Clinical, Epidemiological and Molecular Genetical Research for Spinal Muscular Atrophy

脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种以脊髓运动神经元变性和肌萎缩为特征的常染色体隐性遗传神经肌肉疾病。SMA是由运动神经元存活基因（SMN）突变引起的。我们对SMA患者进行了分子遗传学分析，并将临床严重程度与SMNt和神经元凋亡抑制蛋白（NAIP）基因以及C212和C272微卫星标记的缺失进行了比较。我们分析了89个SMA家族的SMN和NAIP基因; 30个I型，29个II型和30个III型。使用多拷贝微卫星C212和C272标记，我们进行了单倍型分析，在41个家庭; 15个I型，15个II型和11个III型。我们将0-2拷贝/ 2染色体定义为H4 F5基因缺失，其中78例（87.6%）同时缺失或仅缺失SMN基因。两种基因缺失的I型患者比例显著较高（p<0.05）。SMN和NAIP基因均缺失的病例显示出明显更早的疾病发作。在我们的研究对象中有六对兄弟姐妹。每个兄弟姐妹的疾病严重程度是可比的，但两个兄弟姐妹对显示出不同的疾病严重程度。5例I型病例具有跨越H4 F5、SMN和NAIP基因的广泛缺失。41例患者中有24例（58.5%）除SMN基因缺失外，还存在C272或C212和C272的缺失。我们通过单倍型分析确定了其染色体上存在的C212等位基因的数量。在48%的I型（2个拷贝）和60-80%的II型和III型（3个拷贝）中发现C212等位基因减少。共有60%的对照组显示4个拷贝。结果表明，Ⅰ型患者为C212纯合性缺失，Ⅱ型和Ⅲ型患者为同一条染色体上C212的复合杂合性缺失。

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by mutation of the survival motor neuron (SMN) gene. We conducted a molecular genetic analysis of SMA patients and compared clinical severity with deletions of the SMNt and neuronal apoptosis inhibitory protein (NAIP) genes, and C212 and C272 microsatellite markers. We analyzed the SMN and NAIP genes in 89 SMA families ; 30 type I, 29 type II and 30 type III. Using the multi-copy microsatellite C212 and C272 markers, we performed haplotype analysis in 41 familes ; 15 type I, 15 type II and 11 type III. We defined 0-2 copies/ 2 chromosomes as a deletion of he H4F5 gene.Seventy-eight cases (87.6%) showed deletion of both genes or only the SMN gene. A significantly higher proportion of type I patients had deletion of both genes (p<0.05). Cases who had deletion of both the SMN and NAIP genes showed significantly earlier onset of disease. There were six sibling pairs in our subjects. Disease severity in each sibling was comparable, but two sibling pairs showed different disease severity. Five type I cases had a broad deletion that spanned the H4F5, SMN and NAIP genes. A significantly higher proportion of type I subjects had this deletion.Twenty-four of 4l (58.5%) showed C272 deletion or C212 and C272 deletion in addition to deletion of the SMN gene. We determined the number of C212 alleles present on their chromosomes by haplotype analysis. A reduction of C212 alleles was found in 48% of type I (2 copies) and in 60-80% of type II and III (3 copies). A total of 60% of the control subjects showed 4 copies. These results suggested that type I patients had homozygous deletion of C212 and type II and III patiensts had deletion of C212 in one chromosome, which means compound heterozygosity.