Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations

被引:17
|
作者
Moya-Mendez, Mary E. [1 ]
Mueller, David M. [2 ]
Pratt, Milton [1 ]
Bonner, Melanie [3 ]
Elliott, Courtney [1 ]
Hunanyan, Arsen [1 ]
Kucera, Gary [4 ]
Bock, Cheryl [4 ]
Prange, Lyndsey [1 ]
Jasien, Joan [1 ]
Keough, Karen [5 ]
Shashi, Vandana [5 ]
McDonald, Marie [5 ]
Mikati, Mohamad A. [1 ,6 ]
机构
[1] Duke Univ, Dept Pediat, Div Pediat Neurol & Dev Med, Durham, NC 27710 USA
[2] Rosalind Franklin Univ Med & Sci, Ctr Genet Dis, Chicago Med Sch, Chicago, IL USA
[3] Duke Univ, Dept Psychiat, Durham, NC 27706 USA
[4] Duke Univ, Med Ctr, Duke Canc Inst Rodent Canc Models Shared Resource, Durham, NC USA
[5] Univ Texas Austin, Dell Med Sch, Austin, TX 78712 USA
[6] Duke Univ, Dept Neurobiol, Durham, NC 27710 USA
关键词
ATP1A2; Alternating Hemiplegia of Childhood; Familial Hemiplegic Migraine; Encephalopathy; NMDA Receptor Antagonist; Memantine; FAMILIAL HEMIPLEGIC MIGRAINE; MOUSE MODEL; ATPASE; KETAMINE; NA+;
D O I
10.1016/j.yebeh.2020.107732
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
Background: ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. Aim: We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. Methods: A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. Results: Patients (age 2.5-20 years) had symptom onset at an early age (6 days-1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks-4.8 years) with some improvements reported in all five. Conclusions: Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy. (C) 2020 Elsevier Inc. All rights reserved.
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页数:8
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