Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities
Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities
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DOI：
10.1111/j.1528-1167.2007.01122.x
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发表时间：
2007-09-01
期刊：
影响因子：
5.6
通讯作者：
Guerrini, Renzo
中科院分区：
文献类型：
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作者：
Marini, Carla;Mei, Davide;Guerrini, Renzo
目的：SCN1A基因是临床上最相关的癫痫基因，大多数突变可导致婴儿期重度肌阵挛癫痫(SMEI)和全身性癫痫伴热性惊厥发作(GEFS+)。我们研究了132例发热性惊厥的癫痫综合征患者，并进行了SCN1A型和表型的相关性研究。方法：纳入SMEI患者，包括临界性SMEI(SMEB)、GEFS+、热性惊厥(FS)或其他发热性惊厥类型。我们进行了一项以SCN1A为核心的临床和遗传学研究，使用dHPLC、基因测序和MLPA检测SMEI/SMEB患者的基因组缺失/重复。结果：我们将患者分为：SMEI/SMEB=55；GEFS+=26；以及其他表型=51。对37例SMEI/SMEB先证者(67%)和3例GEFS+先证者(11.5%)进行了SCN1A基因突变分析。MLPA显示18例SMEI/SMEB中有2例存在基因组缺失。大多数突变是从头开始的(82%)。携带突变的SMEB患者(8例)更有可能发生错义突变(62.5%)，反之，SMEI患者(31例)有更多的截断、剪接或基因组改变(64.5%)。有截短、剪接点或基因组改变的SMEI/SMEB与错义突变和无突变相比，FS的发病年龄显著提前(P=0.00007，方差分析)。结论：我们在SMEI/SMEB患者中发现了71%的SCN1A异常，在GEFS+先证者中有11.5%。MLPA补充了SCN1A的DNA测序，提高了突变检测率。有截断、剪接点或基因组改变的SMEI/SMEB患者的FS发病年龄明显更早。本研究证实了SCN1A对SMEI/SMEB表型的高度敏感性。
Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations.Methods: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients.Results: We classified patients as: SMEI/SMEB = 55; GEFS+ = 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations.Conclusion: We obtained a frequency of 71% SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes.