Song Fang, Qu Yu-jin, Zou Li-ping, Wang Li-wen, Long Mei-juan, Wang Xu, Yang Yan-ling, Chen Qian, Wang Hong, Jin Yu-wei
Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China.
Zhonghua Er Ke Za Zhi. 2008 Dec;46(12):919-23.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that results in symmetrical muscle weakness and wasting due to degeneration of the anterior horns of the spinal cord. The clinical picture of SMA is variable and childhood SMA has been classified into 3 types on the basis of the age of onset and clinical course. The survival motor neuron (SMN) gene was mapped to chromosome 5q13. The SMN1 gene has been recognized to be responsible for SMA because of homozygous deletions or intragenic mutations in SMN1 results in childhood onset of SMA. The main objective of this study was to determine the deletion frequency of SMN1 gene and to apply gene analysis in children patients with SMA.
The SMA patients were diagnosed and clinically typed according to the international diagnostic criteria, following up cases, and gene analysis. The PCR enzyme assay was used to detect the homozygous deletion of SMN1 gene in SMA patients. A dosage assay that combined multiplexed allele-specific PCR and DHPLC was used to determine the copy numbers of the SMN1 and SMN2 and detect SMN1 heterozygous deletion.
(1) A total of 267 patients with SMA were diagnosed from 338 suspicious cases and 143, 82, and 42 cases were typed as types I, II, and III, with the percentages of 53.6% (143/267), 30.7% (82/267) and 15.7% (42/267), respectively. (2) Results of the present study showed that 68.5% (183/267) of SMA patients had homozygous deletions of exons 7 and 8 of SMN1 gene and 12.7% (34/267) had homozygous deletions of only exon 7 of SMN1 gene. The SMN1 heterozygous deletion was confirmed in 12.4% (33/267) of SMA patients. Non-deletion SMA patients accounted for 6.4%(17/267). The homozygous deletions of only exon 8 of SMN1 gene could not be detected. (3) The rates of homozygous or heterozygous deletion in types I and II were very similar. The rate of homozygous deletion was lower in type III than that in type I or II and rate of heterozygous deletion of type III was higher than that in types I or II.
(1) The frequency and pattern of deletions in the Chinese children patients with SMA are significantly different from that observed in Caucasians populations. Further gene characterization and subtle mutations within the SMN1 gene need to be studied in order to define the molecular basis of SMA in the Chinese population. (2) The gene diagnosis is a special and non invasive method as compared with other methods. A total of 80% patients can be diagnosed through the analysis of the homozygous deletion of SMN1 gene. (3) The clinical diagnosis and gene detection need to be studied in future for the SMA patients with type III.
脊髓性肌萎缩症（SMA）是一种常染色体隐性疾病，由于脊髓前角变性导致对称性肌肉无力和萎缩。SMA的临床表现多样，儿童SMA根据发病年龄和临床病程分为3型。存活运动神经元（SMN）基因定位于5号染色体q13区域。由于SMN1基因的纯合缺失或基因内突变会导致儿童期发病的SMA，因此已确认SMN1基因是SMA的致病基因。本研究的主要目的是确定SMN1基因的缺失频率，并将基因分析应用于儿童SMA患者。
根据国际诊断标准对SMA患者进行诊断、临床分型、随访病例并进行基因分析。采用PCR酶法检测SMA患者中SMN1基因的纯合缺失。采用多重等位基因特异性PCR和变性高效液相色谱相结合的剂量分析法确定SMN1和SMN2的拷贝数，并检测SMN1杂合缺失。
（1）从338例疑似病例中共诊断出267例SMA患者，其中143例、82例和42例分别被分型为I型、II型和III型，所占比例分别为53.6%（143/267）、30.7%（82/267）和15.7%（42/267）。（2）本研究结果显示，68.5%（183/267）的SMA患者存在SMN1基因第7和8外显子的纯合缺失，12.7%（34/267）的患者仅存在SMN1基因第7外显子的纯合缺失。12.4%（33/267）的SMA患者被确认存在SMN1杂合缺失。非缺失型SMA患者占6.4%（17/267）。未检测到仅SMN1基因第8外显子的纯合缺失。（3）I型和II型的纯合或杂合缺失率非常相似。III型的纯合缺失率低于I型或II型，III型的杂合缺失率高于I型或II型。
（1）中国儿童SMA患者的缺失频率和模式与高加索人群中观察到的显著不同。需要进一步研究SMN1基因的基因特征和微小突变，以确定中国人群中SMA的分子基础。（2）与其他方法相比，基因诊断是一种特殊且无创的方法。通过分析SMN1基因的纯合缺失，总共80%的患者可以得到诊断。（3）对于III型SMA患者，未来需要对临床诊断和基因检测进行研究。
