更新于：2024-11-01

DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46

46型发育性癫痫性脑病

更新于：2024-11-01

基本信息

别名

DEE46、DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46、Developmental and Epileptic Encephalopathy 46

+ [3]

简介

An autosomal dominant condition caused by mutation(s) in the GRIN2D gene, encoding glutamate receptor ionotropic, NMDA 2D. It is characterized by developmental delay and intractable seizures.

关联

项与 46型发育性癫痫性脑病相关的药物

Soticlestat

靶点

CH24H

作用机制

CH24H抑制剂

在研机构

武田（中国）国际贸易有限公司 [+6]

原研机构

Takeda Pharmaceutical Co., Ltd.

在研适应症

癫痫发作 [+5]

非在研适应症

染色体15q三体综合征 [+5]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

项与 46型发育性癫痫性脑病相关的临床试验

NCT03166215 / Completed临床1/2期

A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in Subjects With Developmental and/or Epileptic Encephalopathies

The purpose of this study is to characterize the multiple-dose safety and tolerability profile of TAK-935 in adult participants with developmental and/or epileptic encephalopathies.

开始日期2017-08-17

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

[+1]

100 项与 46型发育性癫痫性脑病相关的临床结果

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100 项与 46型发育性癫痫性脑病相关的转化医学

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0 项与 46型发育性癫痫性脑病相关的专利（医药）

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项与 46型发育性癫痫性脑病相关的文献（医药）

2023-09-01·Stem Cell Research

Generation of a human iPSC line (ZJSHDPi001-A) from peripheral blood mononuclear cells of a patient with Developmental epileptic encephalopathy-47 carrying FGF12 gene mutation (c.334G > A)

Article

作者: Guo, Yufan ; Miao, Pu ; Wang, Ye ; Feng, Jianhua ; Lou, Yuting ; Shi, Xinglei ; Gao, Liuyan ; Su, Guofa

Developmental epileptic encephalopathy-47 (DEE47) is a nervous system disease characterized by the onset of intractable seizures that appear the first days or weeks after birth. FGF12 is the disease-causing gene of DEE47 that encodes a small cytoplasm protein, which is a member of the fibroblast growth factor homologous factor (FGF) family. The FGF12-encoded protein interacts with the cytoplasmic tail of voltage-gated sodium channels to enhance the voltage dependence of rapid inactivation of sodium channels in neurons. This study used non-insertion Sendai virus transfection to establish the induced pluripotent stem cells(iPSCs)line with FGF12 mutation. The cell line was obtained from a 3-year-old boy carrying the c.334G > A heterozygous mutation in the FGF12 gene. This iPSC line could facilitate the investigations of pathogeneses of complex nervous system diseases such as developmental epileptic encephalopathy.

2021-07-01·Epilepsia1区 · 医学

Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain‐of‐function FHF1(FGF12) missense mutation

1区 · 医学

Article

作者: Iatckova, Vasilisa ; Goldfarb, Mitchell ; Velíšková, Jana ; Xie, Ying ; Fishman, Glenn I. ; Shekhar, Akshay ; Park, David S. ; Velíšek, Libor ; Liu, Yue ; Marra, Christopher

SummaryObjectiveFibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel‐binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain‐of‐function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice.MethodsThe Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1R52H/F+ mice. Spontaneous epileptiform events in Fhf1R52H/+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure‐induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1BR52H protein was assayed by voltage‐clamp recordings of FHF‐deficient mouse cardiomyocytes infected with adenoviruses expressing wild‐type FHF1B or FHF1BR52H protein.ResultsAll Fhf1R52H/+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19–20‐day‐old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2–53 s after lethal seizure onset, heart rate abruptly declined from 572 ± 16 bpm to 108 ± 15 bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1BR52H in cardiomyocytes induced a 15‐mV depolarizing shift in voltage of steady‐state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in Fhf1R52H/+ mice prior to seizure.SignificanceThe Fhf1 missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both Fhf1 (p.Arg52His) and Scn8a (p.Asn1768Asp) missense mutations enhance sodium channel Nav1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1/Nav1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy.