scholarly journals Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Maricela Rodríguez-Cruz ◽  
Raúl Sanchez ◽  
Rosa E. Escobar ◽  
Oriana del Rocío Cruz-Guzmán ◽  
Mardia López-Alarcón ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Muscular Dystrophy ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Becker Muscular Dystrophy ◽  
Body Fat Mass ◽  
Metabolic Alterations ◽  
Underweight Patients ◽  
Dmd Gene ◽  
Muscle Biopsies

Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR.Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16–74.69) and 50 (OR = 8.73; 95% CI = 1.17–65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue.Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR.

scholarly journals High-Throughput Digital Image Analysis Reveals Distinct Patterns of Dystrophin Expression in Dystrophinopathy Patients

2021 ◽  
Author(s):  
Silvia Torelli ◽  
Domenic Scaglioni ◽  
Valentina Sardone ◽  
Matthew J Ellis ◽  
Joana Domingos ◽  
...  
Keyword(s):  
Image Analysis ◽  
Muscular Dystrophy ◽  
High Throughput ◽  
Expression Patterns ◽  
Becker Muscular Dystrophy ◽  
Clear Understanding ◽  
Incurable Disease ◽  
Dystrophin Expression ◽  
Dmd Gene ◽  
Muscle Biopsies

Abstract Duchenne muscular dystrophy (DMD) is an incurable disease caused by out-of-frame DMD gene deletions while in frame deletions lead to the milder Becker muscular dystrophy (BMD). In the last decade several antisense oligonucleotides drugs have been developed to induce a partially functional internally deleted dystrophin, similar to that produced in BMD, and expected to ameliorate the disease course. The pattern of dystrophin expression and functionality in dystrophinopathy patients is variable due to multiple factors, such as molecular functionality of the dystrophin and its distribution. To benchmark the success of therapeutic intervention, a clear understanding of dystrophin expression patterns in dystrophinopathy patients is vital. Recently, several groups have used innovative techniques to quantify dystrophin in muscle biopsies of children but not in patients with milder BMD. This study reports on dystrophin expression using both Western blotting and an automated, high-throughput, image analysis platform in DMD, BMD, and intermediate DMD/BMD skeletal muscle biopsies. Our results found a significant correlation between Western blot and immunofluorescent quantification indicating consistency between the different methodologies. However, we identified significant inter- and intradisease heterogeneity of patterns of dystrophin expression in patients irrespective of the amount detected on blot, due to variability in both fluorescence intensity and dystrophin sarcolemmal circumference coverage. Our data highlight the heterogeneity of the pattern of dystrophin expression in BMD, which will assist the assessment of dystrophin restoration therapies.

Dystrophinopathy in a Family Due to a Rare Nonsense Mutation Causing Predominant Behavioral Phenotype

2019 ◽  
Vol 18 (04) ◽  
pp. 210-213
Author(s):  
Yohei Harada ◽  
Seth T. Sorensen ◽  
Akilandeswari Aravindhan ◽  
Vikki Stefans ◽  
Aravindhan Veerapandiyan
Keyword(s):  
Intellectual Disability ◽  
Muscular Dystrophy ◽  
Behavioral Problems ◽  
Nonsense Mutation ◽  
Neuromuscular Disorders ◽  
Elevated Serum ◽  
Becker Muscular Dystrophy ◽  
Genetic Changes ◽  
Dmd Gene ◽  
Neurobehavioral Deficits

AbstractDystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are needed to better understand the effects of this rare mutation.

scholarly journals Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

2020 ◽  
Vol 10 (4) ◽  
pp. 241
Author(s):  
Kenji Rowel Q. Lim ◽  
Quynh Nguyen ◽  
Toshifumi Yokota
Keyword(s):  
Muscular Dystrophy ◽  
Neuromuscular Disease ◽  
Becker Muscular Dystrophy ◽  
Neuromuscular Disorder ◽  
Test Results ◽  
Disease Registry ◽  
Reading Frame ◽  
Negative Results ◽  
Genetic Test Results ◽  
Dmd Gene

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. Surprisingly, C-terminal domain mutations were associated with decreased wheelchair use and increased forced vital capacity. Dp116 and Dp71 mutations were also linked with decreased wheelchair use, while Dp140 mutations significantly predicted cardiomyopathy. Finally, we found that 12.3% and 7% of DMD patients in the registry could be treated with FDA-approved exon 51- and 53-skipping therapies, respectively.

scholarly journals Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 765 ◽  
Author(s):  
Kenji Rowel Q. Lim ◽  
Narin Sheri ◽  
Quynh Nguyen ◽  
Toshifumi Yokota
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Cardiac Involvement ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Female Carrier ◽  
Daily Life Activities ◽  
Cardiac Manifestations ◽  
Available Information

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart.

scholarly journals Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach

2007 ◽  
Vol 65 (1) ◽  
pp. 73-76 ◽  
Author(s):  
Aline Andrade Freund ◽  
Rosana Herminia Scola ◽  
Raquel Cristina Arndt ◽  
Paulo José Lorenzoni ◽  
Claudia Kamoy Kay ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscular Atrophy ◽  
Hot Spot ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Congenital Myopathy ◽  
Specific Method ◽  
Dystrophin Deficiency ◽  
Muscle Biopsies ◽  
Female Carriers

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.

scholarly journals Clinicopathologic and molecular profiles of Duchenne and Becker muscular dystrophy

2019 ◽  
Vol 59 (5) ◽  
pp. 257-64
Author(s):  
Ery Kus Dwianingsih ◽  
Meydita Fuzia Putri Insani ◽  
Linda Pratiwi ◽  
Irianiwati Widodo ◽  
Rusdy Ghazali Malueka
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Biopsy ◽  
Clinical Manifestations ◽  
Becker Muscular Dystrophy ◽  
High Serum ◽  
Molecular Profile ◽  
Molecular Profiles ◽  
Weak Expression ◽  
Dmd Gene ◽  
Histopathological Grading

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. Objective To elaborate the clinicopathologic and molecular profiles of DMD/BMD patients in Yogyakarta, Indonesia. 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. 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. 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.

Germinal Mosaicism in a Sample of Families with Duchenne/Becker Muscular Dystrophy with Partial Deletions in the DMD Gene

2014 ◽  
Vol 18 (2) ◽  
pp. 93-97 ◽  
Author(s):  
Cesárea Bermúdez-López ◽  
Benilde García-de Teresa ◽  
Ariadna González-del Angel ◽  
Miguel Angel Alcántara-Ortigoza
Keyword(s):  
Muscular Dystrophy ◽  
Becker Muscular Dystrophy ◽  
Dmd Gene ◽  
Germinal Mosaicism

scholarly journals Exon skipping induced by nonsense/frameshift mutations in DMD gene results in Becker muscular dystrophy

2020 ◽  
Vol 139 (2) ◽  
pp. 247-255 ◽  
Author(s):  
Mariko Okubo ◽  
Satoru Noguchi ◽  
Shinichiro Hayashi ◽  
Harumasa Nakamura ◽  
Hirofumi Komaki ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Nonsense Mutation ◽  
Frameshift Mutation ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Intronic Sequence ◽  
Frameshift Mutations ◽  
Dmd Gene ◽  
Accurate Quantification

AbstractDuchenne muscular dystrophy (DMD) is caused by a nonsense or frameshift mutation in the DMD gene, while its milder form, Becker muscular dystrophy (BMD) is caused by an in-frame deletion/duplication or a missense mutation. Interestingly, however, some patients with a nonsense mutation exhibit BMD phenotype, which is mostly attributed to the skipping of the exon containing the nonsense mutation, resulting in in-frame deletion. This study aims to find BMD cases with nonsense/frameshift mutations in DMD and to investigate the exon skipping rate of those nonsense/frameshift mutations. We searched for BMD cases with nonsense/frameshift mutations in DMD in the Japanese Registry of Muscular Dystrophy. For each DMD mutation identified, we constructed minigene plasmids containing one exon with/without a mutation and its flanking intronic sequence. We then introduced them into HeLa cells and measured the skipping rate of transcripts of the minigene by RT-qPCR. We found 363 cases with a nonsense/frameshift mutation in DMD gene from a total of 1497 dystrophinopathy cases in the registry. Among them, 14 had BMD phenotype. Exon skipping rates were well correlated with presence or absence of dystrophin, suggesting that 5% exon skipping rate is critical for the presence of dystrophin in the sarcolemma, leading to milder phenotypes. Accurate quantification of the skipping rate is important in understanding the exact functions of the nonsense/frameshift mutations in DMD and for interpreting the phenotypes of the BMD patients.

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