杜氏肌营养不良症产前筛查渐上轨道,“力攻”性染色体遗传疾病
2015/12/23
杜氏肌营养不良症(DMD)是一种X染色体隐性遗传疾病,主要发生于男孩。据统计,全球平均每3600个新生男婴中就有一人罹患此病,医学界尚无有效疗法。然而,随着产前筛查技术的发展,DMD新生儿筛查开始慢慢走近我们的生活,且也有不少研究集中于DMD的治疗。


杜氏肌营养不良症(DMD)是一种X染色体隐性遗传疾病,主要发生于男孩。据统计,全球平均每3600个新生男婴中就有一人罹患此病。患者在学龄前就会因骨骼肌不断退化出现肌肉无力或萎缩,导致不便行走。大概在7岁到12岁时,会彻底丧失行走能力,通常到20多岁就会因为心肌、肺肌无力而死亡。针对该病,医学界尚无有效疗法。然而,随着产前筛查技术的发展,DMD新生儿筛查开始慢慢走近我们的生活,且也有不少研究集中于DMD的治疗。

中国首次利用NIPT技术成功诊断DMD

今年年初,发表于《Genetics in Medicine》杂志上的研究报道了中国首次利用NIPT技术成功诊断DMD的案例。该研究由上海交通大学医学院研究人员引领,总共有八个存在DMD风险的家庭参与了此项研究。在该研究中亲本单倍型通过亲本及先证者的目标区域测序数据来确定,胎儿单倍型通过孕妇血浆DNA序列的隐马尔可夫模型(HMM)来确定,通过这些方法研究人员确定了孕妇血浆DNA中的胎儿基因型及亲本基因型。

在此研究中,研究人员准确预测出了8名胎儿的突变状态,其中三名胎儿为女孩,两名不携带DMD基因突变体;剩下的五名胎儿为男性,检测结果为阳性,且通过了羊膜穿刺术证实。在这项研究中,研究人员表明该技术还可有效地确认了一些常染色隐性障碍,包括先天性肾上腺增生、枫糖尿病、先天性耳聋。

美国及其他国家正考虑将DMD纳入常规新生儿筛查项目

根据Medscape网站12月21日报道,基于诊断与治疗方法的快速发展,目前美国及其他国家正考虑将DMD纳入常规筛查项目,关于新生儿DMD筛查的讨论于近日发表于《JAMA Neurology》杂志上。

本文资深作者美国罗彻斯特大学Robert C. Griggs医学博士解释道,“如今越来越意识到早期诊断DMA的优势,因为皮质类固醇疗法可在肌肉纤维化发展和出现临床表征之前开始;其他新的治疗方法,包括基因疗法也变得越来越可行,因此我们认为早期治疗也将从中获利。”

Griggs博士说,“DMD领域效仿了囊性纤维化的步伐,早期发现此类疾病可通过改善保健进而延长患者的寿命,我们希望DMD领域也出现类似的进步。”

对DMD的检测包括对肌酸激酶(CK)水平的筛查,并进行遗传分析,Griggs博士认为遗传分析可鉴别95%的DMD病例。尽管DMD主要发生于男性,但Griggs博士建议男女婴儿都接受筛查,DMD新生儿的筛查不应限制于男孩。此外,有些女孩也可能患有DMD,例如只有一条X染色体的特纳氏综合症患者、其他内分泌出现问题的患者以及一些在遗传学上为男性的女孩,这些女孩的DMD携带状态都可在筛查中被检测到。

Griggs博士的论文基于在已完成的或正在进行的项目中所积累的经验,作者表示,尽管CK筛查的敏感度高,但也可能存在假阴性的结果。出现假阴性的可能性是不可避免的,因为高水平CK是该疾病二次反应的标志,并不是DMD的一个具体指标,同时新生儿CK水平的筛查也可能漏检一些女性的DMD携带状况。然而,作者指出,新生儿筛查可检测出与高水平CK相关的其他疾病,且需进一步开发对高水平CK患者及DMD基因检测阴性结果的评估与管理的方法。

编者结语

然而,尽管技术的发展使得性染色体遗传疾病产前筛查成为了可能,但同时也面临着很大的挑战,编者在《无创产前检测雄心勃勃,却遭PNAS等期刊泼冷水》一文中也谈及性染色体产前筛查面临的一些挑战,如包括筛查精度、咨询挑战、女性的偏好、未来孩子的利益及胎儿性别信息的滥用等,因而性染色体遗传疾病产前筛查要切实走入临床化仍需克服很多障碍。

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
  • 2018/09/06
    杜氏肌营养不良是一种X染色体隐性遗传疾病,主要发生于男孩。全球每5000个男孩中就有1个生来就患有这种致残性疾病。该病源于肌肉中一种称为肌营养不良蛋白的基因突变。近日,斯坦福大学医学院的研究人员证明,在基因治疗杜氏营养不良症模型中,DNA质粒可以在增强肌肉力量的同时降低机体对肌营养不良蛋白的免疫力。
  • 2017/08/17
    根据国家卫生和计划生育委员会公益性行业项目10家参加单位的统计结果,双胎出生缺陷的发生率为6.3%,远高于单胎。为降低双胎出生缺陷率,适时采用安全有效的双胎妊娠产前筛查与诊断技术,特制定本规范。
  • 2017/05/10
    5月8日是世界地贫日,专家也提醒,一定要重视做好孕前检查及产前筛查和诊断,这是减少重型地贫患儿出生的有效措施。
查看更多
  • Identifying Non–Duchenne Muscular Dystrophy–Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs

    Importance Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients. Objectives To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings). Evidence Review Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015. Findings The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD. Conclusions and Relevance Screening for DMD will result in identification of other muscle diseases. Future screening protocols should include infants of both sexes and include follow-up testing algorithms to evaluate patients who do not have DMD gene mutations but may have another muscle disorder associated with elevated neonatal creatine kinase levels. These programs will need to be aware that false-negative results are a possibility.

    展开 收起
  • Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

    Purpose: This study demonstrates noninvasive prenatal testing (NIPT) for Duchenne muscular dystrophy (DMD) using a newly developed haplotype-based approach. Methods: Eight families at risk for DMD were recruited for this study. Parental haplotypes were constructed using target-region sequencing data from the parents and the probands. Fetal haplotypes were constructed using a hidden Markov model through maternal plasma DNA sequencing. The presence of haplotypes linked to the maternal mutant alleles in males indicated affected fetuses. This method was further validated by comparing the inferred single-nucleotide polymorphism (SNP) genotypes to the direct sequencing results of fetal genomic DNA. Prenatal diagnosis was confirmed with amniocentesis, and those results were interpreted in a blinded fashion. Results: The results showed an average accuracy of 99.98% for the total inferred maternal SNPs. With a mean depth of 30× achieved in the 10-Mb target region of each sample, the noninvasive results were consistent with those of the invasive procedure. Conclusion: This is the first report of NIPT for DMD and the first application of a haplotype-based approach in NIPT for X-linked diseases. With further improvements in accuracy, this haplotype-based strategy could be feasible for NIPT for DMD and even other X-linked single-gene disorders.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test