Diagnosis Of Duchenne Muscular Dystrophy Research Articles

РАННЯЯ ДИАГНОСТИКА МИОДИСТРОФИИ ДЮШЕННА: АКТУАЛЬНОСТЬ, ПРОБЛЕМЫ, ВОЗМОЖНОСТИ И ПЕРСПЕКТИВЫ

Duchenne muscular dystrophy (DMD) is an orphan neuromuscular progressive genetic disease that causes muscle breakdown and subsequent loss. Provided early diagnosis, complex standard and pathogenetic therapy significantly changes the trajectory of the disease, making it more benign. Diagnosis of DMD is a two-pillar system with creatine kinase (CK) level measured at the first stage followed by molecular genetic study in case the enzyme threshold values. The quality of genetic diagnostics in Russia has reached the best worldwide standards recently though identifying children with elevated CK levels is yet difficult. The number of diagnosed DMD patients in Russia is significantly lower than the statistically estimated global amount. The average age for diagnosis is not decreasing either. Thus, the median age for DMD and Becker muscular dystrophy (BMD) molecular diagnosis is 7 years and 8 months old. The number of identified children below the age of 2 y/o in Russia has remained consistently low over the past three years. According to the results of a familial cases survey, the correct primary diagnosis of DMD was established in less than half of all cases, 47.1%. The most common incorrect diagnoses were as follows: asymptotic hepatitis (25.1%), perinatal damage to the central nervous system (6.4%), cerebral palsy (2.7%), autism spectrum disorder (ASD) (2.7%) and flat feet, hallux valgus etc. (16% in total). The median duration between the initial DMD manifestation and molecular diagnosis is 3 years and 8 months as yet whilst the age-specific guidelines suggest prescribing standard and pathogenetic therapy during the 2 to 5 y/o period of life. Therefore, the Russia’s average age of DMD diagnosis above 7 y/o lies far beyond the optimal age for initiating of the DMD therapy with the purpose of gaining its maximum possible clinical benefit. The accumulated international and Russian experience demonstrates the possibility for improving of the primary DMD and BMD diagnosis in early preschool age and therefore requires its nationwide introduction.

Assessing the Benefits and Harms Associated with Early Diagnosis from the Perspective of Parents with Multiple Children Diagnosed with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder diagnosed in childhood. Limited newborn screening in the US often delays diagnosis. With multiple FDA-approved therapies, early diagnosis is crucial for timely treatment but may entail other benefits and harms. Using a community-based survey, we explored how parents of siblings with DMD perceived early diagnosis of one child due to a prior child's diagnosis. We assessed parents' viewpoints across domains including diagnostic journey, treatment initiatives, service access, preparedness, parenting, emotional impact, and caregiving experience. We analyzed closed-ended responses on a -1.0 to +1.0 scale to measure the degree of harm or benefit parents perceived and analyzed open-ended responses thematically. A total of 45 parents completed the survey, with an average age of 43.5 years and 20.0% identifying as non-white. Younger siblings were diagnosed 2 years earlier on average (p < 0.001). Overall, parents viewed early diagnosis positively (mean: 0.39), particularly regarding school preparedness (+0.79), support services (+0.78), treatment evaluation (+0.68), and avoiding diagnostic odyssey (+0.67). Increased worry was a common downside (-0.40). Open-ended responses highlighted improved outlook and health management alongside heightened emotional distress and treatment burdens. These findings address gaps in the evidence by documenting the effectiveness of early screening and diagnosis of DMD using sibling data.

Computer-Aided Diagnosis of Duchenne Muscular Dystrophy Based on Texture Pattern Recognition on Ultrasound Images Using Unsupervised Clustering Algorithms and Deep Learning

ObjectiveThe feasibility of using deep learning in ultrasound imaging to predict the ambulatory status of patients with Duchenne muscular dystrophy (DMD) was previously explored for the first time. The present study further used clustering algorithms for the texture reconstruction of ultrasound images of DMD data sets and analyzed the difference in echo intensity between disease stages. Methodsk-means (Kms) and fuzzy c-means (FCM) clustering algorithms were used to reconstruct the DMD data-set textures. Each image was reconstructed using seven texture-feature categories, six of which were used as the primary analysis items. The task of automatically identifying the ambulatory function and DMD severity was performed by establishing a machine-learning model. ResultsThe experimental results indicated that the Gaussian Naïve Bayes and k-nearest neighbors classification models achieved an accuracy of 86.78% in ambulatory function classification. The decision-tree model achieved an identification accuracy of 83.80% in severity classification. A deep convolutional neural network model was established as the main structure of the deep-learning model while automatic auxiliary interpretation tasks of ambulatory function and severity were performed, and data augmentation was used to improve the recognition performance of the trained model. Both the visual geometry group (VGG)-16 and VGG-19 models achieved 98.53% accuracy in ambulatory-function classification. The VGG-19 model achieved 92.64% accuracy in severity classification. ConclusionRegarding the overall results, the Kms and FCM clustering algorithms were used in this study to reconstruct the characteristic texture of the gastrocnemius muscle group in DMD, which was indeed helpful in quantitatively analyzing the deterioration of the gastrocnemius muscle group in patients with DMD at different stages. Subsequent combination of machine-learning and deep-learning technologies can automatically and accurately assist in identifying DMD symptoms and tracking DMD deterioration for long-term observation.

Newborn screening for Duchenne muscular dystrophy: the perspectives of stakeholders

The rapidly evolving clinical landscape of Duchenne muscular dystrophy (DMD) is driving innovative approaches for early diagnosis through genomic newborn bloodspot screening (NBS). However, the potential impact of these programs on families and healthcare systems remains unexplored. This study assessed the perceived benefits, harms, barriers, and enablers for DMD NBS amongst primary caregivers of children with DMD and healthcare professionals (HCPs). This Australian multi-centre cross-sectional study used a mixed-methods convergent methodology. Participants completed a codeveloped questionnaire and their perceptions on the utility, model of care, and processes of DMD NBS were thematically analysed. Participants included 50 caregivers and 26 HCPs (68.5% and 53.1% response rate respectively). Most caregivers (40/50, 80%) perceived net benefits of DMD NBS and highlighted an early diagnosis as actionable knowledge, even with the current paucity of disease modifying therapies. This knowledge was valued to enable access to multidisciplinary supportive care (29/50, 58%), clinical trials (27/50, 54%), psychological support (28/50, 56%), inform reproductive planning (27/50, 54%), and facilitate financial planning based on the future needs of their child (27/50, 54%). Whilst HCPs acknowledged these opportunities, only 16/26 (61.5%) believed there were definite net benefits, with notable concerns over the psychological harms of diagnostic knowledge without a recourse to disease modifying therapeutic intervention early in life. Caregivers and HCPs perceived a range of potential benefits of DMD NBS. Health system readiness will be founded on developing an integrated model of care that not only supports the psychosocial and information needs of families receiving a newborn diagnosis of DMD, but also provides care and clinical surveillance for individuals for whom a diagnosis may remain uncertain. Medical Research Futures fund (GNT2017165, MRF2015965).

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. Italfarmaco.

Screening for Duchenne muscular dystrophy in newborns in the Ningxia region

To evaluate the incidence rate of Duchenne muscular dystrophy (DMD) in the male newborns in the Ningxia region and establish a critical threshold for screening DMD in newborns to distinguish between the normal population and affected individuals. A total of 10 000 male newborns were screened using immunofluorescence analysis of creatine kinase isoenzyme concentrations in heel spot dried blood specimens. Newborns with the concentrations higher than the critical threshold were recalled for serum creatine kinase measurements. Genetic testing was performed to confirm diagnosis in cases showing abnormalities. Among the screened 10 000 male newborns, two were confirmed to have DMD through genetic testing, resulting in a preliminary estimated incidence rate of 1/5 000 for male newborns in the Ningxia region. The critical threshold for creatine kinase isoenzyme concentration in newborns in this region was determined to be 468.57 ng/mL. Screening for DMD in newborns is feasible in the Ningxia region. Early screening, diagnosis, and treatment of DMD can improve the quality of life for affected individuals and help families make informed decisions regarding further pregnancies.

Burden of Disease of Duchenne Muscular Dystrophy in Denmark - A National Register-Based Study of Individuals with Duchenne Muscular Dystrophy and their Closest Relatives.

Duchenne Muscular Dystrophy (DMD) is a progressive genetic disease with a prevalence of 1 per 3,600-6,000 male births. Individuals with DMD are typically diagnosed at age 4-7 years; median survival is 30 years. They require multidisciplinary care, personal assistance, and often special education. The aim was to assess the burden of disease in DMD in Denmark. This includes incidence, prevalence, use of healthcare services, labour market participation, educational outcomes, and overall attributable costs due to DMD. Impact on the closest relatives (siblings and parents) was also investigated. The comprehensive Danish national health and administrative registers were used to assess the burden of disease following individuals with DMD and closest relatives from five years before, and up to 20 years after DMD diagnosis. Individuals with DMD (and relatives) from 1994-2021 were included. All outcomes were compared to matched control groups without the disease drawn from the Danish population. 213 unique individuals with DMD were identified. They had lower grades in school, required more special education and more healthcare and home care compared to their control group. The extra costs of special education summed to EUR 180,900 over the course of 11 years elementary school. They had an annual average productivity loss of EUR 20,200 between the age of 18 to 30. The extra healthcare costs of DMD in the 20 years after diagnosis were estimated to EUR 1,524,000. If an individual with DMD lives to be 30, total extra costs sum to EUR 2,365,800. Using national register data this study presented detailed results on the burden of disease of DMD, including impact on closest relatives. With 60 additional hospital admissions and 200 extra outpatient contacts in 20 years healthcare costs, but also costs of home care and special education, increases as disease progresses.

The Early Care (0-3 Years) In Duchenne Muscular Dystrophy Meeting Report.

This report summarizes the key discussions from the "Early Care (0-3 years) in Duchenne Muscular Dystrophy" meeting, which aimed to address the challenges and opportunities in the diagnosis and care of Duchenne muscular dystrophy (DMD) and female carriers within the 0-3-year age group. The meeting brought together experts and healthcare providers who shared insights, discussed advancements in DMD care, and identified research needs. Presentations covered diagnostic challenges, approved therapies, clinical trials, identification of young female carriers, and the importance of clinical care and support for families. The meeting highlighted the importance of timely diagnosis and the lack of evidence-based guidelines for the care of children with DMD aged 0-3 years. Diagnostic challenges were discussed, including delays in receiving a DMD diagnosis and disparities based on ethnicity. The potential benefits and process of newborn screening were addressed.Approved therapeutic interventions, such as corticosteroids and exon-skipping drugs, were explored, with studies indicating the potential benefits of early initiation of corticosteroid therapy and the safety of exon-skipping drugs in DMD. Clinical trials involving infants and young boys were discussed, focusing on drugs like ataluren, vamorolone, and gene therapies.The meeting emphasized the importance of clinical care and support for families, including comprehensive information provision, early intervention services, and individualized support. The identification and care of young female carriers were also addressed. The meeting provided a platform for experts and healthcare providers to discuss and identify key aspects of early care for children with DMD aged 0-3 years. The meeting emphasized the need for early diagnosis, evidence-based guidelines, and comprehensive care and support for affected children and their families. Further research, collaboration, and the development of consensus guidelines are needed to improve early diagnosis, treatment, and outcomes in this population.

Diagnostic outcome of pro bono neurogenetic diagnostic service in Sri Lanka: A wealth creation.

The inherited disease community in Sri Lanka has been widely neglected. This article aimed to present accumulated knowledge in establishing a pro bono cost-effective national, island-wide, free-of-charge molecular diagnostic service, suggesting a model for other developing countries. The project provided 637 molecular diagnostic tests and reports free of charge to a nation with limited resources. We pioneered the implementation of mobile clinics and home visits, where the research team acted as barefoot doctors with the concept of the doctor and the researcher at the patient's doorstep. Establishing pro bono, cost-effective molecular diagnostics is feasible in developing countries with limited resources and state funding through the effort of dedicated postgraduate students. This service could provide an accurate molecular diagnosis of Duchenne muscular dystrophy, Huntington's disease, Spinocerebellar ataxia, and Spinal muscular atrophy, a diagnostic yield of 54% (343/637), of which 43% (147/343) of the patients identified as amenable for available gene therapies. Initiated human resource development by double doctoral degree opportunities with international collaborations. Established a neurobiobank and a national registry in Sri Lanka, a rich and unique repository, wealth creation for translational collaborative research and sharing of information in neurological diseases, as well as a lodestar for aspiring initiatives from other developing countries.

Identifying hub genes and dysregulated pathways in Duchenne muscular dystrophy

Purpose The aim of this study was to identify the hub genes and dysregulated pathways in the progression of duchenne muscular dystrophy (DMD) and to unveil detailedly the cellular and molecular mechanisms associated with DMD for developing efficacious treatments in the future. Material and methods Three mRNA microarray datasets (GSE13608, GSE38417 and GSE109178) were downloaded from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) between DMD and normal tissues were obtained via R package. Function enrichment analyses were implemented respectively using DAVID online database. The network analysis of protein-protein interaction network (PPI) was conducted using String. Cytoscape and String were used to analyse modules and screen hub genes. The expression of the identified hub genes was confirmed in mdx mice through using qRT-PCR. Results In total, 519 DEGs were identified, consisting of 393 upregulated genes and 126 downregulated genes. The enriched functions and pathways of the DEGs mainly involve extracellular matrix organization, collagen fibril organization, interferon-gamma-mediated signaling pathway, muscle contraction, endoplasmic reticulum lumen, MHC class II receptor activity, phagosome, graft-versus-host disease, cardiomyocytes, calcium signaling pathway. Twelve hub genes were discovered and biological process analysis proved that these genes were mainly enriched cell cycle, cell division. The result of qRT-PCR suggested that increase in expression of CD44, ECT2, TYMS, MAGEL2, HLA-DMA, SERPINH1, TNNT2 was confirmed in mdx mice and the downregulation of ASB2 and LEPREL1 was also observed. Conclusion In conclusion, DEGs and hub genes identified in the current research help us probe the molecular mechanisms underlying the pathogenesis and progression of DMD, and provide candidate targets for diagnosis and treatment of DMD.

Detecting early signs in Duchenne muscular dystrophy: comprehensive review and diagnostic implications.

Despite the early onset of clinical signs suggestive of Duchenne muscular dystrophy (DMD), a diagnosis is often not made until four years of age or older, with a diagnostic delay of up to two years from the appearance of the first symptoms. As disease-modifying therapies for DMD become available that are ideally started early before irreversible muscle damage occurs, the importance of avoiding diagnostic delay increases. Shortening the time to a definite diagnosis in DMD allows timely genetic counseling and assessment of carrier status, initiation of multidisciplinary standard care, timely initiation of appropriate treatments, and precise genetic mutation characterization to assess suitability for access to drugs targeted at specific mutations while reducing the emotional and psychological family burden of the disease. This comprehensive literature review describes the early signs of impairment in DMD and highlights the bottlenecks related to the different diagnostic steps. In summary, the evidence suggests that the best mitigation strategy for improving the age at diagnosis is to increase awareness of the early symptoms of DMD and encourage early clinical screening with an inexpensive and sensitive serum creatine kinase test in all boys who present signs of developmental delay and specific motor test abnormality at routine pediatrician visits.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.

Duchenne Muscular Dystrophy in a Filipino Boy Reaching Adulthood, and Nine Years into Oral Corticosteroids: A Case Report

Rationale: Duchenne muscular dystrophy (DMD) is a disease that primarily manifests in the early stages of life and progressively affects muscle strength resulting in quadriparesis and ultimately resulting in premature death secondary to cardiac or respiratory failure. DMD is the most common x-linked genetic disorder in children that is because of an alteration of a protein called “dystrophin” which is responsible for strengthening muscle fibers and protecting them from injury as muscles contract and relax. Objective: To highlight the case of a 19-year-old male who was diagnosed with DMD at 8 years of age and treated with oral corticosteroid and rehabilitation. Case: We present the case of a 19-year-old male who developed difficulty climbing stairs and was diagnosed with DMD at 8 years old with the use of clinical exome sequencing. Corticosteroid therapy was initiated and rehabilitation perpetuated which dramatically improved his life expectancy. Discussion and Summary: Clinical exome sequencing was employed on our patient to confirm the diagnosis of DMD from other neuromuscular and neurodegenerative diseases. Most cases of DMD succumb to cardiopulmonary arrest before reaching adulthood; however, this case exemplifies DMD from other cases since our patient was able to prolong his life with continuation of oral corticosteroid and rehabilitation and in the absence of extensive life support. Key words: Progressive muscle weakness, Dystrophin, Premature death, DMD

Could Ultrasound be a Game Changer in the Diagnosis of Duchenne Muscular Dystrophy? A Systematic Review and Meta-analysis of the Recent Evidence (P7-9.011)

<h3>Objective:</h3> Adding a noninvasive imaging technique to evaluate muscle changes in Duchenne patients can increase diagnostic certainty and follow-up applications without implementing any potential harm. Thus, we performed a systematic review and meta-analysis to assess the current evidence of sonography. <h3>Background:</h3> Duchenne muscular dystrophy (DMD) is a severe hereditary neuromuscular disease due to variation in the dystrophin gene. Diagnostic criteria rely mainly on clinical and laboratory examination along with genetic analysis. Some studies have recorded different sonographic parameters as a novel method to track disease change. <h3>Design/Methods:</h3> Through Web of Science, PubMed, Scopus, and Embase, we conducted a systematic review and meta-analysis of studies that compared sonographic muscle values between DMD patients and healthy controls. After setting the eligibility criteria, data extraction, and quality assessment of the identified studies, we performed statistical analysis using Revman 5.4 and Open Meta analyst. <h3>Results:</h3> As different sonographic parameters were recorded, twenty studies were included, with a total of 446 patients and 428 controls. DMD patients demonstrated significantly higher values in calibrated muscle backscatter (dB) with a mean difference (MD) of 4.83 and 4.47 for elbow flexors and rectus femoris, respectively. In addition, the grayscale echo intensity (EI) showed higher values with a MD of 24.70 and 31.05 for the biceps and quadriceps, respectively. However, the results of the cross-sectional muscle area, fascial muscle length, and muscle thickness of different muscle groups in DMD patients mostly yielded no potential difference. <h3>Conclusions:</h3> We propose that sonographic application, combined with the standard clinical and serological assessment, adds value to the clinical practice by increasing diagnostic certainty and follow-up longitudinal evaluations. <b>Disclosure:</b> Dr. Ebrahim has nothing to disclose. Mr. Abouelatta has nothing to disclose. Dr. Aboutaleb has nothing to disclose. Dr. Hassan has nothing to disclose. Ms. Maallem has nothing to disclose. Mr. Ebrahim has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Mohamed has nothing to disclose. Dr. Fikry has nothing to disclose. Dr. Al Aref has nothing to disclose. Dr. Mounir has nothing to disclose. Mr. Mohamed has nothing to disclose. Dr. Abdelnaby has nothing to disclose.

A Proof of Principle Proteomic Study Detects Dystrophin in Human Plasma: Implications in DMD Diagnosis and Clinical Monitoring.

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease caused by pathogenic variations in the DMD gene. There is a need for robust DMD biomarkers for diagnostic screening and to aid therapy monitoring. Creatine kinase, to date, is the only routinely used blood biomarker for DMD, although it lacks specificity and does not correlate with disease severity. To fill this critical gap, we present here novel data about dystrophin protein fragments detected in human plasma by a suspension bead immunoassay using two validated anti-dystrophin-specific antibodies. Using both antibodies, a reduction of the dystrophin signal is detected in a small cohort of plasma samples from DMD patients when compared to healthy controls, female carriers, and other neuromuscular diseases. We also demonstrate the detection of dystrophin protein by an antibody-independent method using targeted liquid chromatography mass spectrometry. This last assay detects three different dystrophin peptides in all healthy individuals analysed and supports our finding that dystrophin protein is detectable in plasma. The results of our proof-of-concept study encourage further studies in larger sample cohorts to investigate the value of dystrophin protein as a low invasive blood biomarker for diagnostic screening and clinical monitoring of DMD.

Duchenne Muscular Dystrophy in Kazakhstan: A Journey from Diagnosis to the Treatment, the Biases and Achievements.

Neuro-muscular disorders constitutes a group of rare but heterogeneous conditions. The onset of these diseases ranges widely from birth to elderly. Many of them are life threatening and progressive. Neuromuscular science is a very specialised medical field for which specific knowledge and expertise are necessary. Such an expertise is available only partially in Kazakhstan where underdiagnosis, misdiagnosis and mismanagement of patients with muscle diseases are commonplace. Hopefully, times are changing. With the implementation of international guidelines for the diagnosis and treatment of Duchenne Muscular Dystrophy (DMD), patients are now given better care including pharmacological interventions (including steroids in DMD), respiratory and nutritional support. To report on clinical data and genetic variants in a nationwide cohort of DMD patients. To describe and analyse management strategies applied in Kazakhstan in these patients. The medical records of 84 patients recruited by the national expert-consulting board based at the national multidisciplinary centre of reference in neuro-muscular disorders in Astana, Kazakhstan, have been ascertained for the study. The national expert committee meets monthly to decide over the prescription of disease-modifying therapies in paediatric neuromuscular disorders. Data on the age of disease onset, the age at genetic testing, spectrum of genetic variants, the stage of disease and the serum CK levels have been collected.ResultsThe mean age of 84 examined patients was 10 years. In Kazakhstan, the average age of disease manifestation was 3 years and 3 months. The vast majority of patients passed through genetic test due to the clinical manifestations. The average age of genetic confirmation was 7 years and 6 months. There were 58,33%of gross variations, of which 55,95%were deletions and 2,38%were duplications. Nonsense mutations were identified in 29,7%. The authors contend that strictly keeping the clinical guides in the diagnosis of DMD is essential, as the genetic variations may affect the stage and feasibility of novel therapies. The way of management of neuro-muscular diseases used in Kazakhstan is strictly recommended for implementation in developing countries.

Duchenne Muscular Dystrophy Management and Treatment Access Challenges: Case Report

Introduction: Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease that causes muscle weakness with respiratory and cardiac complications. International DMD standard of care guidelines exist, but their implementation and DMD treatment access in the Middle East have historically been challenging. This report highlights sub-optimal management of DMD in the Middle East together with recommendations for best practices, and the first reported use of ataluren, a mutation-specific treatment for nonsense mutation DMD (nmDMD), in this region. Case Presentation: The management of two patients in the United Arab Emirates diagnosed with nonsense mutation DMD is described. Under multidisciplinary care, both patients were treated with corticosteroids as per international DMD standard of care guidelines. Although both patients presented with typical DMD signs/symptoms, one received a genetic diagnosis and treatment relatively late owing to low awareness of the early signs and symptoms of DMD among physicians in the region; delayed genetic diagnosis of DMD hinders early initiation of mutation-specific treatments such as ataluren. Moreover, this patient demonstrated low adherence to the treatment plan, potentially resulting from low DMD awareness and poor understanding of the-risk-benefit of corticosteroids in the patient’s family. In contrast, the other patient was genetically diagnosed early at 25 months, was administered ataluren whilst ambulatory, and demonstrated high adherence to the management plan. Limited expertise in performing motor function assessments and complications with medical insurance for ataluren in the region created additional obstacles in the management of both patients. Conclusions: The contrasting experiences of these patients highlight the high variability of diagnosis and management of DMD in the Middle East. There is a need in the region to boost disease education for both public and professional communities, establish local DMD networks and guidelines, and improve access to treatments to improve the quality of care that patients with DMD receive.

Molecular Diagnosis of Duchenne Muscular Dystrophy Using Single NGS-Based Assay.

Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular disorder caused by pathogenic variants in the dystrophin gene (DMD; locus Xp21.2). The variant spectrum of DMD is unique in that 65% of causative mutations are intragenic deletions, with intragenic duplications and point mutations (along with other sequence variants) accounting for 6% to 10% and 30% to 35%, respectively. The traditional strategy for molecular diagnostic testing for DMD involves initial screening for deletions/duplications using microarray-based comparative genomic hybridization followed by a full-sequence analysis of DMD for sequence variants. This traditional strategy is expensive and time-consuming due to the involvement of two separate tests to detect all types of variants in the DMD gene. Recent advancements in next-generation sequencing (NGS) technology and improvements in analysis algorithms related to copy number variant detection ultimately resulted in the development of a single NGS-based assay to detect all variant types, including deletions/duplications and sequence variants. This article initially discusses the strategic algorithm for establishing a molecular diagnosis of DMD and later provides detailed molecular diagnostic protocols for DMD, including an NGS-based sequencing assay with sequence and copy number variant analysis. © 2023 Wiley Periodicals LLC. Basic Protocol: Next-generation sequencing of the entire genomic sequence of the DMD gene using IDT xGen Lockdown Probes.

Time to diagnosis of Duchenne muscular dystrophy in Austria and Germany

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder manifesting in early childhood with progressive muscular weakness and atrophy, and resulting in early loss of ambulation. The collection and evaluation of epidemiological data for this disease is crucial for an early diagnosis and disease management. In Germany, data are collected via the TREAT-NMD DMD patient registry (www.dmd-register.de). In contrast, data collection in Austria has not yet been performed systematically. For collecting data from Austrian DMD patients, an online survey of the patient’s caregivers was conducted. Data of 57 patients were collected entailing initial symptoms, diagnosis and therapeutic measures. Comparable data has been collected for Germany via the TREAT-NMD DMD patient registry. 57 DMD patients aged 4–34 years completed the Austrian survey. On average, first symptoms of the disease appeared at the age of 3.1 years. As the most frequent first symptom, 46% of the patients described problems in climbing stairs. In 40% of the patients, DMD was diagnosed early due to an accidentally detected hyperCKemia in infancy or early childhood. Corticosteroids represented the main therapeutic option in our cohort. At the time of the survey, only 52% of the patients were treated with corticosteroids. Patients from Germany reported that first symptoms appeared at the age of 3.06 years. Diagnosis was established by genetic testing or muscle biopsy. 47% of the patients were treated with corticosteroids. Time between first symptoms and diagnosis was 7 months in Austria, and 4.7 months in Germany, respectively. Compared to earlier international studies, the Austrian data show encouraging results regarding earlier start of corticosteroid therapy in a larger percentage of patients. Austrian and German data show a trend towards an earlier diagnosis of DMD, while the age at symptom onset was similar to previous studies. The collection and evaluation of epidemiological data of DMD patients is important and will hopefully contribute to accelerate DMD diagnosis and treatment access for the patients.

Accuracy of Non-Invasive Prenatal Testing for Duchenne Muscular Dystrophy in Families at Risk: A Systematic Review.

Methodological advancements, such as relative haplotype and relative mutation dosage analyses, have enabled non-invasive prenatal diagnosis of autosomal recessive and X-linked diseases. Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by progressive proximal muscular dystrophy and a high mortality rate before the age of twenty. We aimed to systematically present obtainable data regarding a non-invasive prenatal diagnosis of DMD and provide a comprehensive resume on the topic. The emphasis was given to the comparison of different available protocols and molecular methods used for fetal inheritance deduction, as well as their correlation with prognostic accuracy. We searched the Scopus and PubMed databases on 11 November 2022 and included articles reporting a non-invasive prenatal diagnosis of DMD in families at risk using relative dosage analysis methods. Of the 342 articles identified, 7 met the criteria. The reported accuracy of NIPT for DMD was 100% in all of the studies except one, which demonstrated an accuracy of 86.67%. The combined accuracy for studies applying indirect RHDO, direct RHDO, and RMD approaches were 94.74%, 100%, and 100%, respectively. Confirmatory results by invasive testing were available in all the cases. Regardless of the technological complexity and low prevalence of the disease that reduces the opportunity for systematic research, the presented work demonstrates substantial accuracy of NIPT for DMD. Attempts for its implementation into everyday clinical practice raise many ethical and social concerns. It is essential to provide detailed guidelines and arrange genetic counseling in order to ensure the proper indications for testing and obtain informed parental consent.