■遗传性痉挛性截瘫(HSPs)是一组以双侧下肢痉挛为特征的异质性神经退行性疾病。它们可能从婴儿期开始随时出现。尽管下一代测序已经允许鉴定许多致病基因,关于哪些基因与儿科发病变异特异性相关,目前尚不清楚.
■这项研究回顾性评估了遗传分析,家族史临床课程,磁共振成像(MRI)发现,以及在日本一家三级儿科医院诊断为HSP的儿童期患者的电生理发现。使用直接测序进行遗传分析,疾病相关小组,和全外显子组测序。
■在包括的37名患者中,14人有HSP家族史,23人有散发性疾病。在20名患者中,HSP是纯类型,而其余17例患者有复杂类型的HSP。11名纯型患者和16名复杂型患者的遗传数据可用。其中,5例(45%)纯型患者和13例(81%)复合型患者有可能进行基因诊断.在五个孩子中发现了SPAST变体,KIF1A的四种变体,ALS2变体中的三个,SACS和L1CAM变体各两种,和一个ATL1变体。一个孩子有10p15.3p13重复。四名纯型HSP患者有SPAST变异,一名患者有ALT1变异。KIF1A,ALS2SACS,L1CAM变异体和10p15.3p13重复见于复合型HSPs患儿,只有一名患有SPAST变异的复合型患者。与纯型HSPs(19个中的一个[5%])相比,复合型儿童(16个中的11个[69%])在MRI上识别脑异常明显更常见(p<0.001)。与纯型HSPs相比,复合型儿童的神经残疾改良Rankin量表得分也显着较高(3.5±1.0vs.2.1±0.9,p<0.001)。
■在相当大比例的患者中,发现儿科发作的HSP是散发性和遗传性的。纯型和复合型HSP儿童的致病基因模式有所不同。SPAST和KIF1A变体在纯型和复合型HSPs中的致病作用,分别,应该进一步探讨。
UNASSIGNED: Hereditary spastic paraplegias (HSPs) are a set of heterogeneous neurodegenerative disorders characterized by bilateral lower limb spasticity. They may present from infancy onwards at any time. Although next-generation sequencing has allowed the identification of many causative genes, little is known about which genes are specifically associated with pediatric-onset variants.
UNASSIGNED: This
study retrospectively evaluated the genetic analyses, family history clinical courses, magnetic resonance imaging (MRI) findings, and electrophysiologic findings of patients diagnosed with HSP in childhood at a tertiary pediatric hospital in Japan. Genetic analyses were performed using direct sequencing, disease-associated panels, and whole-exome sequencing.
UNASSIGNED: Of the 37 patients included, 14 had a family history of HSP and 23 had a sporadic form of the disease. In 20 patients, HSP was the pure type, whereas the remaining 17 patients had complex types of HSP. Genetic data were available for 11 of the pure-type patients and 16 of those with complex types. Of these, genetic diagnoses were possible in 5 (45%) of the pure-type and 13 (81%) of the complex-type patients. SPAST variants were found in five children, KIF1A variants in four, ALS2 variants in three, SACS and L1CAM variants in two each, and an ATL1 variant in one. One child had a 10p15.3p13 duplication. Four patients with pure-type HSPs had SPAST variants and one had an ALT1 variant. The KIF1A, ALS2, SACS, and L1CAM variants and the 10p15.3p13 duplication were seen in children with complex-type HSPs, with just one complex-type patient having a SPAST variant. The identification of brain abnormalities on MRI was significantly more common among children with complex-type (11 [69%] of 16) than pure-type HSPs (one [5%] of 19) (p < 0.001). Scores on the modified Rankin Scale for Neurologic Disability were also significantly higher among children with complex-type compared with pure-type HSPs (3.5 ± 1.0 vs. 2.1 ± 0.9, p < 0.001).
UNASSIGNED: Pediatric-onset HSP was found to be sporadic and genetic in a substantial proportion of patients. The causative gene patterns differed between children with pure-type and complex-type HSPs. The causative roles of SPAST and KIF1A variants in pure-type and complex-type HSPs, respectively, should be explored further.