Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis.
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SUBMITTER: Pascual-Morena C
PROVIDER: S-EPMC8401629 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive muscle disorder characterized by heterogeneous progression and severity. We aimed to study the effects of single nucleotide polymorphisms (SNPs) in SPP1 and LTBP4 on DMD progression in Chinese patients. Methods: We genotyped LTBP4 haplotypes and the SPP1 promoter SNPs rs28357094, rs11730582, and rs17524488 in 326 patients registered in the neuromuscular database of The First Affiliated Hospital of Sun Yat-sen University. Kaplan-Meier curves and log-rank tests were used to estimate and compare median age at loss of ambulation, while Cox proportional hazard regression models were used as to analyze the effects of glucocorticoids treatments, DMD genotype, and SPP1/LTBP4 SNPs on loss of ambulation. Results: The CC/CT genotype at rs11730582 was associated with a 1.33-year delay in ambulation loss (p = 0.006), with hazard ratio 0.63 (p = 0.008), in patients with truncated DMD genotype and undergoing steroid treatment. On the other hand, rs17524488 in SPP1 and the IAAM/IAAM haplotype in LTBP4 were not associated with time to ambulation loss. Conclusions: SPP1 rs11730582 is a genetic modifier of the long-term effects of steroid treatment in Chinese DMD patients. Thus, any future clinical study in DMD should adjust for glucocorticoids use, DMD genotype, and SPP1 polymorphisms.
| S-EPMC7403400 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.
| S-EPMC4626372 | biostudies-literature
Project description:ObjectiveRespiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS).Methods and resultsGeneralized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF.InterpretationThese findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.
| S-EPMC7261745 | biostudies-literature
Project description:BACKGROUND:Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Eteplirsen received conditional approval in the United States in 2016. To date, no systematic reviews or meta-analyses of randomized controlled trials (RCTs) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD. METHODS:A systematic review and meta-analysis of double-blind RCTs comparing exon-skipping drugs with placebo in DMD was performed. Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017. The primary outcomes were changes in the 6-min walk test (6MWT) distance, North Star Ambulatory Assessment (NSAA) scores, and adverse events. Random-effects meta-analysis and assessment of risk of bias were performed. This systematic review was registered at PROSPERO (CRD42016037504). RESULTS:Five studies involving 322 participants were included, investigating eteplirsen in one and drisapersen in four studies. There were no changes in 6MWT distance (mean difference [MD] -?9.16, 95% confidence interval [CI] -?21.94 to 3.62) or NSAA scores (MD 1.20, 95% CI -?2.35 to 4.75) after 24 weeks of treatment in the exon-skipping group compared with placebo. Subgroup analysis for a 6 mg/kg weekly injection of drisapersen showed significant changes in the 6MWT, favoring drisapersen after 24 weeks (MD -?20.24; 95% CI -?39.59 to -?0.89). However, drisapersen resulted in a significant increase in injection site reactions (risk ratio [RR] 3.67, 95% CI 1.96 to 6.89, p?<?0.0001) and renal toxicity (RR 1.81, 95% CI 1.11 to 2.94, p?=?0.02). Risk of bias was high in two of the five studies, including the eteplirsen and one drisapersen study. CONCLUSIONS:Current available data do not show evidence that exon-skipping drugs are effective in DMD. Despite potential effectiveness when used at a specific dose, significant side effects were reported with drisapersen. The small number of RCTs with relatively small numbers of participants indicate the difficulty in conducting sufficiently powered studies of DMD. Prospectively planned meta-analysis and utilization of the real-world data may provide a more precise estimate of the effect of exon skipping in this disease.
| S-EPMC6003096 | biostudies-literature
Project description:BACKGROUND:Duchenne Muscular Dystrophy (DMD) is a rare disorder caused by mutations in the dystrophin gene. A recent systematic review and meta-analysis of global DMD epidemiology is not available. This study aimed to estimate the global overall and birth prevalence of DMD through an updated systematic review of the literature. METHODS:MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of DMD from inception until 1st October 2019. Studies were included if they were original observational research articles written in English, reporting DMD prevalence and/or incidence along with the number of individuals of the underlying population. The quality of the studies was assessed using a STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist adapted for observational studies on rare diseases. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using random-effects logistic models for overall and birth prevalence and within two different underlying populations (i.e. all individuals and in males only), separately. Heterogeneity was assessed using Cochran's Q-test along with its derived measure of inconsistency I2. RESULTS:A total of 44 studies reporting the global epidemiology of DMD were included in the systematic review and only 40 were included in the meta-analysis. The pooled global DMD prevalence was 7.1 cases (95% CI: 5.0-10.1) per 100,000 males and 2.8 cases (95% CI: 1.6-4.6) per 100,000 in the general population, while the pooled global DMD birth prevalence was 19.8 (95% CI:16.6-23.6) per 100,000 live male births. A very high between-study heterogeneity was found for each epidemiological outcome and for all underlying populations (I2 >?90%). The test for funnel plot asymmetry suggested the absence of publication bias. Of the 44 studies included in this systematic review, 36 (81.8%) were assessed as being of medium and 8 (18.2%) of low quality, while no study was assessed as being of high quality. CONCLUSIONS:Generating epidemiological evidence on DMD is fundamental to support public health decision-making. The high heterogeneity and the lack of high quality studies highlights the need to conduct better quality studies on rare diseases.
| S-EPMC7275323 | biostudies-literature
Project description:INTRODUCTION:In recent years, important advances have been made in the treatment of Duchenne muscular dystrophy (DMD). This protocol proposes a methodology for carrying out a systematic review and meta-analysis that aims to: (1) improve the evidence of the benefits of different pharmacological treatments in boys with DMD, and (2) compare the benefit of treatments specifically aimed at delaying the progression of disease in the functional outcomes. METHODS AND ANALYSIS:This protocol is guided by the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and by the Cochrane Collaboration Handbook. A thorough selection of the literature will be done through the MEDLINE, EMBASE and Web of Science databases. The search will be conducted in English and Spanish. The Risk of Bias 2.0 tool from the Cochrane Collaboration will be used to assess the risk of bias. A narrative synthesis of the data will be performed. Meta-analysis will be conducted for effect of treatment on the 6 min walking distance (6MWD), North Star Ambulatory Assessment and Timed Functional Tests. Subgroup analyses will be performed by age or baseline values of the 6MWD, and overall bias. ETHICS AND DISSEMINATION:The approval of an ethical committee is not required. All the included trials will comply with the current ethical standards and the Declaration of Helsinki. The results of this proposed systematic review and meta-analysis will provide a general overview and evidence concerning the effectiveness of pharmacological treatments in Duchenne muscular dystrophy. Findings will be disseminated to academic audiences through peer-reviewed publications, as well as to clinical audiences, patients' associations and policy makers, and may influence guideline developers in order to improve outcomes for these patients. PROSPERO REGISTRATION NUMBER:CRD42018102207.
| S-EPMC6731948 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP.
| S-EPMC4668935 | biostudies-literature
Project description:Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018.
| S-EPMC5759757 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials.Duchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates.We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss.This study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials.
| S-EPMC4602257 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes.We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers.The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.
| S-EPMC4994242 | biostudies-other