ApoE基因多态性对低铜蓝蛋白血症相关性运动障碍临床表型影响的研究
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摘要
目的探讨低铜蓝蛋白血症相关性运动障碍(hypoceruloplasminemiarelatedmovement disorder,HCMD)人群中,ApoE基因多态性与其临床表现之间的关系。
方法2003年1月至2007年6月在上海中山医院神经内科门诊及病房就诊的运动障碍者均接受血清铜蓝蛋白(ceruloplasmin,CP)、总铜含量和24小时尿铜检测,若血清铜蓝蛋白小于实验室检查正常低限(0.20g几),并排除角膜K-F环阳性和其它相关疾患者拟诊为HCMD,入选为研究组,并按不同临床表现分为6个亚组,包括帕金森病样的强直少动症候群、单纯肢体震颤、变形性肌张力障碍症候群(扭转痉挛或痉挛性斜颈)、共济失调、多系统变性、抽动—秽语综合征症候群。以同期临床诊断为Wilson's病(WD)的病人作为病例对照组。选择年龄、性别与研究组无统计学差异的健康人群作为正常对照组。所有入组者均接受ApoE基因型检测,比较各组间临床表现、发病年龄、血铜蓝蛋白等方面的差异,研究ApoE基因多态性是否与HCMD人群的临床表现存在相关性。
结果血清铜蓝蛋白低于0.20g/l的患者共有29人,其中同期临床诊断WD者5人,HCMD组24人,同时检测血CP的正常对照组25人。HCMD组平均CP浓度为0.17±0.023 g/L,WD组平均CP浓度为0.055±0.029g/L,正常对照组平均CP浓度为0.291±0.049g/L,家族对照组平均CP浓度为0.197±0.058g/L。
HCMD组CP较WD组水平高(p＜0.05),较家族对照组低,较正常对照组低(p＜0.05);而家族对照组CP较正常对照组明显低(p＜0.05)。
HCMD组中,平均血清铜浓度为0.579±0.302μg/L,低于临床检验的正常低限(≤0.80μg/L),家族对照组平均血清铜浓度为0.485±0.228μg/L,低于临床检验的正常低限。HCMD组尿铜均值为297.47±226.44μg/24h,明显高于我们临床检验的正常高限(≤70μg/24h)。
HCMD组中,平均发病年龄为26.4±19.01岁,初发神经症状的年龄范围从5岁至68.5岁。其中男性22人(22/24),女性2人(2/24)。按临床表现分组,帕金森病样的强直-少动表现者5例、单纯肢体震颤者7例、变形性肌张力障碍者6例、共济失调者3例、多系统变性为主要表现者2例、抽动—秽语综合征为主要表现者1例。以帕金森样强直少动为主要表现者一般较单纯肢体震颤、共济失调组发病年龄晚(42.63±15.63岁),但与以变形性肌张力障碍症候群、多系统变性、抽动—秽语综合征为主要表现的各组发病年龄在统计学上无明显差异。
ApoE基因分型中,非ε3/3型在HCMD组中占11/24,对照组占7/25,WD组占4/5。HCMD、对照组、WD之间无明显统计学差异。ApoE基因型与HCMD表现型无明显统计学关联。等位基因ε3出现频率在HCMD组(30/48)和对照组(39/50)间无统计学差异,而ε3出现频率在WD组(4/10)较正常对照组显著降低(p＜0.05)。
结论HCMD表现复杂多样、男性多见、大多起病于50岁之前,其中以帕金森样强直少动为主要临床表现者起病较以其它临床表现为主要表现者晚。其有血缘的家属可无相关临床神经症状表现,但同样存在铜蓝蛋白较正常者低的表现,提示遗传因素在HCMD人群中有一定影响作用;HCMD临床表现与ApoE基因型、基因多态性无明显关联;WD患者中ε3出现频率较正常对照组低。
Objective:To investigate the effect of ApoE genotype on clinical phenotype of hypoceruloplasminemia-related movement disorder(HCMD) without Kayser-Fleischer rings.
Methods:From January of 2003 to June of 2007,all patients with movement disorder who enrolled in the out-patient and ward of Department of Neurology of Zhongshan Hospital,Fudan University were screened serum ceruloplasmin(CP) with immuno-nephelometry kit of N antiserum against human CP(Dade Behring,Marburg, Germany) using the described procedure.The patients screened with decreased CP were retested the content of serum CP and,if being confirmed,further investigated total serum copper and 24 hours urine copper with atomic absorption spectrophotometry(Z-8000 Atomic Absorption Spectrophotometer,Hitachi Corporation,Japan).
The patients with serum CP≤0.20g/L were further screened through inquiry of medical history,examination of slit lamp corneal microscope,experimental investigation,hepatic ultrasonography,and cranial CT and/or MR scanning.The patients were enrolled as HCMD when they sufficed the following exclusion criteria: Kayser-Fleischer(K-F) ring,hepatic disturbance,renal dysfunction,thyroid disease, parathyroid disease,severe anemia,severe malnutrition,hypoproteinemia,and associated known diseases of basal ganglia.All patients were also excluded possible MD and HA through the consultation discussion of two or more experienced senior neurologists,if necessary,according to both clinical features and experimental data.
We identified twenty-eight cases with HCMD and the five WD patients at the same term,which served as WD controls.
Twenty-five health volunteers(twenty men and five women) without relative connection and familial history of hereditary diseases were recruited from the students of Shanghai Medical College and served as normal controls.
Clinical feature,serum CP,serum copper,urine copper,and Apo E genotypes were investigated in the patients with HCMD and WD.Serum CP and Apo E genotypes were investigated in health control.
The results were showed as mean±SEM.Mann-Whitney U test or t test was used as the methods of statistical analysis.The level of significance was assumed to be 5%.
Results:Serum CP in HCMD group(0.17±0.023g/L) was lower than that of normal control group(0.291±0.049g/L,p＜0.05).Serum CP in HCMD group was higher than that of WD control group(0.055±0.029g/L,p＜0.05).Serum copper in HCMD group(0.579±0.302μg/L) is higher than that of normal level.Urine copper in HCMD group(297.47±226.44μg/24h) is lower than that of normal level.
The frequency of non-ε3/3 genotype of HCMD group(11/24) did not present significant decrease compared with that of normal group(7/25).The frequency of alleleε3 in HCMD group(30/48) did not manifest significant decrease compared with that of normal group(39/50).However,the frequency of alleleε3 in WD group was significantly between WD(4/10) group and normal group.
Conelusion:HCMD manifests complicated symptoms and attacks often before 50 years.ApoE genotype does not exert the influence on HCMD clinical phenotype.
方法2003年1月至2007年6月在上海中山医院神经内科门诊及病房就诊的运动障碍者均接受血清铜蓝蛋白(ceruloplasmin,CP)、总铜含量和24小时尿铜检测,若血清铜蓝蛋白小于实验室检查正常低限(0.20g几),并排除角膜K-F环阳性和其它相关疾患者拟诊为HCMD,入选为研究组,并按不同临床表现分为6个亚组,包括帕金森病样的强直少动症候群、单纯肢体震颤、变形性肌张力障碍症候群(扭转痉挛或痉挛性斜颈)、共济失调、多系统变性、抽动—秽语综合征症候群。以同期临床诊断为Wilson's病(WD)的病人作为病例对照组。选择年龄、性别与研究组无统计学差异的健康人群作为正常对照组。所有入组者均接受ApoE基因型检测,比较各组间临床表现、发病年龄、血铜蓝蛋白等方面的差异,研究ApoE基因多态性是否与HCMD人群的临床表现存在相关性。
结果血清铜蓝蛋白低于0.20g/l的患者共有29人,其中同期临床诊断WD者5人,HCMD组24人,同时检测血CP的正常对照组25人。HCMD组平均CP浓度为0.17±0.023 g/L,WD组平均CP浓度为0.055±0.029g/L,正常对照组平均CP浓度为0.291±0.049g/L,家族对照组平均CP浓度为0.197±0.058g/L。
HCMD组CP较WD组水平高(p＜0.05),较家族对照组低,较正常对照组低(p＜0.05);而家族对照组CP较正常对照组明显低(p＜0.05)。
HCMD组中,平均血清铜浓度为0.579±0.302μg/L,低于临床检验的正常低限(≤0.80μg/L),家族对照组平均血清铜浓度为0.485±0.228μg/L,低于临床检验的正常低限。HCMD组尿铜均值为297.47±226.44μg/24h,明显高于我们临床检验的正常高限(≤70μg/24h)。
HCMD组中,平均发病年龄为26.4±19.01岁,初发神经症状的年龄范围从5岁至68.5岁。其中男性22人(22/24),女性2人(2/24)。按临床表现分组,帕金森病样的强直-少动表现者5例、单纯肢体震颤者7例、变形性肌张力障碍者6例、共济失调者3例、多系统变性为主要表现者2例、抽动—秽语综合征为主要表现者1例。以帕金森样强直少动为主要表现者一般较单纯肢体震颤、共济失调组发病年龄晚(42.63±15.63岁),但与以变形性肌张力障碍症候群、多系统变性、抽动—秽语综合征为主要表现的各组发病年龄在统计学上无明显差异。
ApoE基因分型中,非ε3/3型在HCMD组中占11/24,对照组占7/25,WD组占4/5。HCMD、对照组、WD之间无明显统计学差异。ApoE基因型与HCMD表现型无明显统计学关联。等位基因ε3出现频率在HCMD组(30/48)和对照组(39/50)间无统计学差异,而ε3出现频率在WD组(4/10)较正常对照组显著降低(p＜0.05)。
结论HCMD表现复杂多样、男性多见、大多起病于50岁之前,其中以帕金森样强直少动为主要临床表现者起病较以其它临床表现为主要表现者晚。其有血缘的家属可无相关临床神经症状表现,但同样存在铜蓝蛋白较正常者低的表现,提示遗传因素在HCMD人群中有一定影响作用;HCMD临床表现与ApoE基因型、基因多态性无明显关联;WD患者中ε3出现频率较正常对照组低。
Objective:To investigate the effect of ApoE genotype on clinical phenotype of hypoceruloplasminemia-related movement disorder(HCMD) without Kayser-Fleischer rings.
Methods:From January of 2003 to June of 2007,all patients with movement disorder who enrolled in the out-patient and ward of Department of Neurology of Zhongshan Hospital,Fudan University were screened serum ceruloplasmin(CP) with immuno-nephelometry kit of N antiserum against human CP(Dade Behring,Marburg, Germany) using the described procedure.The patients screened with decreased CP were retested the content of serum CP and,if being confirmed,further investigated total serum copper and 24 hours urine copper with atomic absorption spectrophotometry(Z-8000 Atomic Absorption Spectrophotometer,Hitachi Corporation,Japan).
The patients with serum CP≤0.20g/L were further screened through inquiry of medical history,examination of slit lamp corneal microscope,experimental investigation,hepatic ultrasonography,and cranial CT and/or MR scanning.The patients were enrolled as HCMD when they sufficed the following exclusion criteria: Kayser-Fleischer(K-F) ring,hepatic disturbance,renal dysfunction,thyroid disease, parathyroid disease,severe anemia,severe malnutrition,hypoproteinemia,and associated known diseases of basal ganglia.All patients were also excluded possible MD and HA through the consultation discussion of two or more experienced senior neurologists,if necessary,according to both clinical features and experimental data.
We identified twenty-eight cases with HCMD and the five WD patients at the same term,which served as WD controls.
Twenty-five health volunteers(twenty men and five women) without relative connection and familial history of hereditary diseases were recruited from the students of Shanghai Medical College and served as normal controls.
Clinical feature,serum CP,serum copper,urine copper,and Apo E genotypes were investigated in the patients with HCMD and WD.Serum CP and Apo E genotypes were investigated in health control.
The results were showed as mean±SEM.Mann-Whitney U test or t test was used as the methods of statistical analysis.The level of significance was assumed to be 5%.
Results:Serum CP in HCMD group(0.17±0.023g/L) was lower than that of normal control group(0.291±0.049g/L,p＜0.05).Serum CP in HCMD group was higher than that of WD control group(0.055±0.029g/L,p＜0.05).Serum copper in HCMD group(0.579±0.302μg/L) is higher than that of normal level.Urine copper in HCMD group(297.47±226.44μg/24h) is lower than that of normal level.
The frequency of non-ε3/3 genotype of HCMD group(11/24) did not present significant decrease compared with that of normal group(7/25).The frequency of alleleε3 in HCMD group(30/48) did not manifest significant decrease compared with that of normal group(39/50).However,the frequency of alleleε3 in WD group was significantly between WD(4/10) group and normal group.
Conelusion:HCMD manifests complicated symptoms and attacks often before 50 years.ApoE genotype does not exert the influence on HCMD clinical phenotype.
引文
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[13]周常文,徐江涛,桂俊豪等.载脂蛋白E基因多态性和帕金森病的相关性.癌变,畸变,突变,2004,16:21-23.
[14]Zareparsi S,Camicioli R,Sexton G,et al.Age at onset of Parkinson disease and apolipoprotein E genotypes.Am J Med Genet,2002,107:156-161.
[15]Lopez M,Guerrero J,Yescas P,et al.Apolipoprotein E epsilon4 allele is associated with Parkinson disease risk in a Mexican Mestizo population.Mov Disord,2007, 22:417-420.
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