Duchenne Muscular Dystrophy
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2021 ◽  
Vol 21 (1) ◽  
Asanka Rathnasiri ◽  
Udara Senarathne ◽  
Visvalingam Arunath ◽  
Thabitha Hoole ◽  
Ishara Kumarasiri ◽  

Abstract Background Contiguous gene deletion syndromes are rare genomic disorders caused by deletion of large segments of DNA resulting in co-occurrence of apparently unrelated multiple clinical phenotypes. We report a boy with contiguous gene deletion involving Xp21 genomic location. Case presentation A Sri Lankan boy with developmental delay and failure to thrive first presented at three years of age with hypovolaemia, hyperpigmentation and drowsiness. Investigations done at that time revealed hypoglycaemia, hyponatraemia, hyperkalaemia, low cortisol, low aldosterone, high ACTH and low 17-hydroxyprogesterone. He was diagnosed to have primary adrenal insufficiency. During follow-up at five years, he was noted to have progressive difficulty in walking, waddling gait, hypotonia, calf hypertrophy and positive Gower’s sign. His creatine kinase was very high, and the electromyogram showed myopathy. Genetic analysis revealed hemizygous deletion involving the final 35 exons of the dystrophin gene confirming the diagnosis of Duchenne muscular dystrophy. Further investigations revealed pseudohypertriglyceridemia, large glycerol peak on urine organic acid analysis and hemizygous deletion of the glycerol kinase gene confirming glycerol kinase deficiency. Based on the presence of Duchenne muscular dystrophy, glycerol kinase deficiency and probable congenital adrenal hypoplasia along with genetic confirmation of deletions involving dystrophin and glycerol kinase genes, the diagnosis of Xp21 contiguous gene deletion syndrome was made. Conclusions We report a child with contiguous gene deletion syndrome who was initially diagnosed as having isolated primary adrenal insufficiency probably due to congenital adrenal hypoplasia. Later he was confirmed to have Duchenne muscular dystrophy and glycerol kinase deficiency, as well. This case report highlights the importance of pre-emptive evaluation and identification of genetic defects when patients present with seemingly unrelated diseases that could aid in accurate diagnoses of contiguous gene deletion syndromes.

2021 ◽  
pp. 088307382110470
Aida Soim ◽  
Bailey Wallace ◽  
Nedra Whitehead ◽  
Michael G. Smith ◽  
Joshua R. Mann ◽  

In this retrospective cohort study, we characterize the health profile of preterm males with Duchenne muscular dystrophy. Major clinical milestones (ambulation cessation, assisted ventilation use, and onset of left ventricular dysfunction) and corticosteroids use in males with Duchenne muscular dystrophy identified through a population-based surveillance system were analyzed using Kaplan-Meier survival curves and Cox proportional hazards modeling. The adjusted risk of receiving any respiratory intervention among preterm males with Duchenne muscular dystrophy was 87% higher than among the corresponding full-term males with Duchenne muscular dystrophy. The adjusted risks for ambulation cessation and left ventricular dysfunction were modestly elevated among preterm compared to full-term males, but the 95% confidence intervals contained the null. No difference in the start of corticosteroid use between preterm and full-term Duchenne muscular dystrophy males was observed. Overall, the disease course seems to be similar between preterm and full-term males with Duchenne muscular dystrophy; however, pulmonary function seems to be affected earlier among preterm males with Duchenne muscular dystrophy.

2021 ◽  
Ai VU Hong ◽  
Nathalie Bourg ◽  
Peggy Sanatine ◽  
Jerome Poupiot ◽  
Karine Charton ◽  

Background: Duchenne Muscular Dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. While mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. We recently identified in DMD and in other muscular dystrophies the upregulation of a large number of the Dlk1-Dio3 clustered miRNAs (DD-miRNAs), in both the muscle and the serum. The objective of the present study was to define the biological functions of DD-miRNAs in skeletal muscle, particularly in the context of muscular dystrophy. Methods: DD-miRNAs expression pattern was characterized in vitro and in vivo, in normal and dystrophic situations. Epigenomic characterization was performed, to elucidate the molecular control of DD-miRNAs dysregulation. The biological effect of muscle DD-miRNAs dysregulation was investigated by an in vivo simultaneous overexpression of 14 DD-miRNAs in the wild-type muscle, together with CRISPR-Cas9-based knockdown of the entire DD-miRNA cluster in an iPS-derived myotubes. Omics data and bioinformatics tools were used for the prediction of DD-miRNAs biological functions, and functional characterization of mitochondrial pathways was performed. Results: We found that DD-miRNAs dysregulation is not specific to DMD since observed in mouse models for other muscular dystrophies. We showed that DD-miRNAs expression in mdx, is reduced in satellite cells, but highly upregulated in regenerating myofibers, suggesting a myofibers origin of DD6miRNA upregulation in muscular dystrophy in both muscles and serum. We demonstrated that upregulation of DD-miRNAs in the dystrophic muscle is controlled epigenetically by DNA and histone methylation (p<0.0001 and p=0.001, respectively) at the Intergenic Differentially Methylated Region (IG-DMR) of Dlk1-Dio3 locus. Transcriptomic analysis revealed a substantial overlap between the dystrophic muscle of the mdx mouse and the normal muscle that overexpressed 14 DD-miRNAs. Bioinformatics analysis predicted that DD-miRNAs could regulate mitochondrial functions. The ectopic overexpression of 14 DD-miRNAs, in the healthy muscle, resulted in a drastic downregulation of mitochondrial oxidative phosphorylation (OxPhos) (NES=-2.8, p=8.7E-17), similarly to the level in dystrophic muscles of mdx mice and DMD patients (NES=-2.88, p=7.7E-28). Knocking down the entire DD-miRNA cluster in iPS-derived myotubes resulted in increased mitochondrial OxPhos expression and activities. Conclusions: The present study provides evidence for the modulation of mitochondrial activity in the dystrophic muscle by the upregulated DD-miRNAs and supports an updated model for mitochondrial dysfunction in DMD. The regulation of mitochondrial OxPhos by DD-miRNAs may have a broader impact beyond DMD in physiological and pathological situations of muscle adaptation and regeneration.

2021 ◽  
Vol 73 (1) ◽  
Mahmoud Shehta ◽  
Mona Mostafa Rayan ◽  
Nagia Aly Fahmy ◽  
Ahmed Onsy ◽  
Islam Bastawy

Abstract Background With the continuous improvement of the respiratory care of Duchenne muscular dystrophy patients, cardiac manifestations (heart failure and arrhythmias) become the leading causes of morbidity and mortality. Early identification of cardiac muscle affection is crucial to start anti-failure drugs that reverse remodeling and improve prognosis. This study aimed to detect subtle cardiac changes in Duchenne muscular dystrophy patients and carriers using electrocardiography and echocardiography. Results This study included genetically diagnosed Duchenne muscular dystrophy patients (28 males) and carriers (25 females) and compared them to healthy gender-matched control groups. All study participants underwent clinical assessment, 12-lead electrocardiography, and global longitudinal strain augmented echocardiography. In the current study, Duchenne muscular dystrophy patients had higher heart rates, smaller left ventricular internal diameters, left atrial diameter, lower ejection fraction, and worse left ventricular global longitudinal strain in comparison with the control group. The global longitudinal strain inversely correlated with the age of Duchenne muscular dystrophy patients. The number of exon mutations did not affect electrocardiography and echocardiographic findings. Exon mutations 45–47 and 51–54 were significantly associated with an ejection fraction less than 60%. Duchenne muscular dystrophy carriers had smaller left ventricular wall diameters, left ventricular end-diastolic diameter, left atrial diameter, and worse left ventricular global longitudinal strain in comparison with the control group. Conclusions Left ventricular global longitudinal strain could detect subtle left ventricular systolic dysfunction in Duchenne muscular dystrophy patients and carriers before the decline of left ventricular ejection fraction.

2021 ◽  
Luana da Costa Lima ◽  
Evellyn Câmara Grilo ◽  
Thais Alves Cunha ◽  
Bárbara Gurgel Magalhães de Araújo ◽  
José Brandão-Neto ◽  

Abstract Duchenne muscular dystrophy (DMD) patients are at risk of developing conditions that can compromise their bone health, such as fractures and walking impairment. We aimed to assess bone mineral density as a function of the age of DMD patients. The cross-sectional study included 48 patients distributed into four groups by age: G1 (5.1-9.2 years), G2 (9.3-10.7 years), G3 (11.2-15.9 years), and G4 (18-24.7 years). Lumbar spine and total body bone mineral density (BMD) measurements were performed with dual-energy X-ray absorptiometry. There was a moderate negative correlation between age and the lumbar spine BMD z-score (p = 0.001; r = -0.45) and a strong negative correlation between age and the total body BMD z-score (p = 0.001; r = -0.79). The lumbar spine BMD z-scores in G3 and G4 were significantly lower than those in G1 and G2 (p < 0.05). The total body BMD z-score in G3 was lower than those in G1 and G2 (p < 0.05), and in G4 was lower ​​than those in the other groups (p < 0.05). Conclusion: The older patients had lower lumbar spine and total body BMD z-score values than younger patients. Moreover, these values ​​were negatively correlated with the age of the patients.

2021 ◽  
Vol 61 ◽  
pp. 298-304
Wendy A. Chouteau ◽  
Carolyn Burrows ◽  
Samuel G. Wittekind ◽  
Meilan M. Rutter ◽  
Jean E. Bange ◽  

2021 ◽  
Vol 23 (1) ◽  
Ke Xu ◽  
Hua-yan Xu ◽  
Rong Xu ◽  
Lin-jun Xie ◽  
Zhi-gang Yang ◽  

Abstract Background Progressive cardiomyopathy accounts for almost all mortality among Duchenne muscular dystrophy (DMD) patients.‍ Thus, our aim was to comprehensively characterize myocardial involvement by investigating the heterogeneity of native T1 mapping in DMD patients using global and regional (including segmental and layer-specific) analysis across a large cohort. Methods We prospectively enrolled 99 DMD patients (8.8 ± 2.5 years) and 25 matched male healthy controls (9.5 ± 2.5 years). All subjects underwent cardiovascular magnetic resonance (CMR) with cine, T1 mapping and late gadolinium enhancement (LGE) sequences. Native T1 values based on the global and regional myocardium were measured, and LGE was defined. Results LGE was present in 49 (49%) DMD patients. Global native T1 values were significantly longer in LGE-positive (LGE +) patients than in healthy controls, both in basal slices (1304 ± 55 vs. 1246 ± 27 ms, p < 0.001) and in mid-level slices (1305 ± 57 vs. 1245 ± 37 ms, p < 0.001). No significant difference in global native T1 was found between healthy controls and LGE-negative (LGE−) patients. In segmental analysis, LGE + patients had significantly increased native T1 in all analyzed segments compared to the healthy control group. Meanwhile, the comparison between LGE− patients and healthy controls showed significantly elevated values only in the basal anterolateral segment (1273 ± 62 vs. 1234 ± 40 ms, p = 0.034). Interestingly, the epicardial layer had a significantly higher native T1 in LGE− patients than in healthy controls (p < 0.05), whereas no such pattern was noticed in the global myocardium. Epicardial layer native T1 resulted in the highest diagnostic performance for distinguishing between healthy controls and DMD patients in receiver operating curve analyses (area under the curve [AUC] 0.84 for basal level and 0.85 for middle level) when compared to global native T1 and endocardial layer native T1. Conclusions Myocardial regional native T1, particularly epicardial native T1, seems to have potential as a novel robust marker of very early cardiac involvement in DMD patients. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) ChiCTR1800018340, 09/12/2018, Retrospectively registered.

2021 ◽  
Vol 22 (20) ◽  
pp. 11040
Barbara Zabłocka ◽  
Dariusz C. Górecki ◽  
Krzysztof Zabłocki

Duchenne muscular dystrophy (DMD) leads to disability and death in young men. This disease is caused by mutations in the DMD gene encoding diverse isoforms of dystrophin. Loss of full-length dystrophins is both necessary and sufficient for causing degeneration and wasting of striated muscles, neuropsychological impairment, and bone deformities. Among this spectrum of defects, abnormalities of calcium homeostasis are the common dystrophic feature. Given the fundamental role of Ca2+ in all cells, this biochemical alteration might be underlying all the DMD abnormalities. However, its mechanism is not completely understood. While abnormally elevated resting cytosolic Ca2+ concentration is found in all dystrophic cells, the aberrant mechanisms leading to that outcome have cell-specific components. We probe the diverse aspects of calcium response in various affected tissues. In skeletal muscles, cardiomyocytes, and neurons, dystrophin appears to serve as a scaffold for proteins engaged in calcium homeostasis, while its interactions with actin cytoskeleton influence endoplasmic reticulum organisation and motility. However, in myoblasts, lymphocytes, endotheliocytes, and mesenchymal and myogenic cells, calcium abnormalities cannot be clearly attributed to the loss of interaction between dystrophin and the calcium toolbox proteins. Nevertheless, DMD gene mutations in these cells lead to significant defects and the calcium anomalies are a symptom of the early developmental phase of this pathology. As the impaired calcium homeostasis appears to underpin multiple DMD abnormalities, understanding this alteration may lead to the development of new therapies. In fact, it appears possible to mitigate the impact of the abnormal calcium homeostasis and the dystrophic phenotype in the total absence of dystrophin. This opens new treatment avenues for this incurable disease.

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012910
Jonathan Broomfield ◽  
Micki Hill ◽  
Michela Guglieri ◽  
Michael Crowther ◽  
Keith Abrams

Objective:Duchenne Muscular Dystrophy (DMD) is a rare progressive disease, which is often diagnosed in early childhood, and leads to considerably reduced life-expectancy; due to its rarity, research literature and patient numbers are limited. To fully characterise the natural history, it is crucial to obtain appropriate estimates of the life-expectancy and mortality rates of patients with DMD.Methods:A systematic review of the published literature on mortality in DMD up until July 2020 was undertaken, specifically focusing on publications in which Kaplan-Meier (KM) survival curves with age as a time-scale were presented. These were digitised and individual patient data (IPD) reconstructed. The pooled IPD were analysed using the Kaplan-Meier estimator and parametric survival analysis models. Estimates were also stratified by birth cohort.Results:Of 1177 articles identified, 14 publications met the inclusion criteria and provided data on 2283 patients, of whom 1049 had died. Median life-expectancy was 22.0 years (95% CI: 21.2, 22.4). Analyses stratifying by three time-periods in which patients were born showed markedly increased life-expectancy in more recent patient populations; patients born after 1990 have a median life-expectancy of 28.1 years (95% CI 25.1, 30.3).Conclusions:This paper presents a full overview of mortality across the lifetime of a patient with DMD, and highlights recent improvements in survival. In the absence of large-scale prospective cohort studies or trials reporting mortality data for patients with DMD, extraction of IPD from the literature provides a viable alternative to estimating life-expectancy for this patient population.

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