Clinicopathologic and molecular profiles of Duchenne and Becker muscular dystrophy

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.

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

Journal of Pediatric Neurology ◽

10.1055/s-0039-1698437 ◽

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.

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Comprehensive genetic diagnosis of patients with Duchenne/Becker muscular dystrophy (DMD/BMD) and pathogenicity analysis of splice site variants in the DMD gene

Journal of Zhejiang University SCIENCE B ◽

10.1631/jzus.b1800541 ◽

2019 ◽

Vol 20 (9) ◽

pp. 753-765

Author(s):

Yan-mei Yang ◽

Kai Yan ◽

Bei Liu ◽

Min Chen ◽

Li-ya Wang ◽

...

Keyword(s):

Muscular Dystrophy ◽

Splice Site ◽

Genetic Diagnosis ◽

Becker Muscular Dystrophy ◽

Dmd Gene

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Becker muscular dystrophy or spinal muscular atrophy?—Dystrophin studies resolve conflicting results of electromyography and muscle biopsy

Neuromuscular Disorders ◽

10.1016/0960-8966(91)90024-m ◽

1991 ◽

Vol 1 (3) ◽

pp. 195-200 ◽

Cited By ~ 10

Author(s):

Thomas D. McDonald ◽

Rossella Medori ◽

David S. Younger ◽

Hai W. Chang ◽

Carlo Minetti ◽

...

Keyword(s):

Muscular Dystrophy ◽

Spinal Muscular Atrophy ◽

Muscle Biopsy ◽

Muscular Atrophy ◽

Becker Muscular Dystrophy

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

Journal of Personalized Medicine ◽

10.3390/jpm10040241 ◽

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.

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

Genetic Testing and Molecular Biomarkers ◽

10.1089/gtmb.2013.0384 ◽

2014 ◽

Vol 18 (2) ◽

pp. 93-97 ◽

Cited By ~ 10

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

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

Human Genetics ◽

10.1007/s00439-019-02107-4 ◽

2020 ◽

Vol 139 (2) ◽

pp. 247-255 ◽

Cited By ~ 2

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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A clinical case of severe Duchenne muscular dystrophy caused by a nonsense mutation in the DMD gene in a girl

L.O. Badalyan Neurological Journal ◽

10.46563/2686-8997-2021-2-4-227-232 ◽

2021 ◽

Vol 2 (4) ◽

pp. 227-232

Author(s):

Tatyana V. Podkletnova ◽

Olga B. Kondakova ◽

Eugeniya V. Uvakina ◽

Dariya A. Fisenko ◽

Anastasiya A. Lyalina ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

X Chromosome ◽

Clinical Symptoms ◽

Chromosomal Rearrangements ◽

Clinical Manifestations ◽

Severe Form ◽

Rapid Progression ◽

Compound Heterozygous ◽

Dmd Gene

Duchenne muscular dystrophy (DMD) is a hereditary progressive muscular dystrophy, mainly manifested in boys, is characterized by the onset at an early age, gradual symmetrical atrophy of the striated musculature of the limbs, trunk, as well as damage to the heart muscle. As a rule, girls and women inheriting a pathological mutation are classified only as its carriers and do not have clinical manifestations of the disease. Rare cases when women or girls show clinical manifestations of DMD may be due to chromosomal rearrangements involving the region of the short arm of the X chromosome (Xp21.2), deletions of this region, complete loss of the X chromosome (Shereshevsky-Turner syndrome), homogenous X chromosome dysomnia, compound heterozygous state for two pathogenic mutations in the DMD gene, nonequilibrium inactivation of the X chromosome. When female mutation carriers have DMD clinical symptoms, they usually manifest much milder than boys and young males. Descriptions of patients with the severe course and rapid progression of the disease, comparable in the rate of progression with boys, are rare. In this article, the authors share their experience of observing a girl patient who suffered from a severe form of DMD.

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