Mutation Location and Cognitive Impairment in Duchenne Muscular Dystrophy

ABSTRACT Background: Cognitive impairment is commonly seen in patients with Duchenne muscular dystrophy (DMD). Few studies have shown a correlation between loss of different isoforms of the DMD gene and cognitive impairment. Objective: The objective of the study was to determine whether correlation exists in the location of mutation in DMD gene or loss of different isoforms and cognitive impairment in children with DMD in the Indian population. Materials and Methods: Ten children were evaluated. Gene mutation analysis was done by multiplex ligation-dependent probe amplification method. The isoforms affected were inferred from mutation location in each of these patients. Binet Kamat Intelligence Test (BKT) and Bender Gestalt test (BGT) were administered. Results: All male patients were aged between 4 and 9 years. Genetic analysis showed deletion in all patients, with seven having deletion in “hotspot” regions (exon 43–52). Psychometric analysis by BGT and BKT showed mean score of 8.6 and mean IQ score of 85.5, respectively. Comparison between patients with hotspot mutations and mutations in other regions, for mean IQ score and BGT score, was statistically significant (P = 0.132 and P = 0.005, respectively). The difference in the IQ score between patients with isolated Dp427 loss (n = 3) and cumulative Dp427/Dp260/Dp140utr loss (n = 6) was statistically significant (P = 0.011). Visuomotor functioning was more impaired in patients with isolated Dp427 loss. Conclusion: The role of cumulative loss of isoforms along with importance of loss of Dp140pc isoform was seen in our study. One patient with loss of Dp140utr isoform had intellectual impairment which is not commonly seen. Visuomotor functioning is more affected in more upstream mutations as shown in our study.

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Have Duchenne Muscular Dystrophy Patients an Increased Cancer Risk?

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210676 ◽

2021 ◽

pp. 1-5

Author(s):

Gian Luca Vita ◽

Luisa Politano ◽

Angela Berardinelli ◽

Giuseppe Vita

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Systematic Investigation ◽

Mdx Mice ◽

True Incidence ◽

Patients With Cancer ◽

Dmd Gene ◽

Age Range ◽

Prevalence Of Cancer

Background: Increasing evidence suggests that Duchenne muscular dystrophy (DMD) gene is involved in the occurrence of different types of cancer. Moreover, development of sarcomas was reported in mdx mice, the murine model of DMD, in older age. So far, nine isolated DMD patients were reported with concomitant cancer, four of whom with rhabdomyosarcoma (RMS), but no systematic investigation was performed about the true incidence of cancer in DMD. Methods: All members of the Italian Association of Myology were asked about the occurrence of cancer in their DMD patients in the last 30 years. Results: Four DMD patients with cancer were reported after checking 2455 medical records. One developed brain tumour at the age of 35 years. Two patients had alveolar RMS at 14 and 17 years of age. The fourth patient had a benign enchondroma when 11-year-old. Conclusion: Prevalence of cancer in general in the Italian DMD patients does not seem to be different from that in the general population with the same age range. Although the small numbers herein presented do not allow definitive conclusion, the frequent occurrence of RMS in DMD patients raises an alert for basic researchers and clinicians. The role of DMD gene in cancer merits further investigations.

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Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular Dystrophy Treated with Eteplirsen and Matched Natural History Controls

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200548 ◽

2021 ◽

pp. 1-11

Author(s):

Jerry R. Mendell ◽

Navid Khan ◽

Nanshi Sha ◽

Helen Eliopoulos ◽

Craig M. McDonald ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Gene Mutations ◽

Exon Skipping ◽

Term Treatment ◽

Long Term Treatment ◽

The Difference ◽

Dmd Gene ◽

6 Minute Walk Test

Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51 ®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Objective: Compare long-term ambulatory function in eteplirsen-treated patients versus controls. Methods: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. Results: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients had milder NSAA decline than controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Conclusion: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

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Characterisation of dystrophin during development of human skeletal muscle

Development ◽

10.1242/dev.114.2.395 ◽

1992 ◽

Vol 114 (2) ◽

pp. 395-402 ◽

Cited By ~ 5

Author(s):

A. Clerk ◽

P.N. Strong ◽

C.A. Sewry

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Human Skeletal Muscle ◽

Gradual Increase ◽

Differential Staining ◽

Relative Molecular Mass ◽

Adult Tissue ◽

Dmd Gene

Dystrophin, the 427 × 10(3) Mr product of the Duchenne muscular dystrophy (DMD) gene, was studied in human foetal skeletal muscle from 9 to 26 weeks of gestation. Dystrophin could be detected from at least 9 weeks of gestation at the sarcolemmal membrane of most myotubes, though there was differential staining with antibodies raised to various regions of the protein. Dystrophin immunostaining increased and became more uniform with age and by 26 weeks of gestation there was intense sarcolemmal staining of all myotubes. On a Western blot, a doublet of smaller relative molecular mass than that seen in adult tissue was detected in all foetuses studied. There was a gradual increase in abundance of the upper band from 9 to 26 weeks, and the lower band, although present in low amounts in young foetuses, increased significantly between 20 and 26 weeks of gestation. These data indicate that there are several specific isoforms of dystrophin present in developing skeletal muscle, though the role of these is unknown.

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The problem of Duchenne muscular dystrophy

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1988.0049 ◽

1988 ◽

Vol 319 (1194) ◽

pp. 275-284 ◽

Cited By ~ 2

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Large Deletion ◽

Genomic Sequences ◽

Cdna Clones ◽

Base Pairs ◽

Length Polymorphisms ◽

Autosome Translocation ◽

Male Patients ◽

Dmd Gene

Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disorder. The biochemical defect remains unknown, but the gene responsible has been mapped to band Xp21. The gene has now been cloned in two laboratories solely from knowledge of its map location. L. M. Kunkel and his colleagues isolated genomic sequences (PERT 87) from within a large deletion causing DMD, whereas our group isolated genomic sequences (XJ) spanning the junction of an X-autosome translocation causing the disease. Chromosome walking by both groups has led to the isolation of over 400 kilobases of the PERT 87 and X J region. Subclones of PERT 87 and X J reveal restriction fragment length polymorphisms that segregate with the dmd gene in 95 % of meioses, and fail to hybridize with DNA from about 8 % of male patients. Selected subclones of P E R T 87 and XJ contain exons that hybridize to musclederived complementary DNA (cDNA) clones. The cDNA clones detect a large (16 kilobase) message. Analysis of deletions, mutations and translocations suggests a DMD gene of between two million and three million base pairs. The clones obtained so far are useful for attempts to generate antibody against the gene product and for carrier identification and prenatal diagnosis.

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Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2014-0071 ◽

2014 ◽

Vol 17 (2) ◽

pp. 25-35 ◽

Cited By ~ 13

Author(s):

Milic V. Rasic ◽

D. Vojinovic ◽

J. Pesovic ◽

G. Mijalkovic ◽

V. Lukic ◽

...

Keyword(s):

Cognitive Impairment ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Dystrophin Gene ◽

Cognitive Status ◽

Intellectual Ability ◽

Gene Deletions ◽

Full Scale Intelligence Quotient ◽

Status Assessment ◽

Dmd Gene

Abstract 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<FSIQ ≤85), while seven (18.92%) were intellectually impaired (FSIQ <70). The FSIQ was not associated with proximal and distal mutations when boundaries were set at exons 30 and 45. However, FSIQ was statistically significantly associated with mutation location when we assumed their functional consequence on dystrophin isoforms and when mutations in the 5’-untranslated region (5’UTR) of Dp140 (exons 45-50) were assigned to affect only Dp427 and Dp260. Mutations affecting Dp140 and Dp71/Dp40 have been associated with more frequent and more severe cognitive impairment. Finally, the same classification of mutations explained the greater proportion of FSIQ variability associated with cumulative loss of dystrophin isoforms. In conclusion, cumulative loss of dystrophin isoforms increases the risk of intellectual impairment in DMD and characterizing the genotype can define necessity of early cognitive interventions in DMD patients.

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Long-range genomic map of the Duchenne muscular dystrophy (DMD) gene: Isolation and use of J66 (DXS268), a distal intragenic marker

Genomics ◽

10.1016/0888-7543(87)90032-2 ◽

1987 ◽

Vol 1 (4) ◽

pp. 329-336 ◽

Cited By ~ 36

Author(s):

G.J.B. van Ommen ◽

C. Bertelson ◽

H.B. Ginjaar ◽

J.T den Dunnen ◽

E. Bakker ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Long Range ◽

Gene Isolation ◽

Dmd Gene ◽

Genomic Map

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ROLE OF PANCHAKARMA IN DUCHENNE MUSCULAR DYSTROPHY

International Journal of Research in Ayurveda and Pharmacy ◽

10.7897/2277-4343.04238 ◽

2013 ◽

Vol 4 (2) ◽

pp. 272-275

Author(s):

Ashutosh Chaturvedi ◽

Prasanna N Rao ◽

Shailaja U ◽

M Ashvini Kumar

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy

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Induced Pluripotent Stem Cells for Duchenne Muscular Dystrophy Modeling and Therapy

Cells ◽

10.3390/cells7120253 ◽

2018 ◽

Vol 7 (12) ◽

pp. 253 ◽

Cited By ~ 15

Author(s):

Lubos Danisovic ◽

Martina Culenova ◽

Maria Csobonyeiova

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Pluripotent Stem Cells ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Cell Reprogramming ◽

Progressive Degeneration ◽

Cardiac Muscles ◽

Dmd Gene ◽

Induced Pluripotent

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutation of the DMD gene which encodes the protein dystrophin. This dystrophin defect leads to the progressive degeneration of skeletal and cardiac muscles. Currently, there is no effective therapy for this disorder. However, the technology of cell reprogramming, with subsequent controlled differentiation to skeletal muscle cells or cardiomyocytes, may provide a unique tool for the study, modeling, and treatment of Duchenne muscular dystrophy. In the present review, we describe current methods of induced pluripotent stem cell generation and discuss their implications for the study, modeling, and development of cell-based therapies for Duchenne muscular dystrophy.

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The microRNA, miR-133b, functions to slow Duchenne muscular dystrophy pathogenesis

10.1101/2020.03.19.988519 ◽

2020 ◽

Author(s):

Thomas Taetzsch ◽

Dillon Shapiro ◽

Randa Eldosougi ◽

Tracey Myers ◽

Robert Settlage ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Skeletal Muscles ◽

Tibialis Anterior Muscle ◽

Muscle Fibers ◽

Progressive Degeneration ◽

Protein Encoding ◽

Small Muscle ◽

Encoding Genes

AbstractDuchenne muscular dystrophy (DMD) is characterized by progressive degeneration of skeletal muscles. To date, there are no treatments available to slow or prevent the disease. Hence, it remains essential to identify molecular factors that promote muscle biogenesis since they could serve as therapeutic targets for treating DMD. While the muscle enriched microRNA, miR-133b, has been implicated in the biogenesis of muscle fibers, its role in DMD remains unknown. To assess the role of miR-133b in DMD-affected skeletal muscles, we genetically ablated miR-133b in the mdx mouse model of DMD. In the absence of miR-133b, the tibialis anterior muscle of juvenile and adult mdx mice is populated by small muscle fibers with centralized nuclei, exhibits increased fibrosis, and thickened interstitial space. Additional analysis revealed that loss of miR-133b exacerbates DMD-pathogenesis partly by altering the number of satellite cells and levels of protein-encoding genes, including previously identified miR-133b targets as well as genes involved in cell proliferation and fibrosis. Altogether, our data demonstrate that skeletal muscles utilize miR-133b to mitigate the deleterious effects of DMD.

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Mast cells in the pathophysiology of Duchenne muscular dystrophy in Golden Retriever dogs

Pesquisa Veterinária Brasileira ◽

10.1590/1678-5150-pvb-6340 ◽

2020 ◽

Vol 40 (10) ◽

pp. 791-797

Author(s):

Isabela M. Martins ◽

Lygia M.M. Malvestio ◽

Jair R. Engracia-Filho ◽

Gustavo S. Claudiano ◽

Flávio R. Moraes ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Mast Cells ◽

Muscular Dystrophy ◽

Fibrous Tissue ◽

Control Group ◽

Golden Retriever ◽

Collagenous Tissue ◽

Muscle Types ◽

Muscle Groups

ABSTRACT: The Golden Retriever muscular dystrophy (GRMD) is one of the best models of Duchenne muscular dystrophy (DMD), with similar genotypic and phenotypic manifestations. Progressive proliferation of connective tissue in the endomysium of the muscle fibers occurs in parallel with the clinical course of the disease in GRMD animals. Previous studies suggest a relationship between mast cells and the deposition of fibrous tissue due to the release of mediators that recruit fibroblasts. The aim of this study was to evaluate the presence of mast cells and their relationship with muscle injury and fibrosis in GRMD dogs of different ages. Samples of muscle groups from six GRMD and four control dogs, aged 2 to 8 months, were collected and analyzed. The samples were processed and stained with HE, toluidine blue, and Azan trichrome. Our results showed that there was a significant increase in infiltration of mast cells in all muscle groups of GRMD dogs compared to the control group. The average number of mast cells, as well as the deposition of fibrous tissue, decreased with age in GRMD dogs. In the control group, all muscle types showed a significant increase in the amount of collagenous tissue. This suggests increased mast cell degranulation occurred in younger GRMD dogs, resulting in increased interstitial space and fibrous tissue in muscle, which then gradually decreased over time as the dogs aged. However, further studies are needed to clarify the role of mast cells in the pathogenesis of fibrosis.

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