scholarly journals The Role of Dystrophin Gene Mutations in Neuropsychological Domains of DMD Boys: A Longitudinal Study

2019 ◽  
Vol 26 (3-4) ◽  
pp. 42-49
Author(s):  
Rahul Tyagi ◽  
Vivek Podder ◽  
Harshita Arvind ◽  
Manju Mohanty ◽  
Akshay Anand
Keyword(s):  
Muscular Dystrophy ◽  
Pediatric Population ◽  
Neuropsychological Functioning ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Long Term Memory ◽  
Ethical Guidelines ◽  
Neuropsychological Rehabilitation ◽  
Neuropsychological Impairments

Background: Duchenne Muscular Dystrophy (DMD) is a fatal muscular dystrophy of pediatric population coupled with other secondary comorbidities including mental retardation and neuropsychological impairments. Mutation location in the dystrophin gene, have been associated with neuropsychological functioning in DMD. Purpose: We investigated temporal changes in the neuropsychological functioning of DMD subjects, hitherto understudied. Methods: Subjects with suspected DMD were enrolled according to the ethical guidelines. Genetic confirmation by Multiplex Ligation Dependent Probe Amplification was carried out to identify pathogenic deletion or duplication in dystrophin gene. Intellectual and neuropsychological functioning was assessed by using standardized batteries. Investigated neuropsychological domains included visual, verbal and working memory, selective and sustained attention, executive functioning, verbal fluency, and visuo-constructive and visuo-spatial abilities. The assessments were carried out at baseline and followed for one time point in 30 cases. Result: The follow-up assessment revealed that neuropsychological functioning did not worsen with time. Improvements were seen in block designing task ( p = 0.050), serial positioning primacy effect ( p = 0.002), Stroop incongruent task ( p = 0.006), visual long-term memory ( p = 0.003) and attention ( p = 0.001). DMD cases with mutation location affecting short dystrophin isoform (Dp140) also showed improvement in these domains. Conclusion: No temporal alterations were found in DMD subjects, though improvements in few domains were observed. Neuropsychological rehabilitation may be useful in improving the quality of life in DMD subjects.

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

scholarly journals Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 765 ◽  
Author(s):  
Kenji Rowel Q. Lim ◽  
Narin Sheri ◽  
Quynh Nguyen ◽  
Toshifumi Yokota
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Cardiac Involvement ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Female Carrier ◽  
Daily Life Activities ◽  
Cardiac Manifestations ◽  
Available Information

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart.

scholarly journals Cognitive profile of patients with facioscapulohumeral muscular dystrophy

2021 ◽  
Vol 15 (4) ◽  
pp. 541-547
Author(s):  
Vanessa Brzoskowski dos Santos ◽  
Jonas Alex Morales Saute ◽  
Laís Alves Jacinto-Scudeiro ◽  
Annelise Ayres ◽  
Rafaela Soares Rech ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Muscular Dystrophy ◽  
Verbal Fluency ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Cognitive Profile ◽  
Life Assessment ◽  
Long Term Memory ◽  
Term Memory

ABSTRACT Although it is predominantly a muscular disease, impairments in the central nervous system in patients with facioscapulohumeral muscular dystrophy (FSHD) have been described in the literature. Objective: To describe the cognitive profile of patients with FSHD and to correlate the impairments found with clinical variables and quality of life. Methods: Cross-sectional and case–control study that evaluated FSHD patients using a series of cognitive assessments (Mini-Mental State Examination — MMSE, Montreal Cognitive Assessment — MoCA, verbal fluency with phonological restriction — FAS, categorical verbal fluency — FAS-cat, trail-making test — TMT, and Rey’s Verbal Auditory Learning Test); a neurological severity scale (Gardner–Medwin–Walton — GMWS); and a quality of life measurement tool (Medical Outcomes Study 36-Item Short-Form Health Survey). Results: Individuals with FSHD (13) and healthy controls (26) were paired by gender and age. Significant differences between case and control groups were found in MMSE, TMT A, and A7 (p≤0.05) and MOCA (p≤0.001) performances. A positive correlation was verified in long-term memory impairments and the age in which symptoms appear (r=-0.593, p=0.033). Regarding quality of life assessment, the emotional domain correlated to MEEM (r=0.657, p=0.015), TMT A (r=-0.601, p=0.030), and A7 (r=0.617, p=0.025) performances. Conclusions: Individuals with FSHD presented mild impairments in the performance of tasks that involve attention, planning, and long-term memory functions. Those impairments were associated neither with the disease duration nor with its neurological severity.

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

2021 ◽  
pp. 1-11
Author(s):  
Jerry R. Mendell ◽  
Navid Khan ◽  
Nanshi Sha ◽  
Helen Eliopoulos ◽  
Craig M. McDonald ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Term Treatment ◽  
Long Term Treatment ◽  
The Difference ◽  
Dmd Gene ◽  
6 Minute Walk Test

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

scholarly journals Sensitivity and Frequencies of Dystrophin Gene Mutations in Thai DMD/BMD Patients As Detected by Multiplex PCR

2008 ◽  
Vol 25 (2) ◽  
pp. 115-121 ◽  
Author(s):  
Thanyachai Sura ◽  
Jakris Eu-ahsunthornwattana ◽  
Sarinee Pingsuthiwong ◽  
Manisa Busabaratana
Keyword(s):  
Muscular Dystrophy ◽  
Multiplex Pcr ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Index Patient ◽  
Becker Muscular Dystrophy ◽  
Large Size ◽  
Different Populations ◽  
The Mean ◽  
Deletion Frequency

Background: Duchenne muscular dystrophy (DMD), a lethal X-linked disease affecting 1 in 3500 male births, and its more benign variant, Becker muscular dystrophy (BMD), are caused by mutations in the dystrophin gene. Because of its large size, analysing the whole gene is impractical. Methods have been developed to detect the commonest mutations i.e. the deletions of the exons. Although these tests are highly specific, their sensitivity is inherently limited by the prevalence of deletions, which differs among different populations.Methods: We reviewed our database for the detection of Dystrophin gene mutation by means of 31-exon multiplex PCR in Thai males, diagnosed clinically and biochemically with DMD or BMD from July 1994 to November 2006. One index patient was chosen from each family for statistical analysis. The overall sensitivity of the test, the number of fragment deleted, and the deletion frequency of each fragment were calculated, along with their 95% confidence intervals (C.I.).Results: We found deletions in 99 out of the 202 index patients (49%; Bayesian 95% C.I. = 42%–56%). 51% of these had deletion in only one of the 31 exons tested, while the patient with the most extensive deletions had 14 exons deleted. The mean number of deleted exons were 2.84 (BCabootstrap 95% C.I. = 2.37–3.48), or 5.02 (3.81–6.85) if all the untested exons adjacent to the confirmed deleted exons were assumed to be deleted. The region spanning exons 44-52 was the most frequently deleted. These were similar to those reported in the Japanese.Conclusion: The multiplex PCR detected deletions only in about half of the Thai patients. The diseases therefore should not be excluded solely on the negative result if DMD/BMD is strongly suspected.

scholarly journals A CASE REPORT ON THE MANAGEMENT OF DUCHENNE’S MUSCULAR DYSTROPHY (DMD) WITH MATRA BASTI

2021 ◽  
Vol p5 (02) ◽  
pp. 2750-2755
Author(s):  
Sharayu Kachole ◽  
Niranjan Rao ◽  
Padmakiran C
Keyword(s):  
Muscular Dystrophy ◽  
Treatment Protocol ◽  
Dystrophin Gene ◽  
Shoulder Girdle ◽  
Recessive Mutation ◽  
Multiple Systems ◽  
Before And After ◽  
Dual Action ◽  
Duchenne's Muscular Dystrophy

Duchenne’s Muscular Dystrophy (DMD) is the most common x-linked disorder in children presenting in early childhood due to recessive mutation of the dystrophin gene. It is characterized by progressive weak-ness in hip and shoulder girdle muscles beginning by age 5. Although there is no absolute cure for DMD, therapies can delay the onset or slow down the progression of disease. Survival beyond the age of 30 years is rare due to the severe chronic complication involving multiple systems. Serum Creatine Phosphokinase (CPK) level determination is the most specific objective parameter for the diagnosis and assessment of se-verity of Muscular Dystrophy (MD). Based on the presentation of DMD, it can be diagnosed as Mamsavru-ta Vatal leading to Mamsa Dhatu Upashoshana which is the consequence of Beejabhagavikruti. There will be continuous destruction of Dhatu leading to Vataprakopa again. Hence, the line of management is con-trolling the Vata and preventing the destruction. The best treatment for it which has this dual action is Mat-ra Basti. With this basic concept, a male child of 10 years diagnosed as Mamsavruta Vata was treated with Matra Basti using Dhanwantara Taila 10 ml/day for about 9 months. As there was associated Sama Do-shavastha, Agnichikitsa Lepa was advised for 7 days initially. The treatment showed significant reduction in the level of CPK tested before and after the treatment. Hence, the treatment protocol followed can be taken up for further research and can prove with evidence that, it can be effectively practiced in the man-agement of DMD. The long-term benefit, improvement in disease, quality of life can be accessed through the research with long term follow-ups.

scholarly journals Genetic Variation Analysis and Treatment Strategy of 20 Patients with Dystrophin Gene Mutations

2020 ◽  
Author(s):  
Yedan Liu ◽  
Jun Chen ◽  
Mei Hou ◽  
Yanhui Zhang ◽  
Ya Guo ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Clinical Manifestation ◽  
De Novo ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Elevated Concentration ◽  
Genetic Sequencing ◽  
First Time

Abstract Background. Dystrophin (DMD) gene mutations canaffect muscular dystrophin isoform expression and result in progressive muscular dystrophy including Duchenne and Becker muscular dystrophies (DMD and BMD). To establish the correlation between phenotype and genotype and exemplify the current and future treatment for muscular dystrophy disorders, we investigated 20 patients suffering from a dystrophinopathy andsummarized clinical manifestation and gene mutations of them. Case presentation.The clinical manifestations, physical examination, laboratory work, and gene mutation results were collected in 20 patients with DMD or BMD diagnosed by clinical phenotype and genetic sequencing from July 2015 to December 2019. Multiplex ligation probe amplification (MLPA) and next-generation sequencing (NGS) were used to detect mutations in the DMD gene, and detected mutations were confirmed by Sanger sequencing. The clinical manifestation of patients was characterized by progressive symmetrical muscle degeneration, limb weakness, and pseudohypertrophy along with the elevated concentration of creatine kinase, alanine aminotransferase,and aspartate aminotransferase.We found 11 dystrophin gene deletions (55%) and 4 duplication mutations (20%) among the affected patients. However, we also found point mutations including 1 nonsense (20%), 3 frameshifts (60%), and 1 splice sites (20%) mutations in the rest 5 patients. Among the 15 cases of exon deletion or duplication mutations, 7 were inherited from the mother, 3 were de-novo, while the other 5 were not tested. Besides, all 5 point-mutation cases were inherited from the mother, among which 4 point mutations were identified for the first time and linked to the disease phenotype. Conclusions.We provided clinical portraits, genetic results, and the molecular effects of mutations in patients. Four novel point mutations were identified for the first time and associated with the development of DMD and BMD. Further, we expanded knowledge of the DMD variant spectrum and exemplified the emerging therapies in muscular dystrophy.

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