Neurologic phenotypes associated with COL4A1/2 mutations Expanding the spectrum of disease
Neurologic phenotypes associated with COL4A1/2 mutations Expanding the spectrum of disease
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DOI：
10.1212/wnl.0000000000006567
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发表时间：
2018-11-27
期刊：
影响因子：
9.9
通讯作者：
Sisodiya, Sanjay M.
中科院分区：
文献类型：
--
作者：
Zagaglia, Sara;Selch, Christina;Sisodiya, Sanjay M.
目的探讨与COL4A1/2突变相关的神经表型，并寻求基因型与表型的相关性。方法分析44例COL4A1/COL4A2突变新发患者和55例既往报告患者的临床、脑电图和神经影像学资料。结果儿童期局灶性癫痫最常见，常并发癫痫持续状态和抗癫痫药物耐药。脑电图典型地显示局灶性癫痫样放电在其他异常的背景下，包括广泛性锐波或减慢。在46.4%的局灶性癫痫新发患者中，脑MRI显示的脑孔囊肿与局灶性癫痫样放电区域重合。在脑孔囊肿患者中，脑MRI也经常显示广泛的白质异常，与脑电图的弥漫性脑障碍的发现一致。值得注意的是，我们还确定了癫痫患者亚组作为其主要临床特征，其中脑MRI显示非特异性发现，特别是脑室周围白质脑病和心室不对称。对15个家系的分析表明，在后代中，临床表型的严重程度会恶化，特别是当母系遗传时。与癫痫相关的突变在COL4A1中广泛存在，没有出现明确的基因型-表型相关性。结论col4a1 /COL4A2突变通常导致严重的神经系统疾病和更广泛的轻度表型，其中癫痫是主要特征。早期识别携带COL4A1/COL4A2突变的患者可能具有重要的临床意义，而对于研究工作而言，对脑MRI异常个体的大规模癫痫测序研究的遗漏可能会产生对癫痫总体遗传贡献的误导性估计。
ObjectiveTo characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation.MethodsWe analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.ResultsChildhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge.ConclusionCOL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.