Laboratory of Neurogenetics, Department of Neuroscience, Istituto G. Gaslini, Genova, Italy.
Epilepsia. 2013 Mar;54(3):425-36. doi: 10.1111/epi.12089. Epub 2013 Jan 29.
To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS).
Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method.
A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation.
Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.
剖析婴儿期良性家族性癫痫的遗传学，并评估良性家族性新生儿发作（BFNS）、良性家族性新生儿-婴儿发作（BFNIS）和良性家族性婴儿发作（BFIS）之间遗传重叠的程度。
纳入至少有两名一级亲属受首发于 1 岁以内的局灶性癫痫影响且发作前发育正常的家族。当所有家族成员均发生新生儿发作时，家族被分类为 BFNS；当家族成员的发作起始年龄在 1 至 4 个月之间或同时存在新生儿和婴儿发作时，家族被分类为 BFNIS；当所有家族成员的发作起始年龄均在 4 个月以后时，家族被分类为 BFIS。通过直接测序扩增的基因组 DNA 分析 SCN2A、KCNQ2、KCNQ3、PPRT2 点突变。通过多重依赖探针扩增方法分析涉及 KCNQ2 和 KCNQ3 的基因组缺失。
共收集了 46 个家族，共 165 名受累成员。8 个家族被分类为 BFNS，9 个家族被分类为 BFNIS，29 个家族被分类为 BFIS。遗传分析确定了 41 种突变，其中 14 种影响 KCNQ2，1 种影响 KCNQ3，5 种影响 SCN2A，21 种影响 PRRT2。整个队列的突变检出率为 89%。在 BFNS 中，突变专门涉及 KCNQ2。在 BFNIS 中涉及两个基因（KCNQ2，6 个家族；SCN2A，2 个家族）。BFIS 家族是遗传上最具异质性的，所有四个基因均有涉及，尽管其中约 70%携带 PRRT2 突变。
我们的数据突出了 KCNQ2 在整个疾病谱中的重要作用，尽管随着发病年龄的增加而逐渐减弱。随访期间出现无热惊厥与 KCNQ2 突变相关，可能是一个预测因素。此外，我们还表明 KCNQ3 突变也可能与婴儿期发作的家族有关。总之，我们的数据表明 K 通道基因在典型新生儿癫痫之外具有重要作用。在发作起始年龄在 6 至 8 个月之间的具有婴儿期发作的家族中发现一种新型 SCN2A 突变，进一步证实该基因不仅与 BFNIS 相关，而且还与发病年龄较晚的家族相关。我们的数据表明 PRRT2 突变聚集在 BFIS 家族中。发作性运动诱发性运动障碍作为 PRRT2 家族的一个独特特征出现，尽管在我们的研究系列中并不常见。我们表明，发作的发病年龄与潜在遗传学显著相关，约 90%的典型 BFNS 家族与 KCNQ2 相关，而 BFIS 家族中只有 3%与 PRRT2 相关，PRRT2 是主要基因。
