Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or...Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.展开更多
BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,...BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.展开更多
<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodege...<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>展开更多
目的:探讨氢质子波谱(proton magnetic resonance spectroscopy,~1H-MRS)在脊髓小脑型共济失调3型/马查多–约瑟夫病(hereditary spinocerebellar ataxias 3 and Machado-Joseph,SCA3/MJD)诊断中的价值,同时探讨其与临床病程评分之间的...目的:探讨氢质子波谱(proton magnetic resonance spectroscopy,~1H-MRS)在脊髓小脑型共济失调3型/马查多–约瑟夫病(hereditary spinocerebellar ataxias 3 and Machado-Joseph,SCA3/MJD)诊断中的价值,同时探讨其与临床病程评分之间的联系。方法:SCA3/MJD起病患者、SCA3/MJD未起病患者及年龄匹配健康志愿者进行~1H-MRS检查,经数据后处理获得N–乙酰天门冬氨酸(N-acetylaspartate,NAA),肌酸(creatine,Cr),胆碱(choline-containing compounds,Cho),肌醇(myo-inositol,m I)值及NAA/Cr,Cho/Cr,m I/Cr比值。将以上数据进行对比研究;同时对于SCA3/MJD起病患者进行国际协作共济失调评估量表(International Cooperative Ataxia Rating Scale,ICARS)及共济失调等级量表(Scale for the Assessment and Rating of Ataxia,SARA)评估,计算NAA/Cr,Cho/Cr,m I/Cr比值与临床评分之间的相关性。结果:SCA3/MJD起病患者在桥脑及齿状核的NAA/Cr值较正常对照组明显减低。SCA3/MJD起病患者小脑齿状核NAA/Cr值与ICARS评分有明显相关性。结论:SCA3/MJD的病变主要位于小脑及脑干,ICARS评分与小脑病变的程度有相关性,能较好地反映临床表现的轻重程度。~1H-MRS对于SCA3/MJD的诊断有一定的应用前景。展开更多
目的:探讨弥散加权成像(diffusion weighted imaging,DWI)在遗传性脊髓小脑型共济失调3型/马查多-约瑟夫病(hereditary spinocerebellar ataxia 3 and the Machado Joseph disease,SCA3/MJD)及遗传性痉挛性截瘫4型(hereditary spastic p...目的:探讨弥散加权成像(diffusion weighted imaging,DWI)在遗传性脊髓小脑型共济失调3型/马查多-约瑟夫病(hereditary spinocerebellar ataxia 3 and the Machado Joseph disease,SCA3/MJD)及遗传性痉挛性截瘫4型(hereditary spastic paraplegia 4,SPG4)的诊断及鉴别诊断中的价值。方法:对13例SPG4患者,30例SCA3/MJD及27名年龄匹配的健康志愿者进行DWI检查,经数据后处理获得了表观扩散系数(apparent diffusion coefficient,ADC)值。将以上数据分组进行对比研究。结果:SCA3/MJD起病患者的ADC值在中央前回、内囊后肢、大脑脚、桥脑、小脑皮层及小脑白质区域较正常对照组升高。SCA3/MJD未起病患者的ADC值仅在小脑齿状核位置较正常对照组增高。SCA3/MJD起病患者仅在小脑皮层较SCA3/MJD未起病患者ADC值明显升高;SCA3/MJD起病患者的ADC值在内囊后肢、小脑皮层、小脑白质及桥脑较SPG4患者明显增高。在中央前回,SPG4患者的ADC值较正常对照组明显增高。结论:DWI对于SCA3/MJD与SPG4的鉴别诊断有一定的应用前景。展开更多
目的通过对云南地区临床诊断为脊髓小脑共济失调的家系进行SCA3基因检测,探讨汉族人群遗传性脊髓小脑共济失调3型(spinocerebellar ataxia type 3,SCA3)患者临床特点与遗传学特征。方法对4个家系26例脊髓小脑共济失调患者进行神经系统...目的通过对云南地区临床诊断为脊髓小脑共济失调的家系进行SCA3基因检测,探讨汉族人群遗传性脊髓小脑共济失调3型(spinocerebellar ataxia type 3,SCA3)患者临床特点与遗传学特征。方法对4个家系26例脊髓小脑共济失调患者进行神经系统检查和家系谱调查,应用聚合酶链反应(PCR)、琼脂糖凝胶电泳和基因测序等技术进行SCA3基因内CAG三核苷酸重复序列,并对异常等位基因片段进行DNA测序。结果临床表现以共济失调和构音障碍为主,其次表现为锥体束征、眼部症状等,认知功能障碍较少见。检出4个家系(26例患者)为SCA3,符合常染色体显性遗传特点,测序证实其异常等位基因CAG重复数目在67~82次之间。结论云南地区汉族的SCAs患者以SCA3型为主,主要表现为共济失调和构音障碍,基因检测仍是其诊断的金标准。展开更多
基金grants from the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period, No. 2006BAI05A07the Major State Basic Research Development Program of China (973 Program), No. 2006cb500700+5 种基金the National Key Technologies Research and Development Program of China, No. 2004BA720A03the National Natural Science Foundation of China, No. 30871354, 30710303061 and 30470619the Key Project in the Natural Science Foundation of Hunan Province, No. 08JJ3048the Natural Science Foundation of Hunan Province, No. 11JJ5071the Science and Technology Planning Project of Hunan Province, No. 2009SK3172the Graduate Degree Thesis Innovation Foundation of Central South University, No. 2008yb030
文摘Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.
基金the National Natural Science Foundation of China,No.81874448 and No.81973789.
文摘BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.
文摘<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>
文摘目的:探讨氢质子波谱(proton magnetic resonance spectroscopy,~1H-MRS)在脊髓小脑型共济失调3型/马查多–约瑟夫病(hereditary spinocerebellar ataxias 3 and Machado-Joseph,SCA3/MJD)诊断中的价值,同时探讨其与临床病程评分之间的联系。方法:SCA3/MJD起病患者、SCA3/MJD未起病患者及年龄匹配健康志愿者进行~1H-MRS检查,经数据后处理获得N–乙酰天门冬氨酸(N-acetylaspartate,NAA),肌酸(creatine,Cr),胆碱(choline-containing compounds,Cho),肌醇(myo-inositol,m I)值及NAA/Cr,Cho/Cr,m I/Cr比值。将以上数据进行对比研究;同时对于SCA3/MJD起病患者进行国际协作共济失调评估量表(International Cooperative Ataxia Rating Scale,ICARS)及共济失调等级量表(Scale for the Assessment and Rating of Ataxia,SARA)评估,计算NAA/Cr,Cho/Cr,m I/Cr比值与临床评分之间的相关性。结果:SCA3/MJD起病患者在桥脑及齿状核的NAA/Cr值较正常对照组明显减低。SCA3/MJD起病患者小脑齿状核NAA/Cr值与ICARS评分有明显相关性。结论:SCA3/MJD的病变主要位于小脑及脑干,ICARS评分与小脑病变的程度有相关性,能较好地反映临床表现的轻重程度。~1H-MRS对于SCA3/MJD的诊断有一定的应用前景。
文摘目的通过对云南地区临床诊断为脊髓小脑共济失调的家系进行SCA3基因检测,探讨汉族人群遗传性脊髓小脑共济失调3型(spinocerebellar ataxia type 3,SCA3)患者临床特点与遗传学特征。方法对4个家系26例脊髓小脑共济失调患者进行神经系统检查和家系谱调查,应用聚合酶链反应(PCR)、琼脂糖凝胶电泳和基因测序等技术进行SCA3基因内CAG三核苷酸重复序列,并对异常等位基因片段进行DNA测序。结果临床表现以共济失调和构音障碍为主,其次表现为锥体束征、眼部症状等,认知功能障碍较少见。检出4个家系(26例患者)为SCA3,符合常染色体显性遗传特点,测序证实其异常等位基因CAG重复数目在67~82次之间。结论云南地区汉族的SCAs患者以SCA3型为主,主要表现为共济失调和构音障碍,基因检测仍是其诊断的金标准。