Abstract：
Spastic paraplegia type 4 (SPG4), caused by SPAST mutations, is the most predominant subtype of hereditary spastic paraplegia. Most documented SPG4 patients present as pure form, with the complex form rarely reported. We described the clinical and genetic features of 20 patients with complex phenotypes of SPG4 and further explored the genotype-phenotype correlations. We collected detailed clinical data of all SPG4 patients and assessed their phenotypes. SPAST gene mutations were identified by Multiplex ligation-dependent probe amplification in combination with whole exome sequencing. We further performed statistical analysis in genotype and phenotype among patients with various manifestations and different variants. Out of 90 SPG4 patients, 20 patients (male:female = 16:4) with additional neurologic deficits, namely complex form, were included in our study. The bimodal distribution of age of onset at 0-10 and 21-40 years old is concluded. On cranial MRI, obvious white matter lesions can be observed in five patients. We identified 9 novel and 8 reported SPAST mutations, of which 11 mutations were located in AAA (ATPase associated with various cellular activities) domain. The AAA cassette of spastin is the hottest mutated region among complex SPG4. All patients with cognitive impairment (CI) are males (n = 9/9). Additionally, 80% patients with ataxia are due to frameshift mutations (n = 4/5). Overall, our study summarized and analyzed the genetic and phenotypic characteristics of complex SPG4, making up over 1/5 of in-house SPG4 cohort, among which CI and ataxia are the most common features. Further studies are expected to explore the underlying mechanisms.
摘要：
4型痉挛性截瘫(SPG4),由SPAST突变引起，是遗传性痉挛性截瘫的最主要亚型。大多数有记录的SPG4患者以纯形式出现，复杂的形式很少报道。我们描述了20例SPG4复杂表型患者的临床和遗传特征，并进一步探讨了基因型与表型的相关性。我们收集了所有SPG4患者的详细临床数据，并评估了他们的表型。通过多重连接依赖性探针扩增结合全外显子组测序鉴定SPAST基因突变。我们进一步对具有各种表现和不同变异的患者的基因型和表型进行了统计分析。在90名SPG4患者中，20名患者（男性：女性=16：4）伴有其他神经功能缺损，即复杂形式，包括在我们的研究中。得出发病年龄在0-10岁和21-40岁的双峰分布。在头颅MRI上，5例患者可观察到明显的白质病变。我们鉴定了9个新的和8个报道的SPAST突变，其中11个突变位于AAA（与各种细胞活性相关的ATPase）结构域。Spastin的AAA盒是复杂SPG4中最热的突变区域。所有认知障碍（CI）患者均为男性（n=9/9）。此外,80％的共济失调患者是由于移码突变（n=4/5）。总的来说,我们的研究总结和分析了复杂SPG4的遗传和表型特征，占内部SPG4队列的1/5，其中CI和共济失调是最常见的特征。进一步的研究有望探索潜在的机制。
