Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Epilepsia. 2012 Aug;53(8):1421-8. doi: 10.1111/j.1528-1167.2012.03583.x. Epub 2012 Jul 10.
Dravet syndrome (DS) is an aggressive epileptic encephalopathy. Pharmacoresistant seizures of several types plague most patients with DS throughout their lives. Gait difficulties are a common, but inconsistent finding. The majority of cases are caused by mutations in the SCN1A gene, but little information is available about how particular mutations influence the adult phenotype. The purpose of this study is to correlate different types of SCN1A mutations and (1) seizure control, (2) occurrence of convulsive status epilepticus (cSE), and (3) the presence of crouch gait in adult patients.
In a cohort of 10 adult patients with DS caused by SCN1A mutations, we investigated seizure frequency, history of cSE, and gait. All patients were identified in the epilepsy clinic between 2009 and 2011. SCN1A mutations were divided into four different groups based on location or effect of the mutation. Retrospective chart review and recent physical examination were completed in all cases.
All patients had a pathogenic mutation in the SCN1A gene. Four SCN1A mutations have not been described previously. Greater than 90% seizure reduction was observed (compared to childhood frequency) in six of seven patients with missense mutations in the pore-forming region (PFR) of the Na(v) 1.1 protein (group A) and nonsense mutations (group B). One patient with a splice-site mutation (group C) and another with a mutation outside the PFR (group D) became free of all types of seizures. cSE after the age of 19 years was observed in only one patient. Crouch gait, without spasticity, is identified as an element of the adult DS phenotype. However, only one half of our adult DS cohort demonstrated crouch gait. This feature was observed in five of seven patients from groups A and B.
This study shows that seizure control improves and cSE become less frequent in DS as patients age, independent of their SCN1A mutation type. Complete seizure freedom was seen in two patients (groups C and D). Finally, this study shows that in DS, crouch gait can be observed in up to 50% of adults with SCN1A mutation. Although no definite statistical correlations could be made due to the small number of patients, it is interesting to note that crouch gait was observed only in those patients with nonsense mutations or mutations in the PFR. Future studies with larger cohorts will be required to formally assess an association of gait abnormalities with particular SCN1A mutations.
Dravet 综合征（DS）是一种侵袭性的癫痫性脑病。大多数 DS 患者一生中都会出现多种类型的耐药性癫痫发作。步态困难是一种常见但不一致的发现。大多数病例是由 SCN1A 基因突变引起的，但关于特定突变如何影响成人表型的信息很少。本研究的目的是将不同类型的 SCN1A 突变与（1）癫痫发作控制、（2）惊厥性癫痫持续状态（cSE）的发生和（3）成年患者的蹲伏步态相关联。
在 10 名由 SCN1A 突变引起的 DS 成年患者的队列中，我们调查了癫痫发作频率、cSE 病史和步态。所有患者均于 2009 年至 2011 年间在癫痫诊所中确定。根据突变的位置或效应，将 SCN1A 突变分为四个不同的组。对所有病例进行回顾性图表审查和最近的体格检查。
所有患者均存在 SCN1A 基因的致病性突变。有 4 种 SCN1A 突变以前未被描述过。在 7 名具有孔形成区（PFR）Na（v）1.1 蛋白错义突变（A 组）和无义突变（B 组）的患者中，观察到超过 90%的癫痫发作减少（与儿童时期的频率相比）。1 名具有剪接位点突变（C 组）和另 1 名具有 PFR 外突变（D 组）的患者发作类型完全消失。19 岁后发生 cSE 的仅 1 例。蹲伏步态，无痉挛，被确定为成年 DS 表型的一个特征。然而，我们的成年 DS 队列中只有一半表现出蹲伏步态。A 组和 B 组的 7 名患者中有 5 名观察到该特征。
本研究表明，随着年龄的增长，癫痫发作控制改善，cSE 在 DS 患者中变得不那么频繁，这与 SCN1A 突变类型无关。2 名患者（C 组和 D 组）完全无癫痫发作。最后，本研究表明，在 DS 中，多达 50%的 SCN1A 突变患者可出现蹲伏步态。由于患者数量较少，无法进行明确的统计学相关性分析，但有趣的是，蹲伏步态仅在具有无义突变或 PFR 突变的患者中观察到。需要更大队列的未来研究来正式评估步态异常与特定 SCN1A 突变之间的关联。
