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671.
Patrick B. Moloney Hugh Kearney Katherine A. Benson Daniel J. Costello Gianpiero L. Cavalleri Kathleen M. Gorman Bryan J. Lynch Norman Delanty 《European journal of neurology》2023,30(10):3341-3346
Background
Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy.Methods
We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5–15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline.Results
Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5–16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3%–86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis.Conclusions
Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings. 相似文献672.
Kate Stanley Joseph Hostyk Linh Tran Marta Amengual-Gual Patricia Dugan Justice Clark Hyunmi Choi Dmitry Tchapyjnikov Piero Perucca Cecilia Fernandes Danielle Andrade Orrin Devinsky Gianpiero L. Cavalleri Chantal Depondt Arjune Sen Terence O'Brien Erin Heinzen Tobias Loddenkemper David B. Goldstein Mohamed A. Mikati Norman Delanty 《American journal of medical genetics. Part A》2022,188(1):138-146
Large international consortia examining the genomic architecture of the epilepsies focus on large diagnostic subgroupings such as “all focal epilepsy” and “all genetic generalized epilepsy”. In addition, phenotypic data are generally entered into these large discovery databases in a unidirectional manner at one point in time only. However, there are many smaller phenotypic subgroupings in epilepsy, many of which may have unique genomic risk factors. Such a subgrouping or “microphenotype” may be defined as an uncommon or rare phenotype that is well recognized by epileptologists and the epilepsy community, and which may or may not be formally recognized within the International League Against Epilepsy classification system. Here we examine the genetic structure of a number of such microphenotypes and report in particular on two interesting clinical phenotypes, Jeavons syndrome and pediatric status epilepticus. Although no single gene reached exome-wide statistical significance to be associated with any of the diagnostic categories, we observe enrichment of rare damaging variants in established epilepsy genes among Landau–Kleffner patients (GRIN2A) and pediatric status epilepticus patients (MECP2, SCN1A, SCN2A, SCN8A). 相似文献