背景:遗传性痉挛性截瘫(HSPs)是一组遗传异质性神经退行性疾病。我们的目标是确定遗传证实的儿童期发病的HSP患者的临床和分子特征,并扩展某些罕见HSP亚型的遗传谱。
方法:我们回顾了基因证实儿童期发病HSP的受试者的图表。疾病发作的年龄定义为观察到延迟的运动里程碑的点。延迟的运动里程碑被定义为无法抬起头四个月,九个月没有人帮助坐着,独立行走17个月。如果没有延迟的运动里程碑,发病年龄由腿部僵硬决定,经常跌倒,或者步态不稳定.基因测试是根据延迟的运动里程碑进行的,进行性腿部痉挛,和步态困难。变体分类是根据美国医学遗传学学会的变体解释标准指南确定的。当临床发现与先前描述的致病性变异的疾病表型一致时,不确定显著性变异(VUS)被认为是疾病相关的。此外,在没有另一种病原体的情况下,可能致病,或者可以解释我们病例表型的VUS变体,我们得出结论,该疾病与HSP致病基因中的VUS有关。还对一些患者的父母进行了隔离分析,以证明遗传模型。
结果:共有来自17个家庭的18名患者。症状发作的中位年龄为18个月(2至84个月)。症状发作和基因诊断之间的平均延迟为5.8年(5个月至17年)。所有患者均因进行性腿部痉挛和无力而导致步态困难。67%的患者(n=12)在17个月时未实现独立步行。在我们的队列中,有两名受试者分别使用SPG11,SPG46和SPG50,然后是一名受试者分别使用SPG3A,SPG4,SPG7,SPG8,SPG30,SPG35,SPG43,SPG44,SPG57,SPG62,婴儿起病性上行性痉挛性瘫痪(IAHSP),痉挛型截瘫和精神运动迟缓伴或不伴癫痫发作(SPPRS)。描述了9名患者中的8种新变体。两个受影响的兄弟姐妹在GBA2基因(SPG46)中有一个新的变体,每个受试者在WASHC5(SPG8)中都有一个新的变体,SPG11(SPG11),KIF1A(SPG30),GJC2(SPG44),ERLIN1(SPG62),ALS2(IAHSP),和HACE1(SPPRS)。在新颖的变体中,SPG11中的变体是致病性的,KIF1A中的变体,GJC2和HACE1可能致病。GBA2、ALS2、ERLIN1和WASHC5中的变体被分类为VUS。
结论:HSP的症状发作和基因诊断之间存在明显的延迟。通过检查具有延迟运动里程碑的患者,可以进行早期诊断。进行性痉挛,步态困难,和神经肌肉无力在HSP的背景下。描述了九位患者的八种新变体,临床上类似于先前描述的与致病变异相关的疾病表型。这项研究有助于扩大HSP的一些罕见亚型的遗传谱。
BACKGROUND: Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative disorders. Our objective was to determine the clinical and molecular characteristics of patients with genetically confirmed childhood-onset HSPs and to expand the genetic spectrum for some rare subtypes of HSP.
METHODS: We reviewed the charts of subjects with genetically confirmed childhood-onset HSP. The age at the disease onset was defined as the point at which the delayed motor milestones were observed. Delayed motor milestones were defined as being unable to hold the head up by four months, sitting unassisted by nine months, and walking independently by 17 months. If there were no delayed motor milestones, age at disease onset was determined by leg stiffness, frequent falls, or unsteady gait. Genetic testing was performed based on delayed motor milestones, progressive leg spasticity, and gait difficulty. The variant classification was determined based on the American College of Medical Genetics standard guidelines for variant interpretation. Variants of uncertain significance (VUS) were considered disease-associated when clinical findings were consistent with the previously described disease phenotypes for pathogenic variants. In addition, in the absence of another pathogenic, likely pathogenic, or VUS variant that could explain the phenotype of our cases, we concluded that the disease is associated with VUS in the HSP-causing gene. Segregation analysis was also performed on the parents of some patients to demonstrate the inheritance model.
RESULTS: There were a total of 18 patients from 17 families. The median age of symptom onset was 18 months (2 to 84 months). The mean delay between symptom onset and genetic diagnosis was 5.8 years (5 months to 17 years). All patients had gait difficulty caused by progressive leg spasticity and weakness. Independent walking was not achieved at 17 months for 67% of patients (n = 12). In our cohort, there were two subjects each with SPG11, SPG46, and SPG 50 followed by single subject each with SPG3A, SPG4, SPG7, SPG8, SPG30, SPG35, SPG43, SPG44, SPG57, SPG62, infantile-onset ascending spastic paralysis (IAHSP), and spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). Eight novel variants in nine patients were described. Two affected siblings had a novel variant in the GBA2 gene (SPG46), and one subject each had a novel variant in WASHC5 (SPG8), SPG11 (SPG11), KIF1A (SPG30), GJC2 (SPG44), ERLIN1 (SPG62), ALS2 (IAHSP), and HACE1 (SPPRS). Among the novel variants, the variant in the SPG11 was pathogenic and the variants in the KIF1A, GJC2, and HACE1 were likely pathogenic. The variants in the GBA2, ALS2, ERLIN1, and WASHC5 were classified as VUS.
CONCLUSIONS: There was a significant delay between symptom onset and genetic diagnosis of HSP. An early diagnosis may be possible by examining patients with delayed motor milestones, progressive spasticity, gait difficulties, and neuromuscular weakness in the context of HSP. Eight novel variants in nine patients were described, clinically similar to the previously described disease phenotype associated with pathogenic variants. This study contributes to expanding the genetic spectrum of some rare subtypes of HSP.