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INTRODUCTION/AIMS: There is considerable heterogenicity in clinical outcomes in Duchenne Muscular Dystrophy (DMD). The aim of current study was to assess whether dystrophin gene (DMD) pathogenic variant location influences upper extremity and lower extremity motor function outcomes in a large prospective cohort. METHODS: We used longitudinal timed and quantitative motor function measurements obtained from 154 boys with DMD over a 10-year period by the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS) to understand how the trajectories of motor function differ based on proximal versus distal DMD pathogenic variants. Proximal variants were defined as located proximal to 5’ DMD intron 44, and distal variants as those including nucleotides 3’ DMD including intron 44. Distal DMD variants are predicted to alter the expression of short dystrophin isoforms (Dp140, Dp116, and Dp71). We compared various upper extremity and lower extremity motor function in these two groups, after adjusting for total lifetime corticosteroid use. RESULTS: The time to loss-of-ambulation and timed motor function measurements of both upper and lower limbs over a ten-year period were comparable between boys with proximal (n = 53) and distal DMD pathogenic variants (n = 101). Age had a significant effect on several motor function outcomes. Boys younger than 7 years of age (n = 49) showed gain in function whereas boys 7 years and older (n = 71) declined, regardless of dystrophin pathogenic variant location. DISCUSSION: The longitudinal decline in upper and lower motor functions is independent of proximal versus distal DMD pathogenic variants.

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.

s Background Duchenne muscular dystrophies (DMDs) are X-linked recessive neuromuscular disorders with malfunction or absence of the Dystrophin protein. Precise genetic diagnosis is critical for proper planning of patient care and treatment. In this study, we described a Chinese family with mosaic DMD mutations and discussed the best method for prenatal diagnosis and genetic counseling of X-linked familial disorders. Methods We investigated all variants of the whole dystrophin gene using multiple DNA samples isolated from the affected family and identified two variants of the DMD gene in a sick boy and two female carriers by targeted next generation sequencing (TNGS), Sanger sequencing, and haplotype analysis. Results We identified the hemizygous mutation c.6794delG (p.G2265Efs*6) of DMD in the sick boy, which was inherited from his mother. Unexpectedly, a novel heterozygous mutation c.6796delA (p.I2266Ffs*5) of the same gene, which was considered to be a de novo variant, was detected from his younger sister instead of his mother by Sanger sequencing. However, further NGS analysis of the mother and her amniotic fluid samples revealed that the mother carried a low-level mosaic c.6796delA mutation. Conclusions We reported two different mutations of the DMD gene in two siblings, including the novel mutation c.6796delA (p.I2266Ffs*5) inherited from the asymptomatic mosaic-carrier mother. This finding has enriched the knowledge of the pathogenesis of DMD. If no mutation is detected in obligate carriers, the administration of intricate STR/NGS/Sanger analysis will provide new ideas on the prenatal diagnosis of DMD.

Duchenne and Becker muscular dystrophy (DMD/BMD) are the most com-mon neuromuscular diseases caused by mutations in the dystrophin gene also called (DMD gene), located at Xp21. We report the clinical and genetic analysis of 74Algerian DMD/BMD patients from 62unrelated families who attended the neuromuscular unit of the University Hospital Center of Con-stantine between 2014 and 2017. After informed consent, multiplex poly-merase chain reaction (mPCR)was established to identify deletions. All pa-tients presented a classical phenotype dominated by a bilateral and symmetrical motor deficit predominantly proximal with calf hypertrophy in 91.6% of patients, with very high serum CK levels. Molecular analysis of the DMD gene showed, large deletions at all patients. Most of the deletions were between exons 44 and 53, the most frequent were deletions of exons 45-48, with ex-on 45 as the most common single exon deletion. Our study had generated considerable data on deletions that may promote future experimental thera-pies in Algeria.

Viltolarsen (Viltepso® in Japan) is a phosphorodiamidate morpholino antisense oligonucleotide being developed by Nippon Shinyaku, in collaboration with the National Center of Neurology and Psychiatry (NCNP), for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen binds to exon 53 of the dystrophin mRNA precursor and restores the amino acid open-reading frame by skipping exon 53, resulting in the production of a shortened dystrophin protein that contains essential functional portions. In March 2020, intravenous viltolarsen received its first global approval in Japan for the treatment of DMD in patients with confirmed deletion of the dystrophin gene that is amenable to exon 53 skipping. Viltolarsen is under regulatory review in the USA and clinical trials continue in the USA, Canada and globally. This article summarizes the milestones in the development of viltolarsen leading to the first approval for DMD.

Duchenne muscular dystrophy is a severe muscle wasting disease caused by mutations in the dystrophin gene (dmd). Ataluren has been approved by the European Medicines Agency for treatment of Duchenne muscular dystrophy. Ataluren has been reported to promote ribosomal read‐through of premature stop codons, leading to restoration of full‐length dystrophin protein. However, the mechanism of Ataluren action has not been fully described. To evaluate the efficacy of Ataluren on all three premature stop codons featuring different termination strengths (UAA > UAG > UGA), novel dystrophin‐deficient zebrafish were generated. Pathological assessment of the muscle by birefringence quantification, a tool to directly measure muscle integrity, did not reveal a significant effect of Ataluren on any of the analysed dystrophin‐deficient mutants at 3 days after fertilization. Functional analysis of the musculature at 6 days after fertilization by direct measurement of the generated force revealed a significant improvement by Ataluren only for the UAA‐carrying mutant dmdta222a. Interestingly however, all other analysed dystrophin‐deficient mutants were not affected by Ataluren, including the dmdpc3 and dmdpc2 mutants that harbour weaker premature stop codons UAG and UGA, respectively. These in vivo results contradict reported in vitro data on Ataluren efficacy, suggesting that Ataluren might not promote read‐through of premature stop codons. In addition, Ataluren had no effect on dystrophin transcript levels, but mild adverse effects on wild‐type larvae were identified. Further assessment of N‐terminally truncated dystrophin opened the possibility of Ataluren promoting alternative translation codons within dystrophin, thereby potentially shifting the patient cohort applicable for Ataluren.

INTRODUCTION Becker muscular dystrophy (BMD) results in decreased dystrophin with implications for mental health. METHODS This is a retrospective case series of neurodevelopmental, behavioral, and emotional symptoms and respective pharmacotherapies of 70 patients with BMD. RESULTS Fifty-four (77.1%) patients exhibited at least one symptom, and 19 (27.1%) patients exhibited four or more symptoms. The most prevalent symptoms were specific learning disabilities or special education needs (31.4%), inattention/hyperactivity (35.7%), language/speech delays (35.7%), and emotional or behavioral dysregulation (38.6%). Fisher's exact tests indicated that anxiety was more prevalent with mutations upstream of exon 30 (P = .049), but the prevalence of other symptoms did not differ with respect to mutation sites. Similarly, the number of symptoms individual patients with BMD exhibited did not differ with respect to mutation sites. Seventeen (24.3%) patients required pharmacotherapy to manage symptoms. DISCUSSION Neurodevelopmental, behavioral, and emotional symptoms are prevalent in patients with BMD regardless of dystrophin gene mutation site.

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.

A diagnosis of autism spectrum disorder is reported in up to 19% of dystrophinopathies. However, over the last ten years, only a few papers have been published on this topic. Therefore, further studies are required to analyze this association in depth and ultimately to understand the role of the brain dystrophin isoform in the pathogenesis of ASD and other neurodevelopmental disorders. In this paper, we report a clinical case of a patient affected by ASD and Duchenne muscular dystrophy, who carries a large deletion of the dystrophin gene. Then we present a brief overview of the literature about similar cases and about the potential role of the dystrophin protein in the neurobiology of autism spectrum disorder.

Objective: To determine the frequency and extent of cardiac involvement in female carriers of pathogenic variants in DMD, 53 women were examined through an observational, cross-sectional study.Methods: Genetically verified female carriers of pathogenic DMD variants were examined by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement, echocardiography, 24-h Holter monitoring, ECG, and blood concentrations of skeletal and cardiac muscle biomarkers.Results: Fifty-three female carriers of pathogenic DMD variants (mean age 49.6 years, 33 associated with DMD, and 20 with BMD) were included in the study. Sixty-two percent had cardiac dysfunction on echocardiography. On CMR, 49% had myocardial fibrosis, 35% had dilated left ventricles, and 10% had left ventricular hypertrophy. ECGs were abnormal in 72%, and abnormal Holter monitoring was found in 43%. Age did not correlate with myocardial fibrosis or cardiac dysfunction. Myocardial fibrosis was more frequent in carriers of pathogenic variants associated with DMD vs. BMD (61 vs. 28%, p = 0.02).Conclusion: This study shows that cardiac involvement, affecting both structure and function of the heart, is found in over 2/3 of women with a pathogenic DMD variant. The study supports early cardiac screening, including ECG, Holter, and cardiac imaging, in this group of carriers, so that symptoms related to pathogenic variants in DMD can be recognized, and relevant treatment can be initiated. Longitudinal studies are needed to assess morbidity and mortality related to single, pathogenic DMD variants in women.

Background: Duchenne muscular dystrophy is a degenerative muscle disease that results from impairment of the dystrophin gene. The disease causes progressive loss in muscle mass and function. Objective: The anti-aging protein, α-klotho, has been implicated in the regulation of muscle regeneration. We previously discovered that mice harboring reduced α-klotho levels exhibited a decline in muscle strength and running endurance. Method: To investigate the ability of α-klotho to improve overall endurance in a dystrophin null murine model, we examined the voluntary wheel running performance of dystrophin-null, mdx4cv mice overexpressing an α-klotho transgene. Results: As expected, compared to wild type, both male and female dystrophic mice exhibited reduced running ability that was characterized by shorter running duration and longer periods of rest between cycles of activity. While our results did not detect an improvement in running performance with α-klotho overexpression, we identified distinct differences in the running patterns between females and males from all mouse strains analyzed (i.e., mdx4cv, mdx4cv overexpressing α-klotho, α-klotho overexpressing, α-klotho hypomorph, and wild type). For all strains, male mice displayed significantly reduced voluntary running ability compared to females. Further analysis of the mdx4cv strains demonstrated that male mice ran for shorter lengths of time and took longer breaks. However, we did not identify gender-associated differences in the actual speed at which mdx4cv mice ran. Conclusion: Our data suggest key differences in the running capabilities of female and male mice, which are of particular relevance to studies of dystrophin-null mice.

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.

This case-control study uses magnetic resonance imaging and spectroscopy to evaluate the association between treatment with recombinant adeno-associated virus serotype rh74 (rAAVrh74) and muscle quality in children with Duchenne muscular dystrophy.

Introduction: DMD, an X-linked muscle degenerative fatal disease, is caused by mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. Since the DMD DCM treatment is limited, novel therapeutic modalities are urgently needed. Hypothesis: We hypothesized that dystrophin mutations in DMD lead to cardiomyopathy-causing bioenergetic/metabolic impairments, which can be therapeutically targeted for improving cardiac function. Methods: The study included iPSC-CMs from a healthy volunteer and 3 DMD patients (young male, YM; adult male, AM; adult female, AF) and mdx mice. We investigated the bioenergetics, electrophysiology, mitochondrial and metabolic features of iPSC-CMs and heart tissues using the SeaHorse Flux Analyzer, patch clamp, confocal fluorescence microscopy and Liquid Chromatography Mass Spectrometry (LC-MS) technologies, respectively. Results: To test the hypothesis, we measured the iPSC-CM respiration rate using the SeaHorse. Compared to healthy, in both AM and AF DMD, but not in YM DMD cardiomyocytes, ATP production decreased by 75%, and basal respiration decreased by 80% and 45%, respectively. In agreement with impaired oxidative phosphorylation capacity, mitochondrial activity measured by 3D life confocal microscopy was attenuated by 35% in AM, but not in YM. Concurring with the healthy-like bioenergetic status, YM iPSC-CMs fired regularly with no arrhythmias, in contrast to the prominent arrhythmias in AM and AF cardiomyocytes. Further, the LC-MS analysis demonstrated that the levels of 13%, 6% and 7% of the 120 metabolite measured, were lower in AM, AF and YM, while 10%, 18% and 43% were higher, respectively, compared to healthy iPSC-CMs ( p ). For example, in AM and AF (but not in YM) the phosphocreatine (PCr) levels were diminished by >80%, compared to healthy iPSC-CMs, indicating a dysfunctional PCr energy system. Finally, the LC-MS analysis of mdx ventricular tissue demonstrated a statistically-significant different metabolic profile in 8 mdx mice vs 8 healthy mice. Conclusion: DMD iPSC-CMs and mdx mice exhibit bioenergetic/metabolic impairments, which constitute novel targets for alleviating the cardiomyopathy in DMD patients.

Highlights • Normalized muscle volumes distinguish between wild type and DE50-MD dogs. • Global muscle T2 signal intensities discriminate between wild type and DE50-MD dogs. • Musculoskeletal changes detected by MRI reflect those seen in human DMD patients. • Musculoskeletal MRI in this model will be useful to assess treatment efficacy., The DE50-MD canine model of Duchenne muscular dystrophy (DMD) has a dystrophin gene splice site mutation causing deletion of exon 50, an out-of-frame transcript and absence of dystrophin expression in striated muscles. We hypothesized that the musculoskeletal phenotype of DE50-MD dogs could be detected using Magnetic Resonance Imaging (MRI), that it would progress with age and that it would reflect those in other canine models and DMD patients. 15 DE50-MD and 10 age-matched littermate wild type (WT) male dogs underwent MRI every 3 months from 3 to 18 months of age. Normalized muscle volumes, global muscle T2 and ratio of post- to pre-gadolinium T1-weighted SI were evaluated in 7 pelvic limb and 4 lumbar muscles bilaterally. DE50-MD dogs, compared to WT, had smaller volumes in all muscles, except the cranial sartorius; global muscle T2 was significantly higher in DE50-MD dogs compared to WT. Muscle volumes plateaued and global muscle T2 decreased with age. Normalized muscle volumes and global muscle T2 revealed significant differences between groups longitudinally and should be useful to determine efficacy of therapeutics in this model with suitable power and low sample sizes. Musculoskeletal changes reflect those of DMD patients and other dog models.

Introduction DMD, an X-linked muscle degenerative fatal disease, is caused by mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. Treatments for DCM in DMD are limited to steroids and standard heart failure medications such as β-blockers and ACE-inhibitors, and therefore novel therapeutic modalities are urgently needed. Purpose We hypothesized that dystrophin mutations in DMD lead to cardiomyopathy-causing bioenergetic/metabolic impairments, which can be therapeutically targeted for improving cardiac function. Methods Induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) were generated from healthy volunteer and 3 DMD patients: young male (YM), adult male (AM) and adult female (AF). We investigated the bioenergetics, electrophysiology, mitochondrial and metabolic features of healthy and DMD iPSC-CMs using the Seahorse Flux analyzer, patch clamp, confocal fluorescence microscopy and Liquid chromatography mass spectrometry (LC-MS) technologies, respectively. Results To test the hypothesis, we measured respiration and glycolytic rates of healthy and DMD iPSC-CMs. Compared to healthy iPSC-CMs, in both AM and AF DMD, but not in YM DMD cardiomyocytes, there was a 75% decrease in ATP production, and 80% and 45% decrease in basal respiration, respectively. In agreement with the healthy-like bioenergetic status of YM, the iPSC-CMs showed no arrhythmias, in contrast to the prominent arrhythmias in AM and AF cardiomyocytes. To determine whether the impairment in the phosphorylation pathway (OXPHOS) affects glycolysis, we measured the cardiomyocytes' response to glycolytic stress test. These experiments showed that the glycolytic rates were similar in healthy and DMD iPSC-CMs. In agreement with impaired OXPHOS, mitochondrial activity measured by 3D life confocal microscopy was attenuated in the DMD male by 35%, compared to healthy cardiomyocytes. Furthermore, the metabolomic LC-MS analyses demonstrated significant differences in metabolite levels in YM, AM and AF DMD iPSC-CMs relative to healthy iPSC-CMs. For example, compared to healthy iPSC-CMs, there was a dramatic fall to undetected levels in phosphocreatine in both AM and AF, but not in YM DMD, indicating a dysfunctional phosphocreatine energy system. Conclusions DMD iPSC-CMs exhibit bioenergetic/metabolic impairments, which constitute novel targets for alleviating the cardiomyopathy in DMD patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ISF - Israel Science Foundation

Becker muscular dystrophy patients generally carry in-frame mutations in the dystrophin gene, allowing the production of partially functional dystrophin protein. The presence of cognitive and behavioral comorbidities and the relation with the location of mutations has been scarcely investigated in Becker. This case report describes the neurocognitive and behavioral profiles of 3 brothers with Becker carrying an in-frame deletion of exons 45-48. The 3 cases underwent 2 consecutive neuropsychological assessments of which one assessment took place when they completed their primary education (age range of the cases: 11.2 -12.1 years). Intellectual abilities were normal to high and all cases had difficulties with processing speed and math. The brothers differed in intellectual abilities, executive functions, working memory, attention and reading abilities. Variability in cognitive development was noted as well. This report suggests that cognitive and behavioral functions in Becker vary regardless of gene mutation and exposer to similar environmental factors.

A significant percentage of Duchenne muscular dystrophy (DMD) cases are caused by premature termination codon (PTC) mutations in the dystrophin gene, leading to the production of a truncated, non-functional dystrophin polypeptide. PTC-suppressing compounds (PTCSC) have been developed in order to restore protein translation by allowing the incorporation of an amino acid in place of a stop codon. However, limitations exist in terms of efficacy and toxicity. To identify new compounds that have PTC-suppressing ability, we selected and clustered existing PTCSC, allowing for the construction of a common pharmacophore model. Machine learning (ML) and deep learning (DL) models were developed for prediction of new PTCSC based on known compounds. We conducted a search of the NCI compounds database using the pharmacophore-based model and a search of the DrugBank database using pharmacophore-based, ML and DL models. Sixteen drug compounds were selected as a consensus of pharmacophore-based, ML, and DL searches. Our results suggest notable correspondence of the pharmacophore-based, ML, and DL models in prediction of new PTC-suppressing compounds.

Nonischemic dilated cardiomyopathy (DCM) often has a genetic etiology, however, its prevalence and etiologies are not completely understood. The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals with enrollees 40-69 years of age. Our group created a custom phenotype of heart failure using ICD-10 codes for several subtypes of heart failure diagnoses including DCM. We then compared the individuals included in the custom heart failure phenotype to control individuals in a 20-to-1 fashion to identify genetic differences. Data were compared using Mixed Model Analysis for Pedigrees/Populations (MMAP) mixed-model regression. We identified 8 unlinked intronic variants in the dystrophin gene ( DMD ) that, when separated by self-identified race, occurred with a combined minor allele frequency of 0.15 in individuals with heart failure who identified as being of African descent. The combined minor allele frequency of these variants was 0.05 in individuals who self-identified as being of European descent. One variant of DMD in particular (rs139029250), was identified with a minor allele frequency of 0.05 in African British with DCM. The unadjusted odds ratio of a diagnosis of heart failure in individuals with rs129029250 was 4.65. When separated by gender, the unadjusted odds ratios are 2.02 for females and 6.44 for males. DMD is most notably known for its role in Duchenne and Becker muscular dystrophy, both of which are known to cause dilated cardiomyopathy in affected individuals. However, none of the individuals (36 female and 43 male) identified in our analysis with rs129029250 have been diagnosed with Duchenne muscular dystrophy, Becker muscular dystrophy, or a primary disorder of muscle (ICD code G70). Additionally, these individuals have an intronic variant of DMD , while Duchene and Becker muscular dystrophy are both due to exonic mutations. These findings suggest a possible common variant in the DMD gene that may contribute to DCM in individuals of African descent.

In the 164 patients with Duchenne/Becker muscular dystrophy, we found 142 different small mutations including 51 novel mutations not listed in the LOVD, the UMD-DMD, the ClinVar, and the HGMD databases. Among all mutations, nonsense mutations occurred in 45.7%, frameshift mutations in 32.9%, and splicing mutations in 19.5%. Small mutations were distributed throughout the whole dystrophin gene. Splicing mutations were twice more common in BMD patients than in DMD patients. Eighty-two percent of mothers of the males affected with DMD/BMD were found to be carriers of small mutations.

Objective The novel morpholino antisense oligonucleotide viltolarsen targets exon 53 of the dystrophin gene, and could be an effective treatment for patients with Duchenne muscular dystrophy (DMD). We investigated viltolarsen’s ability to induce dystrophin expression and examined its safety in DMD patients. Methods In this open‐label, multicenter, parallel‐group, phase 1/2, exploratory study, 16 ambulant and nonambulant males aged 5–12 years with DMD received viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary endpoints were dystrophin expression and exon 53 skipping levels. Results In western blot analysis, mean changes in dystrophin expression (% normal) from baseline to Weeks 12 and 24 were − 1.21 (P = 0.5136) and 1.46 (P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and 4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group (2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53 skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events were judged to be mild or moderate in intensity and none led to study discontinuation. Interpretation Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing trend in dystrophin expression and exon 53 skipping levels, and was safe and well tolerated. The decline in motor function appeared less marked in patients with higher dystrophin levels; this may warrant further investigation. This study supports the potential clinical benefit of viltolarsen.

Duchenne muscular dystrophy (DMD) is a devastating, progressive neuromuscular disorder for which there is no cure. As the dystrophin gene is located on the X chromosome, DMD occurs predominately in males. DMD is caused by a lack of functional dystrophin protein resulting from mutations in the 2.2-Mb DMD gene, whichdisrupts the reading frame. Care considerations for DMD advocate a coordinated, multidisciplinary approach to the management of DMD in order to optimize management of the primary manifestations of DMD as well as any secondary complications that may arise. This review provides an overview of the multidisciplinary clinical management of DMD with regard to the respiratory, cardiology, orthopedic, and nutritional needs of patients with DMD. Recent advances in novel disease-modifying treatments for DMD are also discussed with specific reference to exon skipping and suppression of premature stop codons as promising genetic therapies. The combination of multidisciplinary clinical management alongside novel gene therapiesoffers physicians a powerful armamentarium for the treatment of DMD.

Background In individuals with Duchenne muscular dystrophy (DMD), exon skipping treatment to restore a wild-type phenotype or correct the frame shift of the mRNA transcript of the dystrophin (DMD) gene are mutation-specific. To explore the molecular characterization of DMD rearrangements and predict the reading frame, we simultaneously screened all 79 DMD gene exons of 45 unrelated male DMD patients using a multiplex ligation-dependent probe amplification (MLPA) assay for deletion/duplication patterns. Multiplex PCR was used to confirm single deletions detected by the MLPA. Results There was an obvious diagnostic delay, with an extremely statistically significant difference between the age at initial symptoms and the age of clinical evaluation of DMD cases (t value, 10.3; 95% confidence interval 5.95–8.80, P

Background: Duchenne muscular dystrophy (DMD), one of the most common X linked muscular disorder, affecting 1 in 3500 male births and is caused by mutation in dystrophin gene. 65% of DMD cases are caused by large deletion of dystrophin gene, followed by duplication (5-10%) or point mutation (25-30%). There is wide mutation spectrum of the mutations in dystrophin gene. Hence, population specific information is needed on mutation spectrum and frequency of common mutations occurring in that particular population for appropriate counseling, prenatal diagnosis and for developing genetic therapy in future. Aims and Objectives: To find out the frequency and distribution of deletion in dystrophin gene in DMD patients along with contribution of pathology and genetic testing in diagnosis of DMD and Becker muscular dystrophy (BMD) in North Indian population.Materials and Methods: Dystrophin gene was screened for deletion by multiplex polymerase chain reaction (PCR). Out of 41 patients, 09 patients underwent muscle biopsy, on which immunohistochemistry was performed for dystrophin, sarcoglycan, dysferlin and merosin.Results: Majority of the deletions were located in distal hotspot region (26/39 ~66.66%) which includes the exons 45-55 and 15.38% of deletions were located at the proximal hotspot region (2- 19 exons).Conclusion: In the present study, 34% patients only showed deletion. Hence complete work up of any muscular dystrophy requires immnohistochemical analysis to see the expression of muscle proteins along with multipleplex PCR test to detect any exon deletion, multiplex ligation-dependent probe amplification (MLPA) to detect point mutation and duplication and western blotting to quantify the dystrophin protein.Asian Journal of Medical Sciences Vol.8(6) 2017 13-18

Duchenne and Becker muscular dystrophy (DMD/BMD) are caused by mutations in the dystrophin gene and are characterized by severe and mild progressive muscle wasting, respectively. Short stature has been reported as a feature of DMD in the Western hemisphere, but not yet confirmed in Orientals. Height of young BMD has not been fully characterized. Here, height of ambulant and steroid naive Japanese 179 DMD and 42 BMD patients between 4 and 10 years of age was retrospectively examined using height standard deviation score (SDS). The mean height SDS of DMD was -1.08 SD that was significantly smaller than normal (p

The results of the analysis of exon deletions and duplications in the dystrophin gene sequences from 121 Duchenne and Becker muscular dystrophy patients from Ukraine are presented. It is shown that the level of de novo deletions in these families reaches 53%, and most of the deletions are localized in the distal part of the gene. It is important to take into account these data in genetic counseling to assess the risk of birth of patients with DMD/BMD, including in prenatal diagnostics, in families with Duchenne and Becker muscular dystrophy patients.

Background Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder. Patients with DMD usually have severe and fatal symptoms, including progressive irreversible muscle weakness and atrophy complicated with gastrocnemius muscle pseudohypertrophy. DMD is caused by mutations in the dystrophin-encoding DMD gene, including large rearrangements and point mutations. This retrospective study was aimed at supplying information on our 4-year clinical experience of DMD genetic and prenatal diagnosis at the Department of Prenatal Diagnosis in Women’s Hospital of Nanjing Medical University. Methods Multiplex ligation-dependent probe amplification (MLPA) was used to detect the exon deletions or duplications. And Ion AmpliSeq™ panel for inherited disease was used as the next-generation sequencing (NGS) method to identify the point mutations in exons of DMD gene, but the introns were not sequenced. Results In this study, the large deletions and duplications of DMD gene were detected in 32 (51.6%) of the 62 families, while point mutations were detected in 20 families (32.3%). The remaining 10 families with a negative genetic diagnosis need to be reevaluated for clinical symptoms or be detected by other molecular methods. Notably, six novel mutations were identified, including c.412A > T(p.Lys138*), c.2962delT(p.Ser988Leufs*16), c.6850dupA (p.Ser2284Lysfs*7), c.5139dupA (p.Glu 1714Argfs*5), c.6201_6203delGCCins CCCA(p.Val2069Cysfs*14) and c.10705A > T (p.Lys3569*). In 52 families with positive results, 45 mothers (86.5%) showed positive results during carrier testing and de novo mutations arose in 7 probands. The prenatal diagnosis was offered to 34 fetuses whether the pregnant mother was a carrier or not. As a result, eight male fetuses were affected, three female fetuses were carriers, and the remaining fetuses had no pathogenic mutation. Conclusions This study reported that MLPA and NGS could be used for screening the DMD gene mutations. Furthermore, the stepwise procedure of prenatal diagnosis of DMD gene was shown in our study, which is important for assessing the mutation type of fetuses and providing perinatal care in DMD high-risk families.

Gene therapies using adeno-associated viral (AAV) vectors have advanced into clinical trials for several diseases, including Duchenne muscular dystrophy (DMD). A limitation of AAV is the carrying capacity (∼5 kb) available for genes and regulatory cassettes (RCs). These size constraints are problematic for the 2.2-Mb dystrophin gene. We previously designed a variety of miniaturized micro-dystrophins (μDys) that displayed significant, albeit incomplete, function in striated muscles. To develop μDys proteins with improved performance, we explored structural modifications of the dystrophin central rod domain. Eight μDys variants were studied that carried unique combinations of between four and six of the 24 spectrin-like repeats present in the full-length protein, as well as various hinge domains. Expression of μDys was regulated by a strong but compact muscle-restricted RC (CK8e) or by the ubiquitously active cytomegalovirus (CMV) RC. Vectors were evaluated by intramuscular injection and systemic delivery to dystrophic mdx4cv mice, followed by analysis of skeletal muscle pathophysiology. Two μDys designs were identified that led to increased force generation compared with previous μDys while also localizing neuronal nitric oxide synthase to the sarcolemma. An AAV vector expressing the smaller of these (μDys5) from the CK8e RC is currently being evaluated in a DMD clinical trial., Gene therapy for DMD is complicated by the enormous dystrophin gene. AAV vectors can only deliver partially functional micro-dystrophin genes. In this report, improved micro-dystrophin cassettes are described that increase muscle strength, avoid muscle-tendon injury, and persist more than 2 years. These improved vectors have great promise for DMD therapy.

In the material of 227 families with Becker muscular dystrophy (BMD), we found nine non-consanguineous families with 17 male individuals carrying a rare mutation—a single exon 48 deletion of the dystrophin gene—who were affected with a very mild or subclinical form of BMD. They were usually detected thanks to accidental findings of elevated serum creatine phosphokinase (sCPK). A thorough clinical analysis of the carriers, both children (12) and adults (5), revealed in some of them muscle hypotonia (10/17) and/or very mild muscle weakness (9/17), as well as decreased tendon reflexes (6/17). Adults, apart from very mild muscle weakness and calf hypertrophy in some, had no significant abnormalities on neurological assessments and had good exercise tolerance. Parents of the children carriers of the exon 48 deletion are usually unaware of their children being affected, and possibly at risk of developing life-threatening cardiomyopathy. The same concerns the adult male carriers. Therefore, the authors postulate undertaking preventive measures such as cascade screening of the relatives of the probands. Newborn screening programmes of Duchenne muscular dystrophy (DMD)/BMD based on sCPK marked increase may be considered.

Duchenne muscular dystrophy (DMD) is X-linked recessive neuromuscular disorders caused due to mutation in dystrophin gene, leading to progressive muscle weakness. This study was done to identify mutation in dystrophin gene in Nepalese patients with DMD using Multiplex Ligation Dependent Probe Amplification (MLPA) assay in Nepal. Twenty one patients from different regions of Nepal, who were clinically diagnosed as DMD were enrolled in the study. Peripheral blood samples were collected in EDTA vials, gDNA was extracted, and deletion mutation in the dystrophin gene was analysed using Multiplex Ligation Dependent Probe Amplification (MLPA) assay.Exon deletion mutation in the dystrophin gene was observed in 14 (66.6%) out of 21 DMD cases. The most common exon deletion was observed and confined in exon 7-14 and 45-53 of dystrophin gene. The location of deletion in dystrophin gene is apparently non-random with a preponderance found in the hot spot regions. Use of MLPA is useful in detecting copy number changes in DMD proband and suspected carriers in Nepal.

Duchenne m uscular dystrophy is heterogeneous group of inherited disorders characterized by progressive muscle weakness and wasting. In Duchenne muscular dystrophy involves mutations in the dystrophin gene. Dystrophin is one of the large structural proteins in the cell membrane and absence of dystrophin leads integrity of muscle cells. Ayu r vedic diagnose can be made as Adibala Pravrit Mamsa - Vata - Kshaya due to Srothorodha. No any specified treatment schedule in any medical field related to Duchenne muscular dystrophy. Therapeutic approach of muscular dy strophy is represents on cortico steroids, physical therapy , and respiration assistance and gene therapy or muscle transducti on. The Ayurvedic treatments relevant to Rasayana group of he rbo - mineral medicines and specified Panchkarma therapies have definite protective influence and long survival on Dhat u K shaya a ccording to A yurvedic clas s ics. Keep upon this view es pecially Rajay apana Bast i is selected for present conceptual study because of its beneficial Sad hyo B alajanana and Rasayana effects . So this is a n attempt has been made to review the relevant effect of Rajayapana Basti in Ayurveda with reference to D uchenne muscular dystrophy.

Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics.In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed.For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.

Background: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscular dystrophy that affects young boys and is caused by mutation of the dystrophin gene located over X chromosome. Materials and Methods: In this prospective study, 120 clinically diagnosed DMD patients were tested for exon deletions, duplication or point mutation. Results: Of the 120 clinically suspected DMD patients, the diagnosis of DMD was confirmed by the genetic study or muscle biopsy in 116 patients. The mean age of onset was 3.2 years and the mean age at presentation was 7.2 years. 110/120 cases were confirmed by genetic testing and six were by absence of staining for dystrophin on muscle biopsy. DMD gene deletion was present in 78.5%, duplication in 5.3% and point mutation in 11.2% cases. 70.3% of patients had deletion located at a distal hot spot region. Single exon deletion was found in 16.5%. Distal hotspot exons 47, 48 and 50 were the commonly deleted exons. Conclusions: In our study, 94.8% cases showed genetic change in the DMD gene. Muscle biopsy was the choice of investigation in earlier days. Detection of DMD by DNA based method eliminates the need to do an invasive procedure for diagnosis. Hence the genetic testing should be the investigation of choice in suspected cases of DMD. The pattern of deletion, obtained in the population of Rajasthan was similar when compared with other ethnic groups of the Indian population. It would be helpful for researchers to develop drugs specific to exons or for ongoing mutation-specific therapies.

Introduction We studied neurodevelopmental and behavioral/emotional symptoms in patients with Duchenne muscular dystrophy (DMD). Methods Retrospective case series of neurodevelopmental and behavioral/emotional symptoms obtained through review of systems of 700 DMD patients in relation to dystrophin gene mutations. Results The most common symptoms encountered were emotional/behavioral dysregulation (38.7%), inattention/hyperactive features (31.4%), obsessive and compulsive features (25.0%), and language/speech delays (24.4%). Most patients (72.7%) had at least one symptom. Patients with mutations near the 3' end of the dystrophin gene were at higher risk for developing inattention/hyperactive features, language/speech delays, and global intellectual delays. Those with mutations between exon 31 and 79 had higher risk of clustering of symptoms when compared with those upstream of exon 30. Discussion Neurodevelopmental, emotional, and behavioral symptoms are common comorbidities in DMD. There is higher prevalence of inattention/hyperactive features, language/speech delays, and global intellectual delays in genotypes affecting the 3' end of the dystrophin gene.

Introduction: The frequency and distribution of dystrophin gene deletions vary in patients with Duchene/Becker muscular dystrophy (DMD/BMD). Objective: In this study, we aimed to analyze clinical, biochemical, and dystrophin gene deletion pattern, by using multiplex polymerase chain reaction (PCR) in the population of eastern Uttar Pradesh and the adjoining districts of Bihar and Madhya Pradesh. Material and Method: After clinical assessment, 225 patients of DMD/BMD were analyzed for deletion in dystrophin gene. Clinical features and biochemical parameters were noted. For genetic study, all samples were tested for deletion from 25 exons of DMD gene by using multiplex PCR. Result: Deletions were detected in 169 (75.1%) patients of DMD/BMD. Deletions were observed in both proximal and mid-distal hot spot regions with maximum deletion localized in the mid-distal hot spot region of the gene. The most frequent deletions were observed in exon 50 (14.9%) and exon 49 (10.8%). Conclusion: This study concludes that mid-distal region of dystrophin is highly polymorphic in the population of eastern Uttar Pradesh and responsible for pathogenesis of DMD. The population of eastern Uttar Pradesh shows similar pattern of deletion in dystrophin gene when compared with other ethnic groups of the Indian population.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder resulting from a mutation in the dystrophin gene. Loss of dystrophin function leads to progressive muscle wasting and cardiomyopathy. In 2018, advanced cardiomyopathy is the primary mode of death, despite the application of standard of care CHF therapies. Our group has recently undertaken a cardiac MRI study demonstrating that adult DMD patients have small hearts with very low LV mass as compared to patients with non-ischemic cardiomyopathy or healthy patients. The central hypothesis is DMD-associated cardiomyopathy develops secondary to dysregulation of various cardiac signaling pathways that modulate cardiac growth, namely cardiomyocyte proliferation. Utilizing the mdx mouse, a model of DMD, decreased heart/body weight ratios were noted from birth (P1: Hrt/BW 5.6 ± 0.16 vs. 4.8 ± 0.18 NTg vs mdx pNTg and m dx hearts have similar cardiomyocyte cell size (WGA staining: 0.08 ± 0.001 vs 0.08 ± 0.002 NTg vs mdx pmdx hearts. FACS analysis indicated mdx hearts have fewer cardiomyocytes than NTg hearts (35% reduction; 51.7e 4 ± 4.9e 4 vs. 33.8e 4 ± 3.5e 4 NTg vs mdx pmdx hearts (Ki67: 4.8 ± 0.3 vs 2.0 ± 0.1 NTg vs mdx pNTg vs mdx pmdx hearts (Ki67: 13.7 ± 1.2 vs. 6.0 ± 1.0 NTg vs mdx pmdx P4 hearts. Cell cycle targets of YAP were reduced in P4 mdx hearts (20/27 genes, n=3) suggesting a disruption of the Hippo-Yap pathways in mdx hearts. Collectively, the current study provides a unique insight into the mechanism leading to the development DMD cardiomyopathy and directs investigation into potential therapeutic targets for the amelioration of DMD-associated cardiomyopathy.

Duchenne and Becker muscular dystrophies are the most common muscle diseases and are both currently incurable. They are caused by mutations in the dystrophin gene, which lead to the absence or reduction/truncation of the encoded protein, with progressive muscle degeneration that clinically manifests in muscle weakness, cardiac and respiratory involvement and early death. The limits of animal models to exactly reproduce human muscle disease and to predict clinically relevant treatment effects has prompted the development of more accurate in vitro skeletal muscle models. However, the challenge of effectively obtaining mature skeletal muscle cells or satellite stem cells as primary cultures has hampered the development of in vitro models. Here, we discuss the recently developed technologies that enable the differentiation of skeletal muscle from human induced pluripotent stem cells (iPSCs) of Duchenne and Becker patients. These systems recapitulate key disease features including inflammation and scarce regenerative myogenic capacity that are partially rescued by genetic and pharmacological therapies and can provide a useful platform to study and realize future therapeutic treatments. Implementation of this model also takes advantage of the developing genome editing field, which is a promising approach not only for correcting dystrophin, but also for modulating the underlying mechanisms of skeletal muscle development, regeneration and disease. These data prove the possibility of creating an accurate Duchenne and Becker in vitro model starting from iPSCs, to be used for pathogenetic studies and for drug screening to identify strategies capable of stopping or reversing muscular dystrophinopathies and other muscle diseases.

Duchenne muscular dystrophy (DMD) is a common X-linked recessive disorder, which is caused by deletion, duplication, or point mutations of the dystrophin gene. This article discusses genetic counseling and prenatal diagnosis in DMD and highlights the need for confirmation of diagnosis by molecular studies in the index case for future prenatal diagnosis. It also addresses how the family can be provided prenatal diagnosis, if the patient is deceased. These principles are illustrated by four case scenarios.

Objective To describe the deletion patterns and distribution characteristics of the dystrophin gene in a Chinese population of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). Methods Patients with DMD/BMD were recruited. Deletions in 19 exons of the dystrophin gene were evaluated using accurate multiplex polymerase chain reaction (PCR). Result Multiplex PCR identified deletions in 238/401 (59.4%) patients with DMD/BMD. Of these, 196 (82.4%) were in the distal hotspot, 32 (13.4%) were in the proximal hotspot, five (2.1%) were in both regions and five (2.1%) were in neither hotspot. Deletions were classified into 54 patterns. Exon 49 was the most frequently deleted. The reading frame rule was upheld for 91.9% of cases. Conclusion Accurate multiplex PCR for 19 exons is an effective diagnostic tool.

In a cohort of 40 consecutive patients with dystrophinopathy, 29 (72.5%) showed dystrophin gene deletions. Five (17.2%) of these deletions had two non-contiguous deletions involving proximal and central hotspot regions i.e. double deletions. Patients with double deletions tended to have superior functional grading than those with single or no deletion. Double deletions within the dystrophin gene form an interesting feature of this cohort of Indian patients. Sporadic cases amounted to 75% (30/40). Deletions in the sporadic Duchenne muscular dystrophy patients were localized to the central hotspot region. The proximal hotspot mutations were seen exclusively in the families with affected siblings. Clinical course of affected siblings was largely concordant, except for one family. One family with intrafamilial phenotypic variability is reported. The three male cousins in this family had phenotypes varying from Duchenne muscular dystrophy, Becker's muscular dystrophy to cramp myalgia.

Hardware and software for measuring respiration rate in mice are described. The design is based on slightly modified source code of the QPULSECAPTURE project. The measuring device based on an 86x PC and a webcam enables measurements with absolute error of 18 breaths/min in the frequency range from 200 to 320 breaths/min. The device was used for comparative study of a group of mdx-mice with mutated dystrophin gene and a normal control group. It was found that the respiration rate in the mdx-mouse group was significantly higher.

Introduction: Becker muscular dystrophy (BMD) is a progressive X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Duchenne muscular dystrophy (DMD) is also caused by such mutations but shows rapidly progressive muscle wasting. Therefore, studies aimed at establishing treatments have been focused on DMD. Fortunately, most DMD treatments can also be applied as BMD treatments because of the common pathophysiology. Although the natural history of BMD is very heterogeneous, this is a debilitating disease with progressive muscle weakness. Thus, treatments for BMD are urgently needed.Areas covered: Treatments for BMD are described by reviewing treatments for DMD, as BMD and DMD share a common pathophysiology caused by dystrophin abnormalities. Additionally, the characteristics of BMD patients aged over 60 years are summarized.Expert opinion: Until now, many efforts have been made to establish treatments for DMD, while efforts toward BMD treatments have not been prominent. It is now time ...

We report a patient with a typical phenotype and clinical history of Duchenne muscular dystrophy who is currently 53 years old. Because of improvements in cardiopulmonary care, there has been a great improvement in survival and preservation of quality of life for many of these patients. Whereas it is no longer rare to find patients with Duchenne muscular dystrophy living into their fifth decade, this is the first report of a patient in his sixth decade of life. We believe that besides use of continuous noninvasive respiratory support, the fortuitous absence of dilated cardiomyopathy associated with the particular point mutation of his dystrophin gene has permitted prolonged survival.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular degenerative disorder initiated by mutation in the dystrophin gene that is located on chromosome Xp21.The present case is a novel repo...

Duchenne muscular dystrophy (DMD) is a recessive X-linked genetic disease caused by a mutation in the dystrophin gene. The new drug NS-065/NCNP-01 utilizing exon-skipping therapy targeting specific deletions has been used in a first-in-human trial for the treatment of DMD. We surveyed 10 pairs of DMD participants and their parents within this clinical trial via an iPad survey form and through interviews regarding their understanding of the trial, expectations, anxieties, and reasons for participating in the trial. Approximately half of the participants actively decided to participate of their own volition, and none considered quitting the trial. This indicates that participants participated more positively in this clinical trial than previously expected. However, some potential concerns were also revealed, with one being that the desire to please those around them might be more important to the DMD participants than the effects of the drug. Another issue is the possibility of biased information originating from the study subjects' parents; while seven out of 10 of the parents told their children that the study drug might work, only four of these parents also explained that it might not work. Only two study participants received an explanation concerning the drug's side effects from their parents. This result implies that caution should be taken when family expectations are high, and there is a possibility that subjects will be given biased information from their parents.

Objectives To determine the cost-effectiveness ratio of different courses of action for the diagnosis of Duchenne or Becker muscular dystrophy in Colombia. Methods The cost-effectiveness analysis was performed from the Colombian health system perspective. Decision trees were constructed, and different courses of action were compared considering the following tests: immunohistochemistry (IHC), Western blot (WB), multiplex polymerase chain reaction, multiplex ligation-dependent probe amplification (MLPA), and the complete sequencing of the dystrophin gene. The time horizon matched the duration of sample extraction and analysis. Transition probabilities were obtained from a systematic review. Costs were constructed with a type-case methodology using the consensus of experts and the valuation of resources from consulting laboratories and the 2001 Social Security Institute cost manual. Deterministic sensitivity and scenario analyses were performed with one or more unavailable alternatives. Costs were converted from Colombian pesos to US dollars using the 2014 exchange rate. Results In the base case, WB was the dominant strategy, with a cost of US $419.07 and a sensitivity of 100%. This approach remains the dominant strategy down to a 98.2% sensitivity and while costs do not exceed US $837.38. If WB was not available, IHC had the best cost-effectiveness ratio, followed by MLPA and sequencing. Conclusions WB is a cost-effective alternative for the diagnosis of patients suspected of having Duchenne or Becker muscular dystrophy in the Colombian health system. The IHC test is rated as the second-best detection method. If these tests are not available, MLPA followed by sequencing would be the most cost-effective alternative.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs.

Duchenne muscular dystrophy (DMD) is a fatal X-chromosome linked recessive disorder caused by the truncation or deletion of the dystrophin gene. The most widely used animal model of this disease is the dystrophin-deficient mdx mouse which was first discovered 30 years ago. Despite its extensive use in DMD research, no effective treatment has yet been developed for this devastating disease. This review explores what we have learned from this mouse model regarding the pathophysiology of DMD and asks if it has a future in providing a better more thorough understanding of this disease or if it will bring us any closer to improving the outlook for DMD patients.