Background： X-linked Charcot-Marie-Tooth type 1 （CMT1 X） disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein （GJB1） gene （also known as connexin...Background： X-linked Charcot-Marie-Tooth type 1 （CMT1 X） disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein （GJB1） gene （also known as connexin 32）. This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations. Methods： A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJBI mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing （NGS）. Nucleotide alternations were confirnled with Sanger sequencing. Results： The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years （ranging from 1 year to 42 years）. The sudden onset of cerebral symptoms appeared in four patients （ 18.2%）： two were initial symptoms. One case had constant central nervous system （CNS） signs. There were 19 different heterozygous mutations, including 15 known mutations and tbur novel mutations （c. II5G〉T, c.380T〉A, c.263C〉A, and c.818_819insGGGCT）. Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 （TM1）, 4.5% in TM2, 27.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 （EC1）, 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-ternlinal domain. CMTIX with CNS impairment appeared in five （22.7%） of these patients. Conclusions： This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJBI gene were hotspot in Chinese CMT1X patients.展开更多
Charcot-Marie-Tooth disease （CMT）, also known as hereditary motor and sensory neuropathies,comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progress...Charcot-Marie-Tooth disease （CMT）, also known as hereditary motor and sensory neuropathies,comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progressive distal weakness, muscle atrophy, distal sensory loss and loss of deep tendon reflexes. Following electrophysiological criteria, CMT is divided into two main forms：展开更多
We previously found that the K141N mutation in heat shock protein B8 （HSPB8） was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a tr...We previously found that the K141N mutation in heat shock protein B8 （HSPB8） was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141N HSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the KI41NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141N HSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141N HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the KI4mHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.展开更多
Charcot-Marie-Tooth（CMT） disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the e...Charcot-Marie-Tooth（CMT） disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria： very slow motor nerve conduction velocity（MNCV）（〈15 m/s）, slow MNCV（15–25 m/s）, intermediate MNCV（25–45 m/s）, and normal MNCV（〉45 m/s）. Based on the inheritance pattern, intermediate CMT can be divided into dominant（DI-CMT） and recessive types（RI-CMT）. GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.展开更多
目的·探讨无创产前检测(non-invasive prenatal testing,NIPT)对染色体17p12区域[包含外周髓鞘蛋白22(peripheral myelin protein 22,PMP22)]拷贝数变异(copy number variations,CNVs)的检测效能及临床应用价值。方法·选取202...目的·探讨无创产前检测(non-invasive prenatal testing,NIPT)对染色体17p12区域[包含外周髓鞘蛋白22(peripheral myelin protein 22,PMP22)]拷贝数变异(copy number variations,CNVs)的检测效能及临床应用价值。方法·选取2020年7月—2024年4月在上海交通大学医学院附属国际和平妇幼保健院行NIPT的孕妇,统计NIPT结果提示17p12区域微缺失/重复高风险个体的临床资料,随访相关个体后续产前诊断和孕妇夫妻双方外周血染色体微阵列分析(chromosomal microarray analysis,CMA)结果,分析NIPT筛查17p12区域微缺失/重复的阳性预测值及假阳性的原因。对已明确诊断携带17p12区域CNVs的胎儿及孕妇进行追踪随访,记录妊娠结局及相关临床表型。结果·共61858例孕妇行NIPT,其中24例(0.04%)结果提示17p12区域CNVs高风险,包括17p12微重复高风险6例、17p12微缺失高风险18例。24例孕妇均进行了后续遗传咨询,其中21例(87.50%)进行介入性产前诊断。介入性产前诊断结果提示胎儿17p12重复异常4例、17p12缺失异常9例、未见异常8例,阳性预测值61.90%(13/21)。对8例胎儿假阳性的孕妇外周血行CMA分析,提示孕妇自身均携带17p12区域微缺失/重复。对NIPT提示母源CNVs高风险的孕妇进一步分析提示,孕妇自身均携带相关CNVs。成功随访其中20例孕妇,除1例因胎儿新发17p12区域微重复选择终止妊娠外,其余均正常分娩。正常分娩的胎儿随访至今(平均年龄1.5岁),暂未报告相关异常。对16例携带17p12区域CNVs的孕妇进行评估,有2例表现出与17p12区域CNVs相关的临床表型特征,其余暂未见异常。结论·NIPT对17p12区域CNVs有较好的检测效能,母体CNVs是导致NIPT检测假阳性的主要原因。展开更多
基金This study was supported by a grant from the National Science Foundation of China （No. 81471185）.
文摘Background： X-linked Charcot-Marie-Tooth type 1 （CMT1 X） disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein （GJB1） gene （also known as connexin 32）. This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations. Methods： A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJBI mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing （NGS）. Nucleotide alternations were confirnled with Sanger sequencing. Results： The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years （ranging from 1 year to 42 years）. The sudden onset of cerebral symptoms appeared in four patients （ 18.2%）： two were initial symptoms. One case had constant central nervous system （CNS） signs. There were 19 different heterozygous mutations, including 15 known mutations and tbur novel mutations （c. II5G〉T, c.380T〉A, c.263C〉A, and c.818_819insGGGCT）. Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 （TM1）, 4.5% in TM2, 27.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 （EC1）, 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-ternlinal domain. CMTIX with CNS impairment appeared in five （22.7%） of these patients. Conclusions： This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJBI gene were hotspot in Chinese CMT1X patients.
文摘Charcot-Marie-Tooth disease （CMT）, also known as hereditary motor and sensory neuropathies,comprises a genetically heterogeneous group of inherited peripheral neuropathies. Clinically it is characterized by progressive distal weakness, muscle atrophy, distal sensory loss and loss of deep tendon reflexes. Following electrophysiological criteria, CMT is divided into two main forms：
基金funded by the National Natural Science Foundation of China,No.81071001,30900805
文摘We previously found that the K141N mutation in heat shock protein B8 （HSPB8） was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141N HSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the KI41NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141N HSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141N HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the KI4mHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.
文摘Charcot-Marie-Tooth（CMT） disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria： very slow motor nerve conduction velocity（MNCV）（〈15 m/s）, slow MNCV（15–25 m/s）, intermediate MNCV（25–45 m/s）, and normal MNCV（〉45 m/s）. Based on the inheritance pattern, intermediate CMT can be divided into dominant（DI-CMT） and recessive types（RI-CMT）. GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.
文摘目的·探讨无创产前检测(non-invasive prenatal testing,NIPT)对染色体17p12区域[包含外周髓鞘蛋白22(peripheral myelin protein 22,PMP22)]拷贝数变异(copy number variations,CNVs)的检测效能及临床应用价值。方法·选取2020年7月—2024年4月在上海交通大学医学院附属国际和平妇幼保健院行NIPT的孕妇,统计NIPT结果提示17p12区域微缺失/重复高风险个体的临床资料,随访相关个体后续产前诊断和孕妇夫妻双方外周血染色体微阵列分析(chromosomal microarray analysis,CMA)结果,分析NIPT筛查17p12区域微缺失/重复的阳性预测值及假阳性的原因。对已明确诊断携带17p12区域CNVs的胎儿及孕妇进行追踪随访,记录妊娠结局及相关临床表型。结果·共61858例孕妇行NIPT,其中24例(0.04%)结果提示17p12区域CNVs高风险,包括17p12微重复高风险6例、17p12微缺失高风险18例。24例孕妇均进行了后续遗传咨询,其中21例(87.50%)进行介入性产前诊断。介入性产前诊断结果提示胎儿17p12重复异常4例、17p12缺失异常9例、未见异常8例,阳性预测值61.90%(13/21)。对8例胎儿假阳性的孕妇外周血行CMA分析,提示孕妇自身均携带17p12区域微缺失/重复。对NIPT提示母源CNVs高风险的孕妇进一步分析提示,孕妇自身均携带相关CNVs。成功随访其中20例孕妇,除1例因胎儿新发17p12区域微重复选择终止妊娠外,其余均正常分娩。正常分娩的胎儿随访至今(平均年龄1.5岁),暂未报告相关异常。对16例携带17p12区域CNVs的孕妇进行评估,有2例表现出与17p12区域CNVs相关的临床表型特征,其余暂未见异常。结论·NIPT对17p12区域CNVs有较好的检测效能,母体CNVs是导致NIPT检测假阳性的主要原因。
