GFAP基因新突变致罕见表现的亚历山大病临床及基因突变分析
|
摘要
目的报道1例临床罕见的Ⅱ型亚历山大病病例,总结临床表型和基因型特征,扩展Ⅱ型亚历山大病临床表型和基因突变谱。方法与结果男性患者,41岁,发作性右侧肢体僵硬10年,表现为右侧痉挛性偏瘫步态、双侧锥体束征;头部MRI可见双侧延髓、延髓脑桥交界区和上颈髓呈长T_2信号影,双侧侧脑室旁白质轻度脱髓鞘;激素冲击治疗无效,抗癫药物部分有效。基因检测患者及其母存在胶质纤维酸性蛋白(GFAP)基因杂合性缺失突变[c.del1044～1079GTACCAGGACCTGCTCAATGTCAAGCTGGCCCTGGA(p.E348DdelY349～D360)],为新发突变。明确诊断为Ⅱ型亚历山大病,该家系证实为Ⅱ型亚历山大病家系。结论 GFAP基因缺失突变为新发突变,扩大了Ⅱ型亚历山大病的基因突变谱。同一家系中不同患者的临床表型差异较大。
Objective To report the clinical phenotype and genetic characteristics of an Alexander's disease type Ⅱ patient with unusual presentation, so as to extend phenotype and gene mutation spectrum of Alexander's disease type Ⅱ. Methods and Results A 41-year-old male patient suffered from paroxysmal right limb stiffness for 10 years, presenting with spastic hemiparesis on right side and bilateral pyramidal tract sign. Brain MRI showed long T_2 signal in bilateral medulla, bulbar-pontine junction and the upper cervical spinal cord, as well as mild demyelination in bilateral periventricular white matter. Steroid pulse therapy was invalid. Antiepileptic drugs(AEDs) were partially effective. Genetic analysis showed one heterozygous deletion of glial fibrillary acidic protein(GFAP) gene [c.del 1044-1079 GTACCAGGACCTGCTCAATGTCAAGCTGGCCCTGGA(p.E348 DdelY349-D360)] in the proband and his mother. This mutation has not been reported before. The patient was clearly diagnosed as Alexander's disease type Ⅱ, and his family was diagnosed as Alexander's disease type Ⅱ pedigree. Conclusions The novel mutation of GFAP gene expanded the gene mutation spectrum of Alexander's disease. The clinical phenotypes of family members may be variable even in the same family.
Objective To report the clinical phenotype and genetic characteristics of an Alexander's disease type Ⅱ patient with unusual presentation, so as to extend phenotype and gene mutation spectrum of Alexander's disease type Ⅱ. Methods and Results A 41-year-old male patient suffered from paroxysmal right limb stiffness for 10 years, presenting with spastic hemiparesis on right side and bilateral pyramidal tract sign. Brain MRI showed long T_2 signal in bilateral medulla, bulbar-pontine junction and the upper cervical spinal cord, as well as mild demyelination in bilateral periventricular white matter. Steroid pulse therapy was invalid. Antiepileptic drugs(AEDs) were partially effective. Genetic analysis showed one heterozygous deletion of glial fibrillary acidic protein(GFAP) gene [c.del 1044-1079 GTACCAGGACCTGCTCAATGTCAAGCTGGCCCTGGA(p.E348 DdelY349-D360)] in the proband and his mother. This mutation has not been reported before. The patient was clearly diagnosed as Alexander's disease type Ⅱ, and his family was diagnosed as Alexander's disease type Ⅱ pedigree. Conclusions The novel mutation of GFAP gene expanded the gene mutation spectrum of Alexander's disease. The clinical phenotypes of family members may be variable even in the same family.
引文
[1]Messing A,Brenner M,Feany MB,Nedergaard M,Goldman JE.Alexander disease[J].J Neurosci,2012,32:5017-5023.
[2]Prust M,Wang J,Morizono H,Brenner M,Gordon E,Hartka T,Sokohl A,Schiffmann R,Gordish-Dressman H,Albin R,Amartino H,Brockman K,Dinopoulos A,Dotti MT,Fain D,Fernandez R,Ferreira J,Fleming J,Gill D,Griebel M,Heilstedt H,Kaplan P,Lewis D,Nakagawa M,Pedersen R,Reddy A,Sawaishi Y,Schneider M,Sherr E,Takiyama Y,Wakabayashi K,Gorospe JR,Vanderver A.GFAP mutations,age of onset,and clinical subtypes in Alexander disease[J].Neurology,2011,77:1287-1294.
[3]Graff-Radford J,Schwartz K,Gavrilova RH,Lachance DH,Kumar N.Neuroimaging and clinical features in typeⅡ(lateonset)Alexander disease[J].Neurology,2014,82:49-56.
[4]Ban TT,Wu Y,Zhang SB,Zang LL,Wang JM,Jiang YW.Clinical research of 4 patients with typeⅡAlexander disease and literature review[J].Zhongguo Shi Yong Lin Chuang Er Ke Za Zhi,2016,31:700-704.[班婷婷,吴晔,张伸斌,臧莉莉,王静敏,姜玉武.亚历山大病Ⅱ型4例临床及文献复习[J].中国实用临床儿科杂志,2016,31:700-704.]
[5]Zang LL,Wu Y,Wang JM,Gu Q,Jiang YW,Gao ZJ,Yang YL,Xiao JX,Wu XR.Clinical and genetic study of twelve Chinese patients with Alexander disease[J].Zhonghua Er Ke Za Zhi,2012,50:371-375.[臧莉莉,吴晔,王静敏,顾强,姜玉武,高志杰,杨艳玲,肖江喜,吴希如.亚历山大病12例中国患儿临床及遗传学研究[J].中华儿科杂志,2012,50:371-375.]
[6]Liu YH,Zhou H,Wang HB,Gong XH,Zhou AN,Zhao L,Li XD,Zhang XH.MRI features in familial adult onset Alexander disease:case report[J].BMC Neurol,2016,16:211.
[7]Pareyson D,Fancellu R,Mariotti C,Romano S,Salmaggi A,Carella F,Girotti F,Gattellaro G,Carriero MR,Farina L,Ceccherini I,Savoiardo M.Adult-onset Alexander disease:a series of eleven unrelated cases with review of the literature[J].Brain,2008,131:2321-2331.
[8]Namekawa M,Takiyama Y,Honda J,Shimazaki H,Sakoe K,Nakano I.Adult-onset Alexander disease with typical"tadpole"brainstem atrophy and unusual bilateral basal ganglia involvement:a case report and review of the literature[J].BMCNeurol,2010,10:1-6.
[9]Chang KE,Pratt D,Mishra BB,Edwards N,Hallett M,RayChaudhury A.TypeⅡ(adult onset)Alexander disease in a paraplegic male with a rare D128N mutation in the GFAP gene[J].Clin Neuropathol,2015,34:298-301.
[10]Romano S,Salvetti M,Ceccherini I,De Simone T,Savoiardo M.Brainstem signs with progressing atrophy of medulla oblongata and upper cervical spinal cord[J].Lancet Neurol,2007,6:562-570.
[11]Waln O,Jankovic J.Paroxysmal movement disorders[J].Neurol Clin,2015,33:137-152.
[12]Kim JH,Kim DW,Kim JB,Suh SI,Koh SB.Thalamic involvement in paroxysmal kinesigenic dyskinesia:a combined structural and diffusion tensor MRI analysis[J].Hum Brain Mapp,2015,36:1429-1441.
[13]Ren J,Lei D,Yang T,An DM,Xiao FL,Huang XQ,Gong QY,Zhou D.Increased interhemispheric resting-state functional connectivity in paroxysmal kinesigenic dyskinesia:a restingstate fMRI study[J].J Neurol Sci,2015,351(1/2):93-98.
[14]Pop R,Kipfer S.Paroxysmal kinesigenic dyskinesia-like phenotype in multiple sclerosis[J].Mult Scler,2017,23:1795-1797.
[15]Zittel S,Bester M,Gerloff C,Münchau A,Leypoldt F.Symptomatic paroxysmal kinesigenic choreoathetosis as primary manifestation of multiple sclerosis[J].J Neurol,2012,259:557-558.
[16]Baguma M,Ossemann M.Paroxysmal kinesigenic dyskinesia as the presenting and only manifestation of multiple sclerosis after eighteen months follow up[J].J Mov Disord,2017,10:96-98.
[17]Xia XN,Dong Y,Ye CT,Ji M.A case of Alexander disease[J].Lin Chuang Fang She Xue Za Zhi,2016,35:1540-1541.[夏晓娜,董影,叶春涛,嵇鸣.亚历山大病一例[J].临床放射学杂志,2016,35:1540-1541.]
[18]Hartmann H,Herchenbach J,Stephani U,Ledaal P,Donnerstag F,Lücke T,Das AM,Christen HJ,Hagedorn M,Meins M.Novel mutations in exon 6 of the GFAP gene affect a highly conserved if motif in the rod domain 2B and are associated with early onset infantile Alexander disease[J].Neuropediatrics,2007,38:143-147.
[19]Quinlan RA,Brenner M,Goldman JE,Messing A.GFAP and its role in Alexander disease[J].Exp Cell Res,2007,313:2077-2087.
[2]Prust M,Wang J,Morizono H,Brenner M,Gordon E,Hartka T,Sokohl A,Schiffmann R,Gordish-Dressman H,Albin R,Amartino H,Brockman K,Dinopoulos A,Dotti MT,Fain D,Fernandez R,Ferreira J,Fleming J,Gill D,Griebel M,Heilstedt H,Kaplan P,Lewis D,Nakagawa M,Pedersen R,Reddy A,Sawaishi Y,Schneider M,Sherr E,Takiyama Y,Wakabayashi K,Gorospe JR,Vanderver A.GFAP mutations,age of onset,and clinical subtypes in Alexander disease[J].Neurology,2011,77:1287-1294.
[3]Graff-Radford J,Schwartz K,Gavrilova RH,Lachance DH,Kumar N.Neuroimaging and clinical features in typeⅡ(lateonset)Alexander disease[J].Neurology,2014,82:49-56.
[4]Ban TT,Wu Y,Zhang SB,Zang LL,Wang JM,Jiang YW.Clinical research of 4 patients with typeⅡAlexander disease and literature review[J].Zhongguo Shi Yong Lin Chuang Er Ke Za Zhi,2016,31:700-704.[班婷婷,吴晔,张伸斌,臧莉莉,王静敏,姜玉武.亚历山大病Ⅱ型4例临床及文献复习[J].中国实用临床儿科杂志,2016,31:700-704.]
[5]Zang LL,Wu Y,Wang JM,Gu Q,Jiang YW,Gao ZJ,Yang YL,Xiao JX,Wu XR.Clinical and genetic study of twelve Chinese patients with Alexander disease[J].Zhonghua Er Ke Za Zhi,2012,50:371-375.[臧莉莉,吴晔,王静敏,顾强,姜玉武,高志杰,杨艳玲,肖江喜,吴希如.亚历山大病12例中国患儿临床及遗传学研究[J].中华儿科杂志,2012,50:371-375.]
[6]Liu YH,Zhou H,Wang HB,Gong XH,Zhou AN,Zhao L,Li XD,Zhang XH.MRI features in familial adult onset Alexander disease:case report[J].BMC Neurol,2016,16:211.
[7]Pareyson D,Fancellu R,Mariotti C,Romano S,Salmaggi A,Carella F,Girotti F,Gattellaro G,Carriero MR,Farina L,Ceccherini I,Savoiardo M.Adult-onset Alexander disease:a series of eleven unrelated cases with review of the literature[J].Brain,2008,131:2321-2331.
[8]Namekawa M,Takiyama Y,Honda J,Shimazaki H,Sakoe K,Nakano I.Adult-onset Alexander disease with typical"tadpole"brainstem atrophy and unusual bilateral basal ganglia involvement:a case report and review of the literature[J].BMCNeurol,2010,10:1-6.
[9]Chang KE,Pratt D,Mishra BB,Edwards N,Hallett M,RayChaudhury A.TypeⅡ(adult onset)Alexander disease in a paraplegic male with a rare D128N mutation in the GFAP gene[J].Clin Neuropathol,2015,34:298-301.
[10]Romano S,Salvetti M,Ceccherini I,De Simone T,Savoiardo M.Brainstem signs with progressing atrophy of medulla oblongata and upper cervical spinal cord[J].Lancet Neurol,2007,6:562-570.
[11]Waln O,Jankovic J.Paroxysmal movement disorders[J].Neurol Clin,2015,33:137-152.
[12]Kim JH,Kim DW,Kim JB,Suh SI,Koh SB.Thalamic involvement in paroxysmal kinesigenic dyskinesia:a combined structural and diffusion tensor MRI analysis[J].Hum Brain Mapp,2015,36:1429-1441.
[13]Ren J,Lei D,Yang T,An DM,Xiao FL,Huang XQ,Gong QY,Zhou D.Increased interhemispheric resting-state functional connectivity in paroxysmal kinesigenic dyskinesia:a restingstate fMRI study[J].J Neurol Sci,2015,351(1/2):93-98.
[14]Pop R,Kipfer S.Paroxysmal kinesigenic dyskinesia-like phenotype in multiple sclerosis[J].Mult Scler,2017,23:1795-1797.
[15]Zittel S,Bester M,Gerloff C,Münchau A,Leypoldt F.Symptomatic paroxysmal kinesigenic choreoathetosis as primary manifestation of multiple sclerosis[J].J Neurol,2012,259:557-558.
[16]Baguma M,Ossemann M.Paroxysmal kinesigenic dyskinesia as the presenting and only manifestation of multiple sclerosis after eighteen months follow up[J].J Mov Disord,2017,10:96-98.
[17]Xia XN,Dong Y,Ye CT,Ji M.A case of Alexander disease[J].Lin Chuang Fang She Xue Za Zhi,2016,35:1540-1541.[夏晓娜,董影,叶春涛,嵇鸣.亚历山大病一例[J].临床放射学杂志,2016,35:1540-1541.]
[18]Hartmann H,Herchenbach J,Stephani U,Ledaal P,Donnerstag F,Lücke T,Das AM,Christen HJ,Hagedorn M,Meins M.Novel mutations in exon 6 of the GFAP gene affect a highly conserved if motif in the rod domain 2B and are associated with early onset infantile Alexander disease[J].Neuropediatrics,2007,38:143-147.
[19]Quinlan RA,Brenner M,Goldman JE,Messing A.GFAP and its role in Alexander disease[J].Exp Cell Res,2007,313:2077-2087.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |