King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
Genes Brain Behav. 2010 Nov;9(8):1004-12. doi: 10.1111/j.1601-183X.2010.00648.x. Epub 2010 Oct 18.
We recently showed genomewide linkage of centrotemporal sharp waves (CTS) in classic Rolandic epilepsy (RE) families to chromosome 11p13, and fine-mapped this locus to variants in the ELP4 gene. Speech sound disorder (SSD) is a common comorbidity in RE subjects, of unknown etiology, which co-aggregates in family members in a manner that could hypothetically be explained by shared underlying genetic risk with CTS. Furthermore, the neural mechanism of SSD is unknown, although individuals with rare, Mendelian forms of RE are described with severe verbal and oromotor apraxia. We therefore first performed genomewide linkage analysis for SSD, operationally defined as clinical history consistent with ICD-10 speech articulation disorder, in 38 families singly ascertained through a proband with RE. We tested the hypothesis of shared genetic risk with CTS at the 11p13 locus. In the second part of the study we used computerized acoustic analysis of recorded speech to test the hypothesis of dyspraxia as a mechanism for SSD in a smaller subset of RE probands and relatives. In two-point and multipoint LOD score analysis, we found that evidence for linkage to the 11p13 locus increased substantially when the phenotype was broadened from CTS to CTS/SSD. In multipoint analysis, the LOD score rose by 3.2 to HLOD 7.54 at D11S914 for CTS/SSD, the same marker at which multipoint linkage maximized for CTS alone. Non-parametric, affected-only methods in a sub-set of the data provide further confirmatory evidence for pleiotropy. In acoustic analysis there were voice-onset time abnormalities in 10/18 RE probands, 8/16 siblings and 5/15 parents, providing evidence of breakdown in the spatial/temporal properties of speech articulation consistent with a dyspraxic mechanism. The results from genetic and physiological studies suggest a pleiotropic role for the 11p13 locus in the development of both SSD and CTS, and also indicate a dyspraxic mechanism for the SSD linked to 11p13. Taken together, these data strongly support a neurodevelopmental origin for classic RE.
我们最近发现中央颞区棘波（CTS）在经典 Rolandic 癫痫（RE）家族中的全基因组连锁与 11p13 染色体有关，并将该基因座精细定位到 ELP4 基因的变异上。语音障碍（SSD）是 RE 患者常见的共病，病因不明，但在家庭成员中以聚合的方式聚集在一起，这种方式可以假设与 CTS 的共同潜在遗传风险有关。此外，SSD 的神经机制尚不清楚，尽管有罕见的 Mendelian 形式的 RE 个体被描述为严重的言语和口运动性失用症。因此，我们首先对 38 个通过具有 RE 的先证者单一鉴定的家族进行了 SSD 的全基因组连锁分析，SSD 是指临床病史符合 ICD-10 言语发音障碍的定义。我们检验了与 11p13 基因座共享遗传风险的假设。在研究的第二部分，我们使用记录语音的计算机声学分析来检验较小的 RE 先证者和亲属中作为 SSD 机制的构音障碍假说。在两点和多点 LOD 得分分析中，当表型从 CTS 扩展到 CTS/SSD 时，11p13 基因座的连锁证据大大增加。在多点分析中，对于 CTS/SSD，LOD 分数从 3.2 上升到 HLOD 7.54，在 CTS 单独最大的多点连锁的相同标记 D11S914 处。在数据的子集中，非参数、仅受影响的方法提供了更多的确认证据表明存在多效性。在声学分析中，18 个 RE 先证者中有 10 个、16 个兄弟姐妹中有 8 个和 15 个父母中有 5 个存在语音发声时间异常，这提供了语音发音空间/时间特性中断的证据，与构音障碍机制一致。遗传和生理研究的结果表明，11p13 基因座在 SSD 和 CTS 的发展中具有多效性作用，并且也表明与 11p13 连锁的 SSD 具有构音障碍机制。综上所述，这些数据强烈支持经典 RE 的神经发育起源。
