Keinath Melissa C, Prior Devin E, Prior Thomas W
Pathology, University Hospitals Center for Human Genetics, Cleveland, OH, USA.
Neurology, Mount Auburn Hospital, Cambridge, MA, USA.
Appl Clin Genet. 2021 Jan 25;14:11-25. doi: 10.2147/TACG.S239603. eCollection 2021.
Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene on 5q13 but keep the modifying gene. The most common mutation causing SMA is a homozygous deletion of the exon 7, which can be readily detected and used as a sensitive diagnostic test. Because produces a reduced number of full-length transcripts, the number of copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.
脊髓性肌萎缩症（SMA）是一种遗传性神经肌肉疾病，可导致脊髓前角细胞的α运动神经元退化，从而引起严重的进行性肌张力减退和肌肉无力。SMA的携带频率为1/40 - 1/50，估计发病率为1/10000活产，是第二常见的常染色体隐性疾病。患有SMA的个体在5q13上存在生存运动神经元基因功能的纯合缺失，但保留修饰基因。导致SMA最常见的突变是外显子7的纯合缺失，这可以很容易地检测到，并用作敏感的诊断测试。因为SMN2产生的全长转录本数量减少，SMN2的拷贝数可以改变临床表型，因此成为一个重要的预测因素。基于人群的SMA携带者筛查可识别可能将这种遗传疾病传给后代的携带者夫妇，并使携带者能够做出明智的生育选择或为受影响儿童的立即治疗做好准备。最近美国食品药品监督管理局（FDA）批准了三种治疗方法。诺西那生钠使用反义寡核苷酸来改变SMN2转录本的剪接，从而提高SMN蛋白的表达水平。onasemnogene abeparvovec是一种基因疗法，利用腺相关病毒血清型9载体来提高低功能性SMN蛋白水平。利司扑兰是一种小分子，可改变SMN2的剪接以增加功能性SMN蛋白。已证明对SMA进行新生儿筛查有助于婴儿在运动神经元丧失之前接受治疗，并改善了临床结果。该综述中的一些建议和指南基于在美国进行的研究。
