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中华妇幼临床医学杂志(电子版)

Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition) ›› 2020, Vol. 16 ›› Issue (04): 398 -408. doi: 10.3877/cma.j.issn.1673-5250.2020.04.005

Special Issue: ；

Original Article

Diagnosis and treatment of children with familial acute necrotizing encephalopathy caused by RANBP2 gene mutation and literature review

Zemin Luo1, Jiuwei Li2,†(), Xingyu Liu1, Qiong Jiang1, Shuyao Zhu1, Danfeng Xie1   

  1. 1. Department of Pediatric Neurology, Sichuan Provincial Hospital for Women and Children, Chengdu 610045, Sichuan Province, China
    2. Department of Neurology, Beijing Children′s Hospital Affiliated to Capital Medical University, Beijing 100045, China
  • Received:2019-09-19 Revised:2020-05-21 Published:2020-08-01
  • Corresponding author: Jiuwei Li
  • About author:
    Corresponding author: Li Jiuwei, Email:
  • Supported by:
    Scientific Research Project of Health Commission of Sichuan Province(19PJ256)
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Objective

To investigate clinical characteristics, diagnosis, treatment and prognosis of familial acute necrotizing encephalopathy (ANE1) caused by RANBP2 gene mutation.

Methods

A total of 2 children with ANE1 caused by RANBP2 gene mutation who were confirmed in Beijing Children′s Hospital in January 2018 (case 1) and in Sichuan Provincial Hospital for Women and Children in March 2019 (case 2), were chosen as research subjects. We retrospectively analyzed their clinical case data, including clinical manifestations, laboratory examination results, head MRI features, treatment and follow-up data. Meanwhile, literature related to ANE1 caused by RANBP2 gene mutation were searched in mainstream databases for literature review. And the procedure followed in the whole study were in accordance with World Medical Association Declaration of Helsinki revised in 2013.

Results

① Clinical case data: clinical manifestation of case 1 was presented with headache after fever, drowsiness, poor mental response, indifferent expression, unstable walking in a straight line, and recent memory decline; and of case 2 with fever, headache, vomiting, progressive disturbance of consciousness and facial paralysis after infection of influenza A virus. Their head MRI examinations revealed symmetrical damage to multiple parts of thalamus, insula, pons and external capsule, with some cystic changes. Their gene detection results showed that heterozygosity mutation of RANBP2 gene on exon 12: c. 1754 C>T (p.Thr585Met), a missense mutation. After treatment with gamma globulin, glucocorticoids to regulate immunity, and " mitochondrial cocktail therapy" to repair mitochondrial function, their intracranial lesions improved, and mental and athletic abilities were restored. ② Clinical features of ANE1 caused by RANBP2 gene mutation of 74 cases by literature review and 2 cases in this study were summarized. Their clinical features were as follows: their age of onset ranged from 5 months to 40 years old, median age of first onset was 3.5 years old, the ratio of male to female patients was 35∶41. Among main clinical manifestations, ratio of fever was 82.5% (47/57), epilepsy was 81.1% (41/53), focal neurological deficit (FND) was 28.6% (8/28), encephalopathy was 93.4% (71/76), elevated CSF protein (EP) was 90.3% (56/62), pleocytosis in CSF (Pl) was 28.6% (8/28). Head MRI/CT showed that main lesions of patients were located in thalami (83.1%, 49/59), brainstem (72.9%, 43/59), temporal lobe (71.2%, 42/59), cerebellum (26.3%, 5/19), spinal cord (13.8%, 4/29), basal ganglia (8.5%, 5/59).

Conclusions

ANE1 caused by RANBP2 gene mutation has typical clinical features and characteristic head MRI findings. Febrile disease with symmetrical lesions in thalamus and other brain parts should be a vigilant signal to ANE1 patients. For patients suspected of ANE1, early detection of RANBP2 gene will be helpful to clarify diagnosis, rational treatment and improve their prognosis.

Key words: Acute febrile encephalopathy, Familial, Ran-binding protein 2, Magnetic resonance imaging, Genetics, Mutation, missense, Thalamus, Child
图1 患儿2(男性，6岁5个月)入院时头颅MRI检查结果(图1A～1G：双侧岛叶、边缘间脑结构，双侧颞叶深部局部、脑桥、中脑可见斑片状异常信号，与基底节分界清，累及外囊，内囊未见受累。其中，图1A～1C示病变区T1WI呈低信号，图1D～1G示T2WI及T2WI-FLAIR呈高信号。图1H：DWI外囊及背侧丘脑部分呈高信号)
图2 患儿2(男性，6岁5个月)入院后及随访期头颅MRI与MRS检查结果[图2A～2C：入院7 d时头颅MRS结果示，双侧大脑病变区NAA峰减低，胆碱峰升高，NAA/胆碱、NAA/肌酸降低，左侧大脑病变重，未见确切乳酸峰；图2D～2K：入院7 d时复查头颅MRI结果示，双侧岛叶、边缘间脑结构，双侧颞叶深部局部、脑桥、中脑可见斑点、斑片状异常信号，与基底节分界清，累及外囊，病变区T1WI呈低信号，T2WI高信号，并且双侧岛叶病变中可见串珠样高亮信号(图2F、2J红色箭头所示)，病变区T2WI-FLAIR呈高信号；图2L～2M：入院19 d时复查头颅MRI结果示，双侧边缘系统及丘脑、间脑、外囊系统多灶性病变异常信号，与入院7 d的头颅MRI结果比较，病灶范围缩小，双侧外囊软化灶形成(红色箭头所示)；图2N～2O：出院15 d时复查头颅MRI结果示，左侧大脑脚及脑桥左侧斑点状异常信号，与入院19 d的头颅MRI结果比较，双侧外囊、左侧大脑脚及脑桥左侧异常信号灶范围缩小，双侧外囊软化灶形成(红色箭头所示)]
图4 患儿2(男性，6岁5个月)及父母Sanger法测序图[图4A：患儿RANBP2基因第12外显子c.1754 C>T(p.Thr585Met)杂合突变，为错义突变(红色箭头所示)；图4B：患儿父亲RANBP2基因第12外显子c.1754 C>T(p.Thr585Met)杂合突变(红色箭头所示)；图4C：患儿母亲RANBP2基因相应位点未见异常(绿色箭头所示)]
表1 76例RANBP2基因突变所致ANE1患者的主要临床表现
文献(第1作者，文献发表年) 例数 发病年龄 男性∶女性 发热[%(n/n′)] 癫痫发作[%(n/n′)] FND[%(n/n′)] 脑病[%(n/n′)]
Singh[7]，2014 59 5个月龄至36岁 28∶31 75.0(30/40) 91.9(34/37) 16.7(2/12) 91.5(54/59)
McSwiney[17]，2014 1 3岁 1∶0 100.0(1/1) 0(0/1) 100.0(1/1) 100.0(1/1)
Bloch[18]，2015 2 10、40岁 1∶1 100.0(2/2) 50.0(1/2) 0(0/2) 100.0(2/2)
Anand[19]，2015 1 28个月龄 1∶0 100.0(1/1) 0(0/1) 0(0/1) 100.0(1/1)
朱金兰[5]，2015 1 8个月龄首次、18个月龄再次、25个月龄第3次发作 0∶1 100.0(1/1) 100.0(1/1) 0(0/1) 100.0(1/1)
Sell[20]，2016 2 10、19个月龄 0∶2 100.0(2/2) 100.0(2/2) 50.0(1/2) 100.0(2/2)
Sondhi[21]，2016 1 3.5岁 1∶0 100.0(1/1) 0(0/1) 0(0/1) 100.0(1/1)
Lee[22]，2017 2 12个月龄、2岁 0∶2 100.0(2/2) 100.0(2/2) 0(0/2) 100.0(2/2)
Soriano-Ramos[23]，2018 1 7个月龄首次、10岁再次发作 0∶1 100.0(1/1) 未提及 未提及 100.0(1/1)
Howard[24]，2018 2 17个月龄、5岁 1∶1 100.0(2/2) 100.0(2/2) 0(0/2) 100.0(2/2)
Is?kay[25]，2018 1 12岁首次、14岁再次发作 0∶1 100.0(1/1) 100.0(1/1) 0(0/1) 100.0(1/1)
Kelly[26]，2019 1 15个月龄首次、22岁再次发作 1∶0 100.0(1/1) 0(0/1) 100.0(1/1) 100.0(1/1)
罗泽民，2020 2 6岁5个月龄、10岁4个月龄 1∶1 100.0(2/2) 0(0/2) 50.0(1/2) 100.0(2/2)
文献(第1作者，文献发表年) 脑脊液检查结果[%(n/n′)] 头颅MRI/CT检查病变部位[%(n/n′)]
Singh[7]，2014 EP：93.6(44/47)；Pl：16.7(2/12) 双侧丘脑：78.6(33/42)；基底节：2.4(1/42)；颞叶：78.6(33/42)；脑干：76.2(32/42)；小脑：13.3(2/15)；脊髓：14.8(4/27)
McSwiney[17]，2014 Pl：100.0(1/1) 累及双侧丘脑、海马、脑干、内囊、下丘脑及小脑
Bloch[18]，2015 EP：100.0(2/2)；Pl：50.0(1/2) 100.0(2/2)累及双侧丘脑、脑干及海马
Anand[19]，2015 EP：100.0(1/1)；Pl：100.0(1/1) 累及双侧丘脑及基底节
朱金兰[5]，2015 EP：100.0(1/1)；Pl：100.0(1/1) 累及双侧丘脑、脑干、基底节、胼胝体、颞叶、顶叶及小脑
Sell[20]，2016 EP：50.0(1/2)；Pl：100.0(2/2) 双侧丘脑及脑干：100.0(2/2)；外囊及颞叶：50.0(1/2)
Sondhi[21]，2016 EP：100.0(1/1)；Pl：0(0/1) 累及双侧丘脑、脑干、小脑及颞叶
Lee[22]，2017 EP：100.0(2/2)；Pl：0(0/2) 双侧丘脑：100.0(2/2)；外囊、脑干、基底节及小脑：50.0(1/2)
Soriano-Ramos[23]，2018 EP：100.0(1/1)；Pl：0(0/1) 累及双侧丘脑、颞叶、枕叶、外囊及脑干
Howard[24]，2018 EP：0(0/1)；Pl：0(0/1) 外囊：100.0(2/2)；颞叶：100.0(1/1)；双侧丘脑、脑干及顶叶：50.0(1/2)
Is?kay[25]，2018 EP：0(0/1)；Pl：0(0/1) 累及双侧丘脑、岛叶及基底节
Kelly[26]，2019 EP：100.0(1/1)；Pl：0(0/1) 累及双侧丘脑、脑干及海马
罗泽民，2020 EP：100.0(2/2)；Pl：0(0/2) 双侧丘脑、岛叶、脑干及外囊：100.0(2/2)；基底节及颞叶：50.0(1/2)；脊髓：0(0/2)
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