Follow-up of three patients with a large in-frame deletion of exons 45–55 in the Duchenne muscular dystrophy (DMD) gene

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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Long-term follow-up of dysphagia in adult patients with Duchenne muscular dystrophy

European Journal of Paediatric Neurology ◽

10.1016/j.ejpn.2018.06.004 ◽

2018 ◽

Vol 22 (5) ◽

pp. 786-790 ◽

Cited By ~ 2

Author(s):

Yuka Yamada ◽

Michiyuki Kawakami ◽

Ayako Wada ◽

Shogo Fukui ◽

Koshiro Haruyama ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Adult Patients ◽

Long Term Follow Up

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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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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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Longitudinal Motor Functional Outcomes and Magnetic Resonance Imaging Patterns of Muscle Involvement in Upper Limbs in Duchenne Muscular Dystrophy

Medicina ◽

10.3390/medicina57111267 ◽

2021 ◽

Vol 57 (11) ◽

pp. 1267

Author(s):

Claudia Brogna ◽

Lara Cristiano ◽

Tommaso Verdolotti ◽

Giulia Norcia ◽

Luana Ficociello ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Duchenne Muscular Dystrophy ◽

Magnetic Resonance ◽

Muscular Dystrophy ◽

Resonance Imaging ◽

Muscle Mri ◽

Functional Changes ◽

One Year ◽

Age Range

Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5–16 years), and 17 non ambulant (age range 10–30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.

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Progression of muscular co-activation and gait variability in children with Duchenne muscular dystrophy: A 2-year follow-up study

Clinical Biomechanics ◽

10.1016/j.clinbiomech.2020.105101 ◽

2020 ◽

Vol 78 ◽

pp. 105101

Author(s):

Martina Rinaldi ◽

Maurizio Petrarca ◽

Alberto Romano ◽

Gessica Vasco ◽

Carmen D'Anna ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Gait Variability ◽

Follow Up Study ◽

Co Activation

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Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys

Journal of Personalized Medicine ◽

10.3390/jpm10040164 ◽

2020 ◽

Vol 10 (4) ◽

pp. 164

Author(s):

Shefa Tawalbeh ◽

Alison Samsel ◽

Heather Gordish-Dressman ◽

Yetrib Hathout ◽

CINRG-DNHS Investigators ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Natural History Study ◽

Motor Abilities ◽

Igf I ◽

Comparative Safety ◽

Pharmacodynamic Biomarkers ◽

Larger Sample ◽

Insight Into

Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan® protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan® signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred.

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CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy

Genes ◽

10.3390/genes11030342 ◽

2020 ◽

Vol 11 (3) ◽

pp. 342 ◽

Cited By ~ 1

Author(s):

Kenji Rowel Q. Lim ◽

Quynh Nguyen ◽

Kasia Dzierlega ◽

Yiqing Huang ◽

Toshifumi Yokota

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Animal Models ◽

Mechanical Stress ◽

Muscle Cell ◽

Neuromuscular Disorder ◽

Reading Frame ◽

Advantages And Disadvantages ◽

Short Palindromic Repeat ◽

Dmd Gene

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose well to some extent, each has its own limitations. To help overcome this, clustered regularly interspaced short palindromic repeat (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

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Duchenne muscular dystrophy: genome editing gives new hope for treatment

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2017-135377 ◽

2018 ◽

Vol 94 (1111) ◽

pp. 296-304 ◽

Cited By ~ 2

Author(s):

Vassili Crispi ◽

Antonios Matsakas

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Genome Editing ◽

Genetic Diseases ◽

Wasting Disease ◽

Cardiac Muscles ◽

Dmd Gene ◽

Current Lines ◽

Dystrophin Protein ◽

Potential Therapeutics

Duchenne muscular dystrophy (DMD) is a progressive wasting disease of skeletal and cardiac muscles, representing one of the most common recessive fatal inherited genetic diseases with 1:3500–1:5000 in yearly incidence. It is caused by mutations in the DMD gene that encodes the membrane-associated dystrophin protein. Over the years, many have been the approaches to management of DMD, but despite all efforts, no effective treatment has yet been discovered. Hope for the development of potential therapeutics has followed the recent advances in genome editing and gene therapy. This review gives an overview to DMD and summarises current lines of evidence with regard to treatment and disease management alongside the appropriate considerations.

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238 TAILORED PIG MODEL OF DUCHENNE MUSCULAR DYSTROPHY

Reproduction Fertility and Development ◽

10.1071/rdv24n1ab238 ◽

2012 ◽

Vol 24 (1) ◽

pp. 231 ◽

Cited By ~ 2

Author(s):

N. Klymiuk ◽

C. Thirion ◽

K. Burkhardt ◽

A. Wuensch ◽

S. Krause ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Nuclear Transfer ◽

Muscle Disease ◽

Pig Model ◽

Mdx Mouse ◽

Cell Clones ◽

Fatty Replacement ◽

Dmd Gene ◽

Dystrophin Protein

Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases in humans, affecting 1 in 3500 boys. It is characterised by progressive muscle weakness and wasting due to mutations in the dystrophin (DMD) gene resulting in absence of dystrophin protein in skeletal muscle. Although curative treatments are currently not available, genetic and pharmacological approaches are under investigation including early-phase clinical trials. Existing animal models in different species (e.g. mdx mouse, GRMD dog) have been instrumental to understand the pathophysiology of DMD, but have several limitations. Importantly, the causative point mutations (mdx mouse: nonsense mutation; GRMD dog: splice mutation) are different from the most common human mutations (out-of-frame deletion of one or several exons of the DMD gene). We used gene targeting in somatic cells and nuclear transfer to generate a genetically tailored pig model of DMD. A bacterial artificial chromosome (BAC) from the porcine DMD gene was modified by recombineering to replace exon 52, resulting in a frame shift in the transcript. Modified BAC were transfected into male neonatal kidney cells, which were screened by quantitative polymerase chain reaction for replacement of exon 52 in the X-linked DMD gene. Eight of 436 cell clones were successfully targeted and 2 of them were used for nuclear transfer. For each of the cell clones, a pregnancy was established by transfer of cloned embryos into recipient gilts. Four piglets of the first litter were live born and killed within 48 h and tissue samples were processed for histological characterisation. Two piglets of the second litter died during birth due to obstetric complications, whereas the other 2 piglets were delivered by Caesarean section and raised in an artificial feeding system. Their serum creatine kinase (CK) levels were grossly elevated. Although both piglets showed reduced mobility compared with age-matched controls, they were able to move and feed on their own. Immunofluorescence staining of dystrophin was negative in muscle fibres of DMD mutant piglets and the complete absence of dystrophin protein was confirmed by immunoblot analysis. Histological examination of biceps femoris muscle from DMD mutant pigs showed a degenerative myopathy with fibre size variation, rounded fibres, central nuclei, fibrosis and fatty replacement of muscle tissue mimicking the hallmarks of the human disease. In conclusion, we generated the first pig model for a genetic muscle disease. The DMD mutant pig appears to be a bona fide model of the human dystrophy as ascertained by absence of the dystrophin protein, elevated serum CK levels and early degenerative changes on muscle histology. Because deletion of exon 52 is one of the most frequent mutations found in human DMD, the exon 52 mutated DMD pig represents an excellent model for testing targeted genetic treatments. This study was supported by the Bayerische Forschungsstiftung.

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