PMID- 32805448 OWN - NLM STAT- MEDLINE DCOM- 20210430 LR - 20211204 IS - 1878-0849 (Electronic) IS - 1769-7212 (Linking) VI - 63 IP - 11 DP - 2020 Nov TI - Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation. PG - 104036 LID - S1769-7212(20)30372-4 [pii] LID - 10.1016/j.ejmg.2020.104036 [doi] AB - 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. CI - Copyright (c) 2020. Published by Elsevier Masson SAS. FAU - Hadouiri, Nawale AU - Hadouiri N AD - Centre de Genetique et Centre de Reference Anomalies du Developpement et Syndromes Malformatifs de l'Interregion Est, CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Darmency, Veronique AU - Darmency V AD - Service de Neurophysiologie Clinique, Hopital d'Enfants, CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Guibaud, Laurent AU - Guibaud L AD - Radiologie Pediatrique, Hopital Femme Mere Enfant (HFME), Bron, France. FAU - Arzimanoglou, Alexis AU - Arzimanoglou A AD - Service d'epileptologie Clinique, des Troubles du Sommeil et de Neurologie Fonctionnelle de l'enfant, Coordinateur du Reseau Europeen pour les epilepsies Rares et Complexes, ERN EpiCARE, HCL - GH Est, Hopital Femme Mere Enfant, Bron, France. FAU - Sorlin, Arthur AU - Sorlin A AD - Centre de Genetique et Centre de Reference Anomalies du Developpement et Syndromes Malformatifs de l'Interregion Est, CHU Dijon Bourgogne, 21079, Dijon, France; Genetique des Anomalies du Developpement, UMR1231, Universite de Bourgogne, 21079, Dijon, France. FAU - Carmignac, Virginie AU - Carmignac V AD - Genetique des Anomalies du Developpement, UMR1231, Universite de Bourgogne, 21079, Dijon, France. FAU - Riviere, Jean-Baptiste AU - Riviere JB AD - Genetique des Anomalies du Developpement, UMR1231, Universite de Bourgogne, 21079, Dijon, France; Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du Developpement (TRANSLAD), CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Huet, Frederic AU - Huet F AD - Service de Neurophysiologie Clinique, Hopital d'Enfants, CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Luu, Maxime AU - Luu M AD - Centre d'Investigation Clinique Plurithematique, CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Bardou, Marc AU - Bardou M AD - Centre d'Investigation Clinique Plurithematique, CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Thauvin-Robinet, Christel AU - Thauvin-Robinet C AD - Genetique des Anomalies du Developpement, UMR1231, Universite de Bourgogne, 21079, Dijon, France; Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du Developpement (TRANSLAD), CHU Dijon Bourgogne, 21079, Dijon, France; Centre de Reference Deficiences Intellectuelles de Causes Rares Defi-Bourgogne, CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Vabres, Pierre AU - Vabres P AD - Genetique des Anomalies du Developpement, UMR1231, Universite de Bourgogne, 21079, Dijon, France; Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du Developpement (TRANSLAD), CHU Dijon Bourgogne, 21079, Dijon, France; Centre de Reference des Maladies Rares de la Peau et des Muqueuses d'origine Genetique (MAGEC), CHU Dijon Bourgogne, 21079, Dijon, France. FAU - Faivre, Laurence AU - Faivre L AD - Centre de Genetique et Centre de Reference Anomalies du Developpement et Syndromes Malformatifs de l'Interregion Est, CHU Dijon Bourgogne, 21079, Dijon, France; Genetique des Anomalies du Developpement, UMR1231, Universite de Bourgogne, 21079, Dijon, France; Federation Hospitalo-Universitaire Medecine Translationnelle et Anomalies du Developpement (TRANSLAD), CHU Dijon Bourgogne, 21079, Dijon, France. Electronic address: laurence.faivre@chu-dijon.fr. LA - eng PT - Case Reports PT - Journal Article DEP - 20200814 PL - Netherlands TA - Eur J Med Genet JT - European journal of medical genetics JID - 101247089 RN - 0 (Protein Kinase Inhibitors) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - Cortical Dysplasia-Focal Epilepsy Syndrome SB - IM MH - Child MH - *Compassionate Use Trials MH - Craniofacial Abnormalities/*drug therapy/genetics MH - Epilepsies, Partial/*drug therapy/genetics MH - Everolimus/administration & dosage/*therapeutic use MH - Female MH - *Gain of Function Mutation MH - Humans MH - Malformations of Cortical Development/*drug therapy/genetics MH - Mosaicism MH - Phenotype MH - Protein Kinase Inhibitors/administration & dosage/*therapeutic use MH - TOR Serine-Threonine Kinases/*genetics OTO - NOTNLM OT - Everolimus OT - Mosaic mTOR mutation OT - Seizures OT - Therapy in rare diseases OT - mTOR EDAT- 2020/08/18 06:00 MHDA- 2021/05/01 06:00 CRDT- 2020/08/18 06:00 PHST- 2020/04/22 00:00 [received] PHST- 2020/06/16 00:00 [revised] PHST- 2020/08/08 00:00 [accepted] PHST- 2020/08/18 06:00 [pubmed] PHST- 2021/05/01 06:00 [medline] PHST- 2020/08/18 06:00 [entrez] AID - S1769-7212(20)30372-4 [pii] AID - 10.1016/j.ejmg.2020.104036 [doi] PST - ppublish SO - Eur J Med Genet. 2020 Nov;63(11):104036. doi: 10.1016/j.ejmg.2020.104036. Epub 2020 Aug 14.