肌营养不良蛋白病涵盖了一系列罕见的进行性X连锁肌肉疾病,由DMD突变引起。它们是最常见的小儿肌营养不良症,是杜氏肌营养不良症(DMD)最严重的形式。尽管这些严重的疾病仍然无法治愈,DMD疗法的开发正在取得前所未有的进展。其中一些已经有条件地批准:外显子跳跃和过早终止密码子通读。本工作旨在表征阿根廷队列中DMD的突变谱,为了确定可用的药物遗传学治疗的候选药物,最后,对适用于现有DMD疗法的拉丁美洲(LA)突变频率进行比较分析。我们研究了400例临床诊断为肌萎缩蛋白病的患者,实施诊断分子算法,包括:MLPA/PCR/Sanger/Exome和生物信息学。我们还对LA的DMD可用治疗指标进行了荟萃分析。所采用的算法对于实现鉴别诊断是有效的,检出率达到97%。正因为如此,在371例有肌萎缩蛋白病遗传证实的患者中,皮质类固醇治疗得到了正确的指示和验证.此外,20个有资格进行外显子51的外显子跳跃,21个为外显子53,12个为外显子45,另外70个为过早终止密码子通读疗法。我们确定,87.5%的DMD患者将仅跳过一个外显子即可恢复阅读框。关于废话变体,UGA被证明是观察到的最常见的提前终止密码子(47%)。根据荟萃分析,只有四个洛杉矶国家(阿根廷,巴西,哥伦比亚和墨西哥)为肌营养不良蛋白病提供了完整的分子算法。我们观察到分析人群中外显子跳跃的可用靶标之间的不同关系,但更平均比例的无意义变体(~40%)。总之,该手稿描述了在阿根廷肌萎缩蛋白病患者中进行的治疗。所实现的分子算法被证明是有效的实现鉴别诊断,这在病人管理中起着至关重要的作用,确定护理和遗传咨询的标准。最后,这项工作有助于国际上表征洛杉矶频率和变体的努力,药物开发和治疗的支柱。
Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA\'s metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding
nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of
nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.