Department of Medical Genetics, Medical School, Clinical Center, University of Pécs, Pécs, Hungary.
Bethesda Children's Hospital, Epilepsy Center, Budapest, Hungary.
Neuropediatrics. 2023 Oct;54(5):344-346. doi: 10.1055/a-2104-1614. Epub 2023 Jun 1.
The mechanistic target of the rapamycin signaling pathway serves as a central regulator of cell metabolism, growth, proliferation, and survival. In its regulation, the GTPase-activating protein activity toward Rags1 complex has an inhibitory effect. Mutations in genes encoding this complex protein are among the most common abnormalities in focal epilepsies. Within these mutations, the mutations affecting the gene have been associated with different autosomal dominantly inherited epilepsy types. Due to the limited data available on mTOR inhibitor therapy in nontuberous sclerosis complex epileptic patients, here we present the clinical management of a patient with intractable epilepsy, skin hypopigmentation, and a variant. The patient's phenotype is compatible with a nonlesional -related epileptic encephalopathy. We initiated compassionate, off-label everolimus treatment as the patient's condition continuously deteriorated. Due to bilateral pneumonia occurring at the beginning of the treatment, it was temporarily discontinued, and resumed in half the dose. Follow-up examination after 18 months showed a 90% reduction in seizure frequency with moderate improvement in attention function and nutritional status. Our case report emphasizes the importance of early genetic testing in patients with epileptic encephalopathy. Clinical consequences of mammalian target of rapamycin complex 1 (mTORC1) upregulation may be amenable to tailored treatment with mTOR inhibitors. A clinical trial on an international scale would be needed to draw conclusions.
雷帕霉素信号通路的作用机制靶点是细胞代谢、生长、增殖和存活的中央调节因子。在其调节中，Rags1 复合物的 GTP 酶激活蛋白活性具有抑制作用。编码该复合物蛋白的基因突变是局灶性癫痫中最常见的异常之一。在这些突变中，影响 基因的突变与不同的常染色体显性遗传性癫痫类型有关。由于关于非结节性硬化症癫痫患者使用 mTOR 抑制剂治疗的可用数据有限，我们在这里介绍了一名难治性癫痫、皮肤色素减退和 变异患者的临床管理。患者的表型与非病变相关的癫痫性脑病相吻合。由于患者病情持续恶化，我们开始进行同情性、标签外的依维莫司治疗。由于在治疗开始时发生双侧肺炎，该治疗暂时停止，然后以半剂量恢复。18 个月后的随访检查显示，癫痫发作频率降低了 90%，注意力功能和营养状况有中度改善。我们的病例报告强调了在癫痫性脑病患者中进行早期基因检测的重要性。哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）上调的临床后果可能适合使用 mTOR 抑制剂进行针对性治疗。需要进行国际范围内的临床试验才能得出结论。
