pathophysiology and genetic foundation of DMD are thoroughly examined in this review paper, focusing on the function of the NF-κB signaling system in the disease's progression. An important immune response regulator, NF-κB, is aberrantly activated in DMD, which exacerbates the inflammatory milieu in dystrophic muscles. Muscle injury and fibrosis are exacerbated and muscle regeneration is hampered by the pro-inflammatory cytokines and chemokines that are produced when NF-κB is persistently activated in muscle cells. The paper also examines our existing knowledge of treatment approaches meant to inhibit the progression of disease by modifying NF-κB signaling. These include new molecular techniques, gene treatments, and pharmacological inhibitors that are intended to lessen inflammation and improve muscle healing. Furthermore covered in the analysis is the significance of supportive care for DMD patients, including physical therapy and corticosteroid treatment, in symptom management and quality of life enhancement. The article seeks to provide a thorough understanding of the mechanisms causing DMD, possible therapeutic targets, and developing treatment options by combining recent research findings. This will provide clinicians and researchers involved in DMD care and research with invaluable insights.