Department of Neurological Sciences, University of Rome Sapienza, Rome, Italy.
Epilepsia. 2011 Jul;52(7):1258-64. doi: 10.1111/j.1528-1167.2011.03071.x. Epub 2011 Apr 19.
To describe the clinical and genetic findings of four families with autosomal dominant lateral temporal epilepsy.
A personal and family history was obtained from each affected and unaffected subject along with a physical and neurologic examination. Routine electroencephalography and magnetic resonance imaging (MRI) studies were performed in almost all patients. DNAs from family members were screened for LGI1 mutations. The effects of mutations on Lgi1 protein secretion were determined in transfected culture cells.
The four families included a total of 11 patients (two deceased), six of whom had lateral temporal epilepsy with auditory aura. Age at onset was in the second decade of life; seizures were well controlled by antiepileptic treatment and MRI studies were normal. We found two pathogenic LGI1 mutations with uncommonly low penetrance: the R136W mutation, previously detected in a sporadic case with telephone-induced partial seizures, gave rise to the epileptic phenotype in three of nine mutation carriers in one family; the novel C179R mutation caused epilepsy in an isolated patient from a family where the mutation segregated. Another novel pathogenic mutation, I122T, and a nonsynonymous variant, I359V, were found in the two other families. Protein secretion tests showed that the R136W and I122T mutations inhibited secretion of the mutant proteins, whereas I359V had no effect on protein secretion; C179R was not tested, because of its predictable effect on protein folding.
These findings suggest that some LGI1 mutations may have a weak penetrance in families with complex inheritance pattern, or isolated patients, and that the protein secretion test, together with other predictive criteria, may help recognize pathogenic LGI1 mutations.
描述四组常染色体显性颞叶外侧癫痫家系的临床和遗传学发现。
对每位受影响和未受影响的患者进行个人和家族史采集，同时进行体格检查和神经系统检查。几乎所有患者都进行了常规脑电图和磁共振成像（MRI）研究。对家族成员的 DNA 进行 LGI1 突变筛查。在转染培养细胞中确定突变对 Lgi1 蛋白分泌的影响。
这四个家系共包括 11 名患者（两名已故），其中 6 名患有伴听觉先兆的颞叶外侧癫痫。发病年龄在 20 岁出头；癫痫发作通过抗癫痫治疗得到很好的控制，MRI 研究正常。我们发现了两个具有低外显率的致病性 LGI1 突变：先前在一例由电话诱发的部分性发作的散发病例中检测到的 R136W 突变，导致一个家系中的 9 名突变携带者中的 3 人出现癫痫表型；另一个家系中，新型 C179R 突变导致一名孤立患者发生癫痫。在另外两个家系中还发现了另一个新型致病性突变 I122T 和一个非同义变异 I359V。蛋白分泌试验表明，R136W 和 I122T 突变抑制了突变蛋白的分泌，而 I359V 对蛋白分泌没有影响；由于对蛋白折叠的可预测影响，C179R 未进行测试。
这些发现表明，一些 LGI1 突变可能在具有复杂遗传模式的家系或孤立患者中具有低外显率，并且蛋白分泌试验，连同其他预测标准，可能有助于识别致病性 LGI1 突变。
