PDF(Pubmed)
Abstract：
SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relationship to channel function, 81 patients (36 female, 44%, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their Nav1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal onset, n = 27; infant onset, n = 18; and later onset n = 24; and autism without seizures, n = 12) was strongly correlated with a non-seizure severity index (P = 0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (P = 0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score of 49.5 (>3 standard deviations below the norm-referenced mean of the test). Epileptic spasms were significantly more common in infant-onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (P = 0.007). Primary phenotype was also strongly correlated with variant function (P < 0.0001); gain-of-function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy and to severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups, representing: (i) primarily later-onset epilepsy with moderate loss-of-function variants and low severity indices; (ii) mostly infant-onset epilepsy with moderate loss-of-function variants but higher severity indices; and (iii) late-onset and autism only, with the lowest severity indices (mostly zero) and severe/complete loss-of-function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relationship between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on Nav1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance towards clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.
摘要：
继发于电压门控钠通道NaV1.2功能改变的SCN2A相关疾病很少有临床异质性表达，包括癫痫，自闭症,以及多种严重到严重的损伤和其他疾病。为了进一步了解临床表型及其与通道功能的关系，81例患者（36，44%为女性，中位年龄5.4岁），对69种独特的SCN2A变体进行了系统表型分析，并对其NaV1.2通道功能进行了系统评估。参与者是通过FamileSCN2A基金会招募的。原发性表型（新生儿发作的癫痫，N=27；婴儿发病，N=18；发病后期N=24；自闭症无癫痫发作，（N=12）与非癫痫发作严重程度指数（p=0.002）密切相关，这是基于粗大运动的严重损伤，精细电机，沟通能力,胃造瘘管依赖，以及皮质视觉障碍和脊柱侧凸的诊断。非癫痫发作严重程度在新生儿发作组中最大，在自闭症组中最小（p=0.002）。严重程度指数最低的儿童仍然严重受损，Vineland自适应行为综合得分平均为49.5分(比测试的标准参考平均值低>3SD)。癫痫痉挛在婴儿发作（67％）比新生儿（22％）或晚期（29％）癫痫中明显更常见（p=0.007）。原发性表型也与变异功能密切相关（p<0.0001）；在新生儿发作性癫痫中，功能获得和混合功能变异占主导地位，婴儿发作性癫痫患者的功能逐渐丧失，和严重和完全的功能丧失在后期发作的癫痫和自闭症组。探索性聚类分析确定了五组，代表（1）主要是晚期发作的癫痫，具有中度功能变异和低严重程度指数，（2）大多数婴儿发作性癫痫，功能变异中度丧失，但严重程度指数较高，（3）迟发性和自闭症，仅具有最低的严重程度指数（大多数为0）和功能变异的严重/完全丧失。两个唯一的新生儿群在非癫痫发作严重程度评分上彼此区分，其次在变异功能上彼此区分。主要表型和变异功能之间的关系强调了发育因素在SCN2A变异体对NaV1.2通道功能的影响的差异临床表达中的作用。SCN2A疾病的非癫痫发作严重程度取决于癫痫发作时的年龄（主要表型）和变异功能的组合。随着SCN2A相关疾病的精准治疗迈向临床试验，了解变异功能与临床疾病表达之间的关系对于确定这些试验的合适患者和选择有效的临床结局很有价值.
