慢性肌酸磷酸激酶升高患儿的临床分析暨幼年起病的晚发型Pompe病临床和基因分析
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摘要
背景和目的
因血清肌酶谱升高而就诊的患儿在临床中并不少见。肌酶谱包括肌酸磷酸激酶(CK)、天门冬氨酸氨基转移酶(AST)、乳酸脱氢酶(LDH)和α羟丁酸脱氢酶HBDH。其中CK主要存在于骨骼肌、心肌和脑细胞的胞浆中,少量存在于线粒体中;而AST、LDH、HBDH等除肌肉组织外还存在于肝脏、肾脏、红细胞等其他组织中。CK是可逆催化ATP和肌酸之间高能磷酸转移的转移酶,血清中的CK 95%以上来源于骨骼肌,因此血清CK的升高对于提示肌肉组织病变最为特异。骨骼肌是机体执行运动和能量代谢的重要器官,肌肉病变在成人中患病率约为1%,但由于不少患者没有及时就诊或被误诊误治,真正的患病率要远远超过这个比例。临床上,与CK增高相关的疾病较多,肌源性、脑源性、代谢性、肿瘤性疾病等需要排除;血清CK升高还可见于许多生理和病理情况,如剧烈运动、感染、药物、中毒、内分泌疾病等。在儿童患者,急性CK升高常与心肌炎、肌炎等感染、免疫性疾病相联系;而慢性持续的CK升高,病因比较复杂:可见于免疫炎症性疾病、遗传代谢性疾病以及一些无症状患儿中,诊断不明确,误诊率高,如何建立一个相对科学的诊断流程,已成为困扰临床医生的一个难题;有些疾病只要及时发现,早期治疗,完全可以治愈;有些及时诊断,早期给予适当的治疗则可改善症状,防止肌肉萎缩等并发症的发生,因此明确持续血清肌酸磷酸激酶升高的儿童患者的病因诊断对治疗和判断预后有非常重要的意义。
方法
对2005年1月-2007年3月,从协和医院遗传门诊入院的肌酸磷酸激酶持续升高超过3月患儿的临床资料,实验室检查,肌肉活检组织病理资料,酶生化检测及活性测定,基因分析等进行回顾性分析,明确持续血清肌酸磷酸激酶升高的儿童患者的病因诊断,希望对今后建立一个合理的诊断流程提供参考。
结果
25例患儿,男18例,女7例。年龄从2岁9月-15岁,平均年龄7.8岁。病程3个月-7年。CK值在285 U/L-15720 U/L(18-198U/L)。25例患儿均进行了开放性肌肉活检病理检查,6例进行了皮肤成纤维细胞内溶酶体酸性葡萄糖苷酶活性测定,12例进行了基因分析。病因诊断:16例患儿获得诊断,确诊率64%,诊断分别为:7例dystrophin相关肌营养不良症,1例携带者;2例Pompe病,1例糖原累积症Ⅲ型;1例线粒体肌病,1例戊二酸尿症Ⅱ型,2例炎症性肌肉病,1例脊肌萎缩症。其余9例未能明确诊断。
结论
血清肌酸磷酸激酶持续增高对儿童期患者多提示神经肌肉疾病或累及肌肉的代谢性疾病,病因复杂,除常规生化检查外,肌电图、肌活检、酶活性测定、基因检测等多种检查的综合应用有助于提高诊断率。
背景和目的
糖原累积症Ⅱ型(Pompe病)是一种常染色体隐性遗传病,其代谢基础为溶酶体内α-1,4-葡萄糖苷酶的缺陷,糖原不能被分解,正常结构的糖原堆积在溶酶体和胞质中,造成溶酶体的增生和破坏,相应的脏器结构和功能损害。临床根据发病年龄、主要累及的脏器、进展速度的不同分为早发型和晚发型,早发型又称为经典型,多于生后不久-婴儿期即发病,糖原在心脏、骨骼肌、平滑肌、肾小管上皮,中枢神经系统等全身组织中广泛沉积,多于1-2岁之内死于心脏功能衰竭,或循环合并呼吸衰竭。晚发型在幼年期或成人期起病,以骨骼肌受累为主,表现四肢无力,进展较慢,但呼吸肌受累可合并呼吸功能不全。已证实Pompe病为其基因GAA的突变引起,该基因已被克隆,定位于17q25,全长约20kb,包含20个外显子(其中第一号外显子不翻译),目前国外已发现突变类型100多种,在台湾,婴儿型Pompe病是最为常见的糖原累积病。Pompe病在中国大陆地区从围生期到成人期都有临床病例报道,但对此致病基因及其突变的研究尚少,本研究主要对中国大陆地区幼年起病的晚发型糖原累积症Ⅱ型(Pompe病)患者进行临床和基因突变分析。
方法
对2例经酶学确诊的幼年型Pompe病人(男,2岁9月;女,9岁)进行临床分析,包括实验室生化检测、肌电图、肌活检病理等,提取患儿皮肤成纤维细胞及其父母的外周血DNA,应用聚合酶链反应(PCR)扩增α-1,4-葡萄糖苷酶的19个编码外显子,测序,进行突变检测。同时对50例健康对照100个等位基因进行15号外显子的PCR扩增,测序,确定突变特征。
结果
2例病人临床资料:1例表现进行性近端肌肉无力,肌张力低下,1例表现肌容积减少,血清肌酶升高,合并呼吸肌受累,肺功能检查显示限制性通气障碍,随访15月时因肺部感染诱发死亡。2例均有肌酸激酶升高;肌电图提示肌源性损害;肌活检呈空泡性改变、糖原沉积;皮肤成纤维细胞α-1,4-葡萄糖苷酶活性测定明显低下(0.5-2.7nmol/小时/mg蛋白)。突变检测:在编码区未发现缺失,插入,无义突变等突变类型,测序发现4个杂合错义突变,例1患儿为c796C＞T,p.Pro266Ser;c2105 G＞A,p.Arg702His;例2患儿为c2132 C＞G,p.Thr711Arg;c2167 G＞A,p.Va1723Met。其中后3个为新突变,50例健康对照100个等位基因测序未发现同样突变。
结论
1) 2例幼年起病的晚发型Pompe病患儿在临床表现上存在差异性:可以肌无力为突出表现,或以肌容积减少,肌肉萎缩为主诉,而无力症状轻微。可合并呼吸肌受累。心脏改变不明显。
2)实验室检查:血清CK轻度升高,肌活检病理呈空泡样糖原沉积,皮肤成纤维细胞中α-1,4-葡萄糖苷酶活性明显低下。
3)幼年起病的晚发型Pompe病预后与病程长短,有无呼吸肌受累相关。
4) 2例幼年起病的晚发型Pompe病患儿均在GAA基因发现有突变存在,突变类型为杂合错义突变,未发现插入、缺失、剪切和无义突变类型。
5) 4个复合杂合错义突变中:c796 C＞T,p Pro266Ser突变,仅见丁韩国的晚发型病人,在其他人种中未见报道;3个新发现突变,c2105 G＞A,p.Arg702His;c2132 C＞G,p.Thr711Arg;c2167G＞A,p.Val723Met,位于15号外显子上,为致病突变可能性大。
objective Elevation of serum creatine kinase(CK)levels are related to a variety of diseases including muscle injury,infections,toxins,endocrine diseases,etal.,but persistently increased serum CK levels were considered a hallmark of neuromuscular disease.Different causes have different treatment and prognosis.The aim of our study is to establish the diagnosis of juvenile patients with chronic elevation of serum creatine kinase(CK) levels.Methods We made a retrospective evaluation of 25 juvenile patients with hyperCKemia over three months in the genetic clinic of our department between January 2005 and March 2007.Clinical data,neurological examination and laboratory examinations were analysized.All the patients underwent open muscle biopsy.Biochemical and genetic investigation were added in selected cases.Results There were 7 females and 18 males aged between 2 year 9 month and 15 years [mean 7.8y].The disease duration were beween 3 months and 7 years. Serum CK leverls were between 285 and 15720 U/L(18-198).We made a diagnosis in 16 patients.The diagnosis included dystrophinopathies in 8 patients;Pompe disease in 2 patients;glycogenosis typeⅢin 1 patient;mitochondrial myopathies in 1 patient;glutaric aciduria typeⅡin 1 patient;spinal muscular atrophy in 1 patients;inflammatory myopathies in 2 patients.Diagnosis were not able to confirm in 9 patients, pathological but not conclusive muscle changes were found in 5 patients. Conclusion Neurological and metabolic myopathies disease were the main causes of pesistent hyperckemia in children,muscle biopsy as well as biochemical and genetic investigations were essential to the diagnosis.
Backgrounds and Objective
Glycogen-storage disease typeⅡ(GSDⅡ,Pompe's disease) is an autosomal recessive disorder caused by a functional deficiency of acid alpha-glucosidase(GAA) that leads to glycogen accumulation within lysosomes in most tissues.The GAA gene is located to human chromosome 17q25 and contains 20 exons,19 of which are coding, Clinically,patients with the severe infantile form of GSDⅡhave muscle weakness and cardiomyopathy eventually leading to death before the age of two years.Patients with the juvenile or the adult form of GSDⅡpresent with myopathy with a slow progression over several years or decades,symptoms may start at any age and are related to progressive dysfunction of skeletal muscles.With disease progression,patients become confined to wheelchairs and require artificial ventilation. Respiratory failure is the cause of significant morbidity and mortality in this form of disease.The age of death varies from early childhood to late adulthood,depending on the rate of disease progression and the extent of respiratory muscle involvement.A broad genetic heterogeneity has been described in GSDⅡin Europe,South Africa,USA,Japan and Korea, hower,the investigation has not been performed in the patients from the mainland of China.In this study,clinical analysis and mutations detection were done on Chinese patients.
Methods
Two unrelated juvenile patients with late onset GSDⅡ(one boy,3 year old and one girl,9 year old)were included in the study with the informed consents.The diagnosis was confirmed byα-glucosidase determination in cultured fibroblasts.In addition,their clinical presentation,laboratory findings,electrophysiologic studies and muscle biopsy findings were analyzed in detail.Genomic DNA samples were extracted from fibroblasts of the probands,Genomic DNA samples were extracted from peripheral bloods of their parents and 50 unrelated,normal individuals.All the coding 19 exons and exon-intron boundaries of GAA were detected in the proband by polymerase chain reaction(PCR),direct sequencing.
Results
one patient presented decrease of muscle strength,limb-girdle hypotonia,the other patient presented reduced size of muscle volumes and respiratory problems.Both had increased serum creatinine phosphokinase(CPK) value,myopathic pattern on EMG;vacuoles on muscle biopsy,and deficiency of 1,4-alpha-glucosidase activity.After 1 year follow up,the girl died after pneumonia at 10 year old.One patient was found to be compound heretozygote for the novel mutation Arg702His,and Pro266Ser,previously reported in korean population, with the late-onset phenotype.Two novel missense mutations Thr711Arg, Va1723Met were found on the other patients.As for three new mutations, we were not able to observe the same changes among 100 control chromosomes.
Conclusions
The two cases of juvenile Pompe patients in our study had different characters in the clinical,the involvement of respiratory muscle seems a pronostic factor.We did not find the most commont mutation in the late-onset patients in the white people,and the most prevalent mutation Asp654Glu in the infantile form found in Taiwan district of China were not detected in our patients.The three mutations identified in the patients were new missense mutations causing late onset GSDⅡ,which had not been reported elsewhere before.There is currently no treatment other than supportive care for Pompe disease.With enzyme replacement therapy likely to become available in the near future and other therapies on the horizon,early disease recognition is increasingly important so the patients can receive prompt and appropriate therapy.
因血清肌酶谱升高而就诊的患儿在临床中并不少见。肌酶谱包括肌酸磷酸激酶(CK)、天门冬氨酸氨基转移酶(AST)、乳酸脱氢酶(LDH)和α羟丁酸脱氢酶HBDH。其中CK主要存在于骨骼肌、心肌和脑细胞的胞浆中,少量存在于线粒体中;而AST、LDH、HBDH等除肌肉组织外还存在于肝脏、肾脏、红细胞等其他组织中。CK是可逆催化ATP和肌酸之间高能磷酸转移的转移酶,血清中的CK 95%以上来源于骨骼肌,因此血清CK的升高对于提示肌肉组织病变最为特异。骨骼肌是机体执行运动和能量代谢的重要器官,肌肉病变在成人中患病率约为1%,但由于不少患者没有及时就诊或被误诊误治,真正的患病率要远远超过这个比例。临床上,与CK增高相关的疾病较多,肌源性、脑源性、代谢性、肿瘤性疾病等需要排除;血清CK升高还可见于许多生理和病理情况,如剧烈运动、感染、药物、中毒、内分泌疾病等。在儿童患者,急性CK升高常与心肌炎、肌炎等感染、免疫性疾病相联系;而慢性持续的CK升高,病因比较复杂:可见于免疫炎症性疾病、遗传代谢性疾病以及一些无症状患儿中,诊断不明确,误诊率高,如何建立一个相对科学的诊断流程,已成为困扰临床医生的一个难题;有些疾病只要及时发现,早期治疗,完全可以治愈;有些及时诊断,早期给予适当的治疗则可改善症状,防止肌肉萎缩等并发症的发生,因此明确持续血清肌酸磷酸激酶升高的儿童患者的病因诊断对治疗和判断预后有非常重要的意义。
方法
对2005年1月-2007年3月,从协和医院遗传门诊入院的肌酸磷酸激酶持续升高超过3月患儿的临床资料,实验室检查,肌肉活检组织病理资料,酶生化检测及活性测定,基因分析等进行回顾性分析,明确持续血清肌酸磷酸激酶升高的儿童患者的病因诊断,希望对今后建立一个合理的诊断流程提供参考。
结果
25例患儿,男18例,女7例。年龄从2岁9月-15岁,平均年龄7.8岁。病程3个月-7年。CK值在285 U/L-15720 U/L(18-198U/L)。25例患儿均进行了开放性肌肉活检病理检查,6例进行了皮肤成纤维细胞内溶酶体酸性葡萄糖苷酶活性测定,12例进行了基因分析。病因诊断:16例患儿获得诊断,确诊率64%,诊断分别为:7例dystrophin相关肌营养不良症,1例携带者;2例Pompe病,1例糖原累积症Ⅲ型;1例线粒体肌病,1例戊二酸尿症Ⅱ型,2例炎症性肌肉病,1例脊肌萎缩症。其余9例未能明确诊断。
结论
血清肌酸磷酸激酶持续增高对儿童期患者多提示神经肌肉疾病或累及肌肉的代谢性疾病,病因复杂,除常规生化检查外,肌电图、肌活检、酶活性测定、基因检测等多种检查的综合应用有助于提高诊断率。
背景和目的
糖原累积症Ⅱ型(Pompe病)是一种常染色体隐性遗传病,其代谢基础为溶酶体内α-1,4-葡萄糖苷酶的缺陷,糖原不能被分解,正常结构的糖原堆积在溶酶体和胞质中,造成溶酶体的增生和破坏,相应的脏器结构和功能损害。临床根据发病年龄、主要累及的脏器、进展速度的不同分为早发型和晚发型,早发型又称为经典型,多于生后不久-婴儿期即发病,糖原在心脏、骨骼肌、平滑肌、肾小管上皮,中枢神经系统等全身组织中广泛沉积,多于1-2岁之内死于心脏功能衰竭,或循环合并呼吸衰竭。晚发型在幼年期或成人期起病,以骨骼肌受累为主,表现四肢无力,进展较慢,但呼吸肌受累可合并呼吸功能不全。已证实Pompe病为其基因GAA的突变引起,该基因已被克隆,定位于17q25,全长约20kb,包含20个外显子(其中第一号外显子不翻译),目前国外已发现突变类型100多种,在台湾,婴儿型Pompe病是最为常见的糖原累积病。Pompe病在中国大陆地区从围生期到成人期都有临床病例报道,但对此致病基因及其突变的研究尚少,本研究主要对中国大陆地区幼年起病的晚发型糖原累积症Ⅱ型(Pompe病)患者进行临床和基因突变分析。
方法
对2例经酶学确诊的幼年型Pompe病人(男,2岁9月;女,9岁)进行临床分析,包括实验室生化检测、肌电图、肌活检病理等,提取患儿皮肤成纤维细胞及其父母的外周血DNA,应用聚合酶链反应(PCR)扩增α-1,4-葡萄糖苷酶的19个编码外显子,测序,进行突变检测。同时对50例健康对照100个等位基因进行15号外显子的PCR扩增,测序,确定突变特征。
结果
2例病人临床资料:1例表现进行性近端肌肉无力,肌张力低下,1例表现肌容积减少,血清肌酶升高,合并呼吸肌受累,肺功能检查显示限制性通气障碍,随访15月时因肺部感染诱发死亡。2例均有肌酸激酶升高;肌电图提示肌源性损害;肌活检呈空泡性改变、糖原沉积;皮肤成纤维细胞α-1,4-葡萄糖苷酶活性测定明显低下(0.5-2.7nmol/小时/mg蛋白)。突变检测:在编码区未发现缺失,插入,无义突变等突变类型,测序发现4个杂合错义突变,例1患儿为c796C＞T,p.Pro266Ser;c2105 G＞A,p.Arg702His;例2患儿为c2132 C＞G,p.Thr711Arg;c2167 G＞A,p.Va1723Met。其中后3个为新突变,50例健康对照100个等位基因测序未发现同样突变。
结论
1) 2例幼年起病的晚发型Pompe病患儿在临床表现上存在差异性:可以肌无力为突出表现,或以肌容积减少,肌肉萎缩为主诉,而无力症状轻微。可合并呼吸肌受累。心脏改变不明显。
2)实验室检查:血清CK轻度升高,肌活检病理呈空泡样糖原沉积,皮肤成纤维细胞中α-1,4-葡萄糖苷酶活性明显低下。
3)幼年起病的晚发型Pompe病预后与病程长短,有无呼吸肌受累相关。
4) 2例幼年起病的晚发型Pompe病患儿均在GAA基因发现有突变存在,突变类型为杂合错义突变,未发现插入、缺失、剪切和无义突变类型。
5) 4个复合杂合错义突变中:c796 C＞T,p Pro266Ser突变,仅见丁韩国的晚发型病人,在其他人种中未见报道;3个新发现突变,c2105 G＞A,p.Arg702His;c2132 C＞G,p.Thr711Arg;c2167G＞A,p.Val723Met,位于15号外显子上,为致病突变可能性大。
objective Elevation of serum creatine kinase(CK)levels are related to a variety of diseases including muscle injury,infections,toxins,endocrine diseases,etal.,but persistently increased serum CK levels were considered a hallmark of neuromuscular disease.Different causes have different treatment and prognosis.The aim of our study is to establish the diagnosis of juvenile patients with chronic elevation of serum creatine kinase(CK) levels.Methods We made a retrospective evaluation of 25 juvenile patients with hyperCKemia over three months in the genetic clinic of our department between January 2005 and March 2007.Clinical data,neurological examination and laboratory examinations were analysized.All the patients underwent open muscle biopsy.Biochemical and genetic investigation were added in selected cases.Results There were 7 females and 18 males aged between 2 year 9 month and 15 years [mean 7.8y].The disease duration were beween 3 months and 7 years. Serum CK leverls were between 285 and 15720 U/L(18-198).We made a diagnosis in 16 patients.The diagnosis included dystrophinopathies in 8 patients;Pompe disease in 2 patients;glycogenosis typeⅢin 1 patient;mitochondrial myopathies in 1 patient;glutaric aciduria typeⅡin 1 patient;spinal muscular atrophy in 1 patients;inflammatory myopathies in 2 patients.Diagnosis were not able to confirm in 9 patients, pathological but not conclusive muscle changes were found in 5 patients. Conclusion Neurological and metabolic myopathies disease were the main causes of pesistent hyperckemia in children,muscle biopsy as well as biochemical and genetic investigations were essential to the diagnosis.
Backgrounds and Objective
Glycogen-storage disease typeⅡ(GSDⅡ,Pompe's disease) is an autosomal recessive disorder caused by a functional deficiency of acid alpha-glucosidase(GAA) that leads to glycogen accumulation within lysosomes in most tissues.The GAA gene is located to human chromosome 17q25 and contains 20 exons,19 of which are coding, Clinically,patients with the severe infantile form of GSDⅡhave muscle weakness and cardiomyopathy eventually leading to death before the age of two years.Patients with the juvenile or the adult form of GSDⅡpresent with myopathy with a slow progression over several years or decades,symptoms may start at any age and are related to progressive dysfunction of skeletal muscles.With disease progression,patients become confined to wheelchairs and require artificial ventilation. Respiratory failure is the cause of significant morbidity and mortality in this form of disease.The age of death varies from early childhood to late adulthood,depending on the rate of disease progression and the extent of respiratory muscle involvement.A broad genetic heterogeneity has been described in GSDⅡin Europe,South Africa,USA,Japan and Korea, hower,the investigation has not been performed in the patients from the mainland of China.In this study,clinical analysis and mutations detection were done on Chinese patients.
Methods
Two unrelated juvenile patients with late onset GSDⅡ(one boy,3 year old and one girl,9 year old)were included in the study with the informed consents.The diagnosis was confirmed byα-glucosidase determination in cultured fibroblasts.In addition,their clinical presentation,laboratory findings,electrophysiologic studies and muscle biopsy findings were analyzed in detail.Genomic DNA samples were extracted from fibroblasts of the probands,Genomic DNA samples were extracted from peripheral bloods of their parents and 50 unrelated,normal individuals.All the coding 19 exons and exon-intron boundaries of GAA were detected in the proband by polymerase chain reaction(PCR),direct sequencing.
Results
one patient presented decrease of muscle strength,limb-girdle hypotonia,the other patient presented reduced size of muscle volumes and respiratory problems.Both had increased serum creatinine phosphokinase(CPK) value,myopathic pattern on EMG;vacuoles on muscle biopsy,and deficiency of 1,4-alpha-glucosidase activity.After 1 year follow up,the girl died after pneumonia at 10 year old.One patient was found to be compound heretozygote for the novel mutation Arg702His,and Pro266Ser,previously reported in korean population, with the late-onset phenotype.Two novel missense mutations Thr711Arg, Va1723Met were found on the other patients.As for three new mutations, we were not able to observe the same changes among 100 control chromosomes.
Conclusions
The two cases of juvenile Pompe patients in our study had different characters in the clinical,the involvement of respiratory muscle seems a pronostic factor.We did not find the most commont mutation in the late-onset patients in the white people,and the most prevalent mutation Asp654Glu in the infantile form found in Taiwan district of China were not detected in our patients.The three mutations identified in the patients were new missense mutations causing late onset GSDⅡ,which had not been reported elsewhere before.There is currently no treatment other than supportive care for Pompe disease.With enzyme replacement therapy likely to become available in the near future and other therapies on the horizon,early disease recognition is increasingly important so the patients can receive prompt and appropriate therapy.
引文
1.Chamberlain JS,Gbbs RA,Ranien JE,et al.Deletion screening of the Duchenne musclular dystrophy locus via multiplex DNA amplication.Nucleic Acids Res.1988,16(23):11141-11156
2.Beggs AH,Koening M,Boyce FM,et al.Detection of 98%of DMD/BMD gene deletions by polymerase chain reaction.Hum Genet 1990,86(1):45-48
3.Smard LR,Rochette C,Semionov H,et al.SMN-t and NAIP mutatioins in Canadian families with spinal muscular atrophy(SMA):genotype/phenotype correlations with disease severity.Am J Med Genet 1997;72(1):51-58
4.马素参,袁丽芳,刘天慈等。进行性脊髓性肌肉萎缩症患者神经元存活基因及神经元凋亡抑制蛋白基因的缺失。中国医学科学院学报,2000;22(6):551-554
5.Koenig M.;Monaco A.P.;Kunkel L.M.:The complete sequence ofdystrophin predicts a rod-shaped cytoskeletal protein.Cell 1988;53:219-228.
6.Tennyson C.N.;Klamut H.J.;Worton R.G.The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced.Nature Genet.1995;9:184-190.
7.Bies R.D.;Caskey C.T.;Fenwick,R..An intact cysteine-rich domain is required for dystrophin function.J.Clin.Invest.1992;90:666-672.
8.Worton R.G.Dystrophin:the long and short of it.(Editorial) J.Clin.Invest.1994;93:4.
9.Moser H.Duchene muscular dystrophy:pathogenetic aspects and genetic prevention.Hum Genet,1984;66(1):17-40
10.Davies K.E.;Smith T.J.;Bundey S,et al.Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome.J.Med.Genet.1988;25:9-13.
11.Monaco A.P.;Bertelson C.J.;Liechti-Gallati S,et al.An explanation for phenotypic differences between patients beating partial deletions of DMD locus.Genomics 1988;2:90-95.
12.Nigro G,Comi L,Limongelli F.M.,etal.Prospective study of X-linked progressive muscular dystrophy in Campania.Muscle.Nerve.1983;6:253-262
13.Werneck L C,Scola R H,Maegawa GHB,et al.Comparative analysis of PCR-detection and immunohistochemistry in Brazilian Duchenne and Becker muscular dystrophy patients.Am J Med Gene,2001;103,105-120
14.陈琳,郭玉璞,邹丽萍等,DMD患者骨骼肌抗肌萎缩蛋白表达与临床病理改变。基础医学与临床,2005;25(11):1049-1052
15.Haslett J N,Sanoudou D,Kho A T.et al.Gene expression comparison of biopsies from Duchene muscular dystrophy(DMD) and normal skeletal muscle.Proc Nat Acad Sci 2002;15000-15005
16.Noguchi S,Tsukahara T,Fujita M,et al.cDNA microarray analysis of individual Duchene muscular dystrophy patients.Hum Molec Gemet 2003;12:595-600
17.Raben N,Plotz P,Byrue BJ.Acid alpha- glucosidase deficiency(glyco-genosis type Ⅱ,Pompe disease).Curr Mol Med 2002;2:145-166
18.Van den Hout J.M.P.,Kamphoven J.H.J.,Winkel L.P.F.,et al.Long-Term Intravenous Treatment of Pompe's Disease With Recombinant Human Alpha Glucosidase From Milk.Pediatrics 2004;13:e448-e457
19.Winkel L.P.F.,Van den Hout J.M.P.,Kamphoven J.H.J.,et al.Enzyme replacement therapy in late-onset Pompe's disease:a three-year follow up.Annals of Neurology;2004;55:495-502
20.Momoi,T.;Sano,H.;Yamanaka,C.;Sasaki,H.;Mikawa,H.:Glycogen storage disease type Ⅲ with muscle involvement:reappraisal of phenotypic variability and prognosis.Am.J.Med.Genet.1992;42:696-699.
21.杨艳玲,木村正彦,袁云等,戊二酸尿症Ⅱ型所致脂肪沉积性肌肉病的诊断与治疗分析。中华神经科学杂志,2004;37(5):438-441
22.Alessandro P,Lucia T,Monica S,et al.Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels.J Neurol.2002;249(3):305-311
1. Raben N, Plotz P, Byrue BJ. Acid alpha- glucosidase deficiency (glyco-genosis type II,Pompe disease). Curr Mol Med, 2002, 2: 145-166
2. Hoefsloot LH, Hoogeveen-Westerveld M, Reuser AJ, et al. Characterization of the human lysosomal alpha-glucosidase gene. Biochem J ,1990a, 272: 493-497
3. Martiniuk F, Bodkin M, Tzall S, et al. Isolation and partial characterazation of the structural gene for human acid alpha glucosidase. DNA Cell Biol, 1991, 10: 283-292
4. Hoefsloot LH, Willemsen R, Kroos MA, et al. Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalinan cells. Biochem J,1990b, 272: 485492
5. Moreland RJ, Jin X, Zhang XK, et al. Lysosomal acid alpha glucosidase consists of four different peptides processed from a single chain precusor. J Biol Chem , 2005, 280:6780-6791
6. Family 31 glycosyl hydrolases : www. expasy.ch/cgi.bin/list
7. http://www.hgmd.cf.ac.uk/ac/gene.php? gene=GAA
8. Hermans MM, van Leenen D, Kroos MA, et al. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat 2004, 23: 47-56
9. Montalvo ALE, Bembi B, Donnarumma M, et al. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat, 2006, 27:999-1006
10. Ko TM, Hwu WL, Lin YW, et al. Molecular genetic study of Pompe disease in Chinese patients in Taiwan. Hum Mutat 1999, 13: 380-384
11. Momoi T, Sano H, Yamanaka C, et al. Glycogen storage disease type III with muscle involvement: reappraisal of phenotypic variability and prognosis. Am. J. Med. Genet, 1992,42: 696-699.
12. Laforet P, Nicolino M, Erymard B, et al. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 2000, 55: 1122-8
13. Mellies U, Ragette R, Schwake C, et al. Sleep-disordered breathing and respiratory failure in acid maltase deficiency. Neurology, 2001, 57: 1290-1295
14. Kroos MA, Waitfield AE, Joosse M, et al. A novel acid alpha-glucosidase mutation identified in a Pakistani family with glycogen storage disease type II. J Inherit Metab Dis.1997,20:556-8.
15. Pittis MG, Montalvo AL, Miocic S, et al. Identification of four novel mutations in the alpha glucosidase gene in five Italian patients with infantile onset glycogen storage disease type II. Am JMed Genet A. 2003, 121:225-30.
16. Hermans MMP, Kroos MA, van Beeumen J, et al. Human lysosomal alpha-glucosidase :characterization of the catalytic site. J Biol Chem. 1991, 266: 13507-13512
17. Park YE, Park KH, Lee CH, et al. Two new missense mutations of GAA in late onset glycogen storage disease type II. J Neurosciences , 2006, 251: 113-117.
18. Huie ML, Chen AS, Tsujino S, et al. Aberrant splicing in adult onset glycogen storage type 11(GSD II): molecular identification of an IVS 1(-13T-G) mutation in a majority of patients and a novel IVS 10(+lGT-CT) mutation. Hum Mol Genet 1994, 3: 2231-6
19. Taiwan , Shieh JJ, Lin CY. Frequent mutation in Chinese patients with infantile types of GSD II in Taiwan: evidence for a founder effect. Hum Mutat 1998; 11:306-l 2
20. Van den Hout JM., Kamphoven JH, Winkel LP, et al. Long-Term Intravenous Treatment of Pompe's Disease With Recombinant Human Alpha Glucosidase From Milk. Pediatrics,2004, 113:e448-e457.
21. Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow up. Ann Neurol, 2004,55:495-502.
1. Hers HG Alpha-glucisidase deficiency in generalized glycogen storage disease(Pompe's disease). Biochen J 1963: 86: 11-6
2. Hoefsloot LH, Hoogeveen-Westerveld M, Reuser AJ, et al. Characterization of the human lysosomal alpha-glucosidase gene. Biochem J ,1990a, 272: 493-497
3. Martiniuk F, Bodkin M, Tzall S, et al. Isolation and partial characterazation of the structural gene for human acid alpha glucosidase. DNA Cell Biol, 1991, 10:283-292
4. Hoefsloot LH, Willemsen R, Kroos MA, et al. Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalinan cells.Biochem J, 1990b, 272: 485-492
5. Moreland RJ, Jin X, Zhang XK, et al. Lysosomal acid alpha glucosidase consists of four different peptides processed from a single chain precusor. J Biol Chem ,2005, 280:6780-6791
6. Henrissat B: glycosidase families .Biochem Soc Trans 26: 153, 1998
7. Hannerieke M. P. van den Hout, Wim Hop, et al. The Natural Course of Infantile Pompe's Disease: 20 Original Cases Compared With 133 Cases From the Literature. PEDIATRICS Vol. 112 No. 2 August 2003, pp. 332-340
8. Kishnani,-P-S; Hwu,-W-L; Mandel,-H; et al. A retrospective, multinational,multicenter study on the natural history of infantile-onset Pompe disease.J-Pediatr. 2006 May; 148(5): 671-676
9. Hagemans,-M-L; Winkel,-L-P; Van-Doorn,-P-A; et al. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain. 2005 Mar; 128(Pt 3): 671-7
10. Winkel LPE, Hagemans,-M-L, Van der Van-Doorn,-P-A; et al. The natural course of non-classic Pompe's disease; a review of 225 published cases. J neurol 2005;252: 875-884
11. Umapathysivam K, Hopwood JJ, Meikle PJ, Determination of acid-glucosidase activity in blood spots as a diagnostic test for pompe disease. Clin Chem 2001; 47:1378-1383
12. Chamoles NA, Niizawa G, Blanco M, et al. Glycogen storage disease type II:enzymatic screening in dried blood spots on filter paper. Clin Chim Acta 2004;347: 97-102
13. Jack RM, Gordon C, Scott CR, et al. The use of acarbose inhibition in the measurement of acid alpha-glucosidase activity in blood lymphocytes for the diagnosis of Pompe disease.Genet Med 2006; 8: 307-311
14. An Y, Young SP, Hillman SL, et al. Liquid chromatographic assay for a glucose tetrasaccharide, a putative biomarker for the diagnosis of Pompe disease. Anal Biochem 2000;287: 136-143
15. Young SP, Stevens RD, An Y, et al. Analysis of a glucose tetrasaccharide elevated in Pompe disease by stable isotope dilution-electrosprayionization tandem mass spectrometry.Anal Biochem 2003; 316: 175-180
16. Hermans MM, van Leenen D, Kroos MA, et al. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat 2004, 23: 47-56
17. Montalvo ALE, Bembi B, Donnarumma M, et al. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat, 2006, 27: 999-1006
18. Huie ML, Chen AS, Tsujino S, et al. Aberrant splicing in adult onset glycogen storage type II(GSD II): molecular identification of an IVS 1(-13T-G) mutation in a majority of patients and a novel IVS 10(+lGT-CT) mutation. Hum Mol Genet 1994,3:2231-6
19. Taiwan , Shieh JJ, Lin CY. Frequent mutation in Chinese patients with infantile types of GSD II in Taiwan: evidence for a founder effect. Hum Mutat 1998;11:306-12
20. Bodamer,-O-A; Halliday,-D; Leonard,-J-V 。 The effects of 1-alanine supplementation in late-onset glycogen storage disease type II. Neurology. 2000 Sep 12;55(5):710-2
21.Bodamer,-O-A;Haas,-D;Hermans,-M-M;et al.L-alanine supplementation in late infantile glycogen storage disease type Ⅱ.Pediatr-Neurol.2002 Aug;27(2):145-6
22.Bembi,-B;Ciana,-G;Martini,-C;et al.Efficacy of multidisciplinary approach in the treatment of two cases of nonclassical infantile glycogenosis type Ⅱ.J-Inherit-Metab-Dis.2003;26(7):675-81
23.Mundy,-H-R;Williams,-J-E;Cousins,-A-J;et al.The effect of L-alanine therapy in a patient with adult onset glycogen storage disease type Ⅱ.J-Inherit-Metab-Dis.2006 Feb;29(1):226-9
24.Van-den-Hout,-H;Reuser,-A-J;Vulto,-A-G;et al.Recombinant human alpha-glucosidase from rabbit milk in Pompe patients.Lancet.2000 Jul 29;356(9227):397-8
25.Van den Hout J.M.P.,Kamphoven J.H.J.,Winkel L.P.F.,et al.Long-Term Intravenous Treatment of Pompe's Disease With Recombinant Human Alpha Glucosidase From Milk.Pediatrics.2004 May;113(5):e448-57
26.Kishnani,-P-S;Nicolino,-M;Voit,-T;et al.Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease.J-Pediatr.2006 Jul;149(1):89-97
27.Winkel L.P.F.,Van den Hour J.M.P.,Kamphoven J.H.J.,et al.Enzyme replacement therapy in late-onset Pompe's disease:a three-year follow up.Annals of Neurology;2004,55:495-502
2.Beggs AH,Koening M,Boyce FM,et al.Detection of 98%of DMD/BMD gene deletions by polymerase chain reaction.Hum Genet 1990,86(1):45-48
3.Smard LR,Rochette C,Semionov H,et al.SMN-t and NAIP mutatioins in Canadian families with spinal muscular atrophy(SMA):genotype/phenotype correlations with disease severity.Am J Med Genet 1997;72(1):51-58
4.马素参,袁丽芳,刘天慈等。进行性脊髓性肌肉萎缩症患者神经元存活基因及神经元凋亡抑制蛋白基因的缺失。中国医学科学院学报,2000;22(6):551-554
5.Koenig M.;Monaco A.P.;Kunkel L.M.:The complete sequence ofdystrophin predicts a rod-shaped cytoskeletal protein.Cell 1988;53:219-228.
6.Tennyson C.N.;Klamut H.J.;Worton R.G.The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced.Nature Genet.1995;9:184-190.
7.Bies R.D.;Caskey C.T.;Fenwick,R..An intact cysteine-rich domain is required for dystrophin function.J.Clin.Invest.1992;90:666-672.
8.Worton R.G.Dystrophin:the long and short of it.(Editorial) J.Clin.Invest.1994;93:4.
9.Moser H.Duchene muscular dystrophy:pathogenetic aspects and genetic prevention.Hum Genet,1984;66(1):17-40
10.Davies K.E.;Smith T.J.;Bundey S,et al.Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome.J.Med.Genet.1988;25:9-13.
11.Monaco A.P.;Bertelson C.J.;Liechti-Gallati S,et al.An explanation for phenotypic differences between patients beating partial deletions of DMD locus.Genomics 1988;2:90-95.
12.Nigro G,Comi L,Limongelli F.M.,etal.Prospective study of X-linked progressive muscular dystrophy in Campania.Muscle.Nerve.1983;6:253-262
13.Werneck L C,Scola R H,Maegawa GHB,et al.Comparative analysis of PCR-detection and immunohistochemistry in Brazilian Duchenne and Becker muscular dystrophy patients.Am J Med Gene,2001;103,105-120
14.陈琳,郭玉璞,邹丽萍等,DMD患者骨骼肌抗肌萎缩蛋白表达与临床病理改变。基础医学与临床,2005;25(11):1049-1052
15.Haslett J N,Sanoudou D,Kho A T.et al.Gene expression comparison of biopsies from Duchene muscular dystrophy(DMD) and normal skeletal muscle.Proc Nat Acad Sci 2002;15000-15005
16.Noguchi S,Tsukahara T,Fujita M,et al.cDNA microarray analysis of individual Duchene muscular dystrophy patients.Hum Molec Gemet 2003;12:595-600
17.Raben N,Plotz P,Byrue BJ.Acid alpha- glucosidase deficiency(glyco-genosis type Ⅱ,Pompe disease).Curr Mol Med 2002;2:145-166
18.Van den Hout J.M.P.,Kamphoven J.H.J.,Winkel L.P.F.,et al.Long-Term Intravenous Treatment of Pompe's Disease With Recombinant Human Alpha Glucosidase From Milk.Pediatrics 2004;13:e448-e457
19.Winkel L.P.F.,Van den Hout J.M.P.,Kamphoven J.H.J.,et al.Enzyme replacement therapy in late-onset Pompe's disease:a three-year follow up.Annals of Neurology;2004;55:495-502
20.Momoi,T.;Sano,H.;Yamanaka,C.;Sasaki,H.;Mikawa,H.:Glycogen storage disease type Ⅲ with muscle involvement:reappraisal of phenotypic variability and prognosis.Am.J.Med.Genet.1992;42:696-699.
21.杨艳玲,木村正彦,袁云等,戊二酸尿症Ⅱ型所致脂肪沉积性肌肉病的诊断与治疗分析。中华神经科学杂志,2004;37(5):438-441
22.Alessandro P,Lucia T,Monica S,et al.Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels.J Neurol.2002;249(3):305-311
1. Raben N, Plotz P, Byrue BJ. Acid alpha- glucosidase deficiency (glyco-genosis type II,Pompe disease). Curr Mol Med, 2002, 2: 145-166
2. Hoefsloot LH, Hoogeveen-Westerveld M, Reuser AJ, et al. Characterization of the human lysosomal alpha-glucosidase gene. Biochem J ,1990a, 272: 493-497
3. Martiniuk F, Bodkin M, Tzall S, et al. Isolation and partial characterazation of the structural gene for human acid alpha glucosidase. DNA Cell Biol, 1991, 10: 283-292
4. Hoefsloot LH, Willemsen R, Kroos MA, et al. Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalinan cells. Biochem J,1990b, 272: 485492
5. Moreland RJ, Jin X, Zhang XK, et al. Lysosomal acid alpha glucosidase consists of four different peptides processed from a single chain precusor. J Biol Chem , 2005, 280:6780-6791
6. Family 31 glycosyl hydrolases : www. expasy.ch/cgi.bin/list
7. http://www.hgmd.cf.ac.uk/ac/gene.php? gene=GAA
8. Hermans MM, van Leenen D, Kroos MA, et al. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat 2004, 23: 47-56
9. Montalvo ALE, Bembi B, Donnarumma M, et al. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat, 2006, 27:999-1006
10. Ko TM, Hwu WL, Lin YW, et al. Molecular genetic study of Pompe disease in Chinese patients in Taiwan. Hum Mutat 1999, 13: 380-384
11. Momoi T, Sano H, Yamanaka C, et al. Glycogen storage disease type III with muscle involvement: reappraisal of phenotypic variability and prognosis. Am. J. Med. Genet, 1992,42: 696-699.
12. Laforet P, Nicolino M, Erymard B, et al. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 2000, 55: 1122-8
13. Mellies U, Ragette R, Schwake C, et al. Sleep-disordered breathing and respiratory failure in acid maltase deficiency. Neurology, 2001, 57: 1290-1295
14. Kroos MA, Waitfield AE, Joosse M, et al. A novel acid alpha-glucosidase mutation identified in a Pakistani family with glycogen storage disease type II. J Inherit Metab Dis.1997,20:556-8.
15. Pittis MG, Montalvo AL, Miocic S, et al. Identification of four novel mutations in the alpha glucosidase gene in five Italian patients with infantile onset glycogen storage disease type II. Am JMed Genet A. 2003, 121:225-30.
16. Hermans MMP, Kroos MA, van Beeumen J, et al. Human lysosomal alpha-glucosidase :characterization of the catalytic site. J Biol Chem. 1991, 266: 13507-13512
17. Park YE, Park KH, Lee CH, et al. Two new missense mutations of GAA in late onset glycogen storage disease type II. J Neurosciences , 2006, 251: 113-117.
18. Huie ML, Chen AS, Tsujino S, et al. Aberrant splicing in adult onset glycogen storage type 11(GSD II): molecular identification of an IVS 1(-13T-G) mutation in a majority of patients and a novel IVS 10(+lGT-CT) mutation. Hum Mol Genet 1994, 3: 2231-6
19. Taiwan , Shieh JJ, Lin CY. Frequent mutation in Chinese patients with infantile types of GSD II in Taiwan: evidence for a founder effect. Hum Mutat 1998; 11:306-l 2
20. Van den Hout JM., Kamphoven JH, Winkel LP, et al. Long-Term Intravenous Treatment of Pompe's Disease With Recombinant Human Alpha Glucosidase From Milk. Pediatrics,2004, 113:e448-e457.
21. Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow up. Ann Neurol, 2004,55:495-502.
1. Hers HG Alpha-glucisidase deficiency in generalized glycogen storage disease(Pompe's disease). Biochen J 1963: 86: 11-6
2. Hoefsloot LH, Hoogeveen-Westerveld M, Reuser AJ, et al. Characterization of the human lysosomal alpha-glucosidase gene. Biochem J ,1990a, 272: 493-497
3. Martiniuk F, Bodkin M, Tzall S, et al. Isolation and partial characterazation of the structural gene for human acid alpha glucosidase. DNA Cell Biol, 1991, 10:283-292
4. Hoefsloot LH, Willemsen R, Kroos MA, et al. Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalinan cells.Biochem J, 1990b, 272: 485-492
5. Moreland RJ, Jin X, Zhang XK, et al. Lysosomal acid alpha glucosidase consists of four different peptides processed from a single chain precusor. J Biol Chem ,2005, 280:6780-6791
6. Henrissat B: glycosidase families .Biochem Soc Trans 26: 153, 1998
7. Hannerieke M. P. van den Hout, Wim Hop, et al. The Natural Course of Infantile Pompe's Disease: 20 Original Cases Compared With 133 Cases From the Literature. PEDIATRICS Vol. 112 No. 2 August 2003, pp. 332-340
8. Kishnani,-P-S; Hwu,-W-L; Mandel,-H; et al. A retrospective, multinational,multicenter study on the natural history of infantile-onset Pompe disease.J-Pediatr. 2006 May; 148(5): 671-676
9. Hagemans,-M-L; Winkel,-L-P; Van-Doorn,-P-A; et al. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain. 2005 Mar; 128(Pt 3): 671-7
10. Winkel LPE, Hagemans,-M-L, Van der Van-Doorn,-P-A; et al. The natural course of non-classic Pompe's disease; a review of 225 published cases. J neurol 2005;252: 875-884
11. Umapathysivam K, Hopwood JJ, Meikle PJ, Determination of acid-glucosidase activity in blood spots as a diagnostic test for pompe disease. Clin Chem 2001; 47:1378-1383
12. Chamoles NA, Niizawa G, Blanco M, et al. Glycogen storage disease type II:enzymatic screening in dried blood spots on filter paper. Clin Chim Acta 2004;347: 97-102
13. Jack RM, Gordon C, Scott CR, et al. The use of acarbose inhibition in the measurement of acid alpha-glucosidase activity in blood lymphocytes for the diagnosis of Pompe disease.Genet Med 2006; 8: 307-311
14. An Y, Young SP, Hillman SL, et al. Liquid chromatographic assay for a glucose tetrasaccharide, a putative biomarker for the diagnosis of Pompe disease. Anal Biochem 2000;287: 136-143
15. Young SP, Stevens RD, An Y, et al. Analysis of a glucose tetrasaccharide elevated in Pompe disease by stable isotope dilution-electrosprayionization tandem mass spectrometry.Anal Biochem 2003; 316: 175-180
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