EIF2B基因新突变致白质消融性白质脑病2例及文献复习

doi:10.3969/j.issn.1674-8115.2022.07.018

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (7): 964-970.doi: 10.3969/j.issn.1674-8115.2022.07.018

• 病例报告 • 上一篇

EIF2B基因新突变致白质消融性白质脑病2例及文献复习

刘桃桃¹^,²(), 邬静莹¹, 刘晓黎³, 张梅², 曹立¹()

^1.上海交通大学医学院附属第六人民医院神经内科，上海 200233
^2.安徽理工大学第一附属医院神经内科，淮南 232007
^3.上海市奉贤区中心医院神经内科，上海 201400

收稿日期:2022-02-28 接受日期:2022-06-08 出版日期:2022-07-25 发布日期:2022-07-25
通讯作者: 曹立 E-mail:liutt@rjlab.cn;caoli2000@yeah.net
作者简介:刘桃桃（1991—），女，硕士生；电子信箱：liutt@rjlab.cn。
基金资助:
国家自然科学基金(81870889)

Two cases of leukoencephalopathy with vanishing white matter caused by new mutation of EIF2B gene and literature review

LIU Taotao¹^,²(), WU Jingying¹, LIU Xiaoli³, ZHANG Mei², CAO Li¹()

^1.Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
^2.Department of Neurology, The First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232007, China
^3.Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai 201400, China

Received:2022-02-28 Accepted:2022-06-08 Online:2022-07-25 Published:2022-07-25
Contact: CAO Li E-mail:liutt@rjlab.cn;caoli2000@yeah.net
Supported by:
National Natural Science Foundation of China(81870889)

摘要/Abstract

摘要：

该文报道2例白质消融性白质脑病（leukoencephalopathy with vanishing white matter，VWM）。患者1，女，2岁3个月，临床以反复感染后运动能力倒退为主要表现，病情进展迅速，发病6个月时有癫痫发作，此后患者不能独立行走，吞咽困难；基因检测发现，该患者的EIF2B4基因存在7号外显子c.594C>G（p.I98M）和11号外显子c.1177T>A（p.Y393N）的复合杂合突变，其中前者来自父亲、后者来自母亲，且2个位点均是未曾报道的新错义突变。患者2，女，41岁，临床以进行性双下肢无力及记忆力减退为主要表现；基因检测发现，该患者的EIF2B3基因存在2号外显子c.130G>A（p.G44K）和8号外显子c.934C>G（p.R312G）的复合杂合突变，其中后者位点的突变已有报道，但此突变类型为首次报告，且该患者是中国报道的第2例成人型VWM。2例患者的头颅磁共振成像均表现为弥漫对称性脑白质病变；其中，患者1白质稀薄更突出，患者2主要表现为白质萎缩、脑室扩大。发病年龄是VWM严重程度的临床预测因子，起病越早则病情进展越迅速。应激是发病及神经恶化的诱因，目前VWM尚无有效的治疗方法。该文对上述2个病例进行报道，旨在提升临床医师对疾病的认识及早期诊断的能力，以期延缓疾病的进展、延长患者的生存期。

关键词: 白质消融性白质脑病, EIF2B基因, 癫痫, 感染

Abstract:

Two cases of leukoencephalopathy with vanishing white matter (VWM) were reported. Patient 1 was a two years and three months old girl whose main clinical manifestation was rapidly progressive motor disturbance following recurrent infections. She developed epilepsy after 6 months. After that, she was unable to walk independently and had difficulty in swallowing. Genetic testing revealed that there were compound heterozygous mutations in the EIF2B4 gene of the proband, including the c.594C>G (p.I98M) in exon 7 inherited from father and the c.1177T>A (p.Y393N) in exon 11 inherited from mother that both had not been reported previously. Cranial MRI showed diffuse symmetrical white matter lesions with prominent white matter thinning. Patient 2 was a 41-year-old female, the second adult VWM case reported in China, mainly manifesting as progressive weakness in both lower limbs and memory loss. Genetic testing revealed that there were compound heterozygous mutations in the EIF2B3 gene of the proband, including the c.130G>A (p.G44K) in exon 2 and the c.934C>G (p.R312G) in exon 8, in which the latter mutation type was reported for the first time. Cranial MRI showed white matter atrophy and ventriculomegaly. Age was a clinical predictor of the severity of VWM, and specifically earlier onset could be associated with more severe disability and higher mortality. Stress was a trigger for the disease and could contribute to neurological deterioration. At present, there is no effective therapy method for this disease. This article reports the two cases, aiming to improve clinicians' understanding of the disease and their ability of early diagnosis, so as to delay the progress of the disease and prolong the survival of the patients.

Key words: leukoencephalopathy with vanishing white matter (VWM), EIF2B gene, epilepsy, infection

中图分类号:

R742.8⁺1

刘桃桃, 邬静莹, 刘晓黎, 张梅, 曹立. EIF2B基因新突变致白质消融性白质脑病2例及文献复习[J]. 上海交通大学学报（医学版）, 2022, 42(7): 964-970.

LIU Taotao, WU Jingying, LIU Xiaoli, ZHANG Mei, CAO Li. Two cases of leukoencephalopathy with vanishing white matter caused by new mutation of EIF2B gene and literature review[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 964-970.

图/表 5

图1 患者1发病3、6个月时的头颅磁共振成像Note： A?D. T1WI sequence (A), T2WI sequence (B), FLAIR sequence (C) and DWI sequence (D) of patient 1 at 3 months after onset. E?H. T1WI sequence (E), T2WI sequence (F), FLAIR sequence (G) and DWI sequence (H) of patient 1 at 6 months after onset. Red arrows indicate the lesions mainly involved bilateral periventricular white matter, which shows the hypointense on the T1WI sequence and the hyperintense on the T2WI and DWI sequence. White arrows indicate the lesions closed to cerebrospinal fluid signal, which shows the intralesional hyperintense radiation streaks on FLAIR sequence.

Fig 1 Cranial MRI of patient 1 at 3 and 6 months after onset

图2 患者1的家系图及其家族一代测序图谱Note： A. Pedigree of patient 1. The arrow points to the proband. B. Sanger sequencing map of patient 1 and her parents. Left arrows indicate the c.594C>G (p.I98M) missense mutation in exon 7 of EIF2B4 gene inherited from her father. Right arrows indicate the c.1177T>A (p.Y393N) missense mutation in exon 11 of EIF2B4 gene inherited from her mother.

Fig 2 Pedigree of patient 1 and her family Sanger sequencing map

图3 患者2发病时、发病3年后的头颅磁共振成像Note： A?D. T1WI sequence (A), T2WI sequence (B), FLAIR sequence (C) and DWI sequence (D) of patient 2 at onset. E?H. T1WI sequence (E), T2WI sequence (F), FLAIR sequence (G) and DWI sequence (H) of patient 2 at 3 years after onset. Red arrows indicate the lesions mainly involved bilateral periventricular white matter, which shows the hypointense on the T1WI sequence and the hyperintense on the T2WI, FLAIR and DWI sequence.

Fig 3 Cranial MRI of patient 2 at onset and 3 years later

图4 患者2的家系图及其一代测序图Note： A. Pedigree of patient 2. The arrow points to the proband. B. Sanger sequencing map of patient 2 and her daughter. Left arrow indicates the c.130G>A (p.G44K) missense mutation in exon 2 of EIF2B3 gene, and her daughter is wild-type in this site. Right arrows indicate the c.934C>G (p.R312G) missense mutation in exon 8 of EIF2B3 gene, and her daughter has this variant.

Fig 4 Pedigree of patient 2 and her Sanger sequencing map

表1 国内外报道的成人型VWM患者的基因、性别及首发症状

Tab 1 Gene， gender and first symptoms of adult VWM patients reported at home and abroad

Gene	Number of patients （n=62）/n（%）	Male （n=8）/ n	Female （n=54）/ n	First symptom/n
Gene	Number of patients （n=62）/n（%）	Male （n=8）/ n	Female （n=54）/ n	Cerebellar ataxia （n=39）	Cognitive decline （n=10）	Premature ovarian failure （n=6）	Others （n=7）
EIF2B1	2 （3.2）	1	1	1^［15］	1^［16］	‒	‒
EIF2B2	5 （8.1）	0	5	4^{［10， 17-19］}	1^［11］	‒	‒
EIF2B3	5 （8.1）	0	5	2^{［16， 18］}	0	2^{［8， 20］}	Migraine （n=1）^［21］
EIF2B4	4 （6.4）	0	4	3^{［10， 22］}	1^［18］	‒	‒
EIF2B5	46 （74.2）	7	39	29^{［7-8， 10， 18， 23-25］}	7^{［18， 26-27］}	4^{［8， 10， 18， 23， 28］}	Psychosis （n=4）^{［18， 23， 29-30］}，migraine （n=2）^{［10， 18］}

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EIF2B基因新突变致白质消融性白质脑病2例及文献复习

Two cases of leukoencephalopathy with vanishing white matter caused by new mutation of EIF2B gene and literature review

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