Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, CHU Dijon Bourgogne, 21079, Dijon, France.
Service de Neurophysiologie Clinique, Hôpital d'Enfants, CHU Dijon Bourgogne, 21079, Dijon, France.
Eur J Med Genet. 2020 Nov;63(11):104036. doi: 10.1016/j.ejmg.2020.104036. Epub 2020 Aug 14.
The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.
MTOR 基因编码雷帕霉素靶蛋白（mTOR），它是 PI3K-AKT-mTOR 信号通路的核心组成部分。合子后 MTOR 变体导致各种镶嵌表型，在 OMIM 中称为 Smith-Kinsgmore 综合征或局灶性皮质发育不良。我们在此报告了一例患者，其皮肤细胞中存在 MTOR 镶嵌获得性功能变异（p.Glu2419Lys），占 41%，接受依维莫司的同情用药治疗难治性癫痫。这名 12 岁女孩表现为精神运动倒退、难治性癫痫、沿着 Blaschko 线（ Ito 色素减退症）的色素减退、不对称区域性身体过度生长和眼部异常，以及左大脑半球肥大伴一些局部潜在的迁移障碍。由于患者癫痫发作越来越频繁，开始给予依维莫司（在医院伦理委员会批准后）5mg/天，并逐渐增加至 12.5mg/天。在密切监测 5 个月（包括神经心理学和脑电图评估）后，未观察到癫痫发作频率降低。尽管病理生理学原理很好，但依维莫司治疗未观察到显著的临床反应。需要进行临床试验得出结论，但由于表型极为罕见，肯定需要在国际范围内进行。
