脆性X综合征的发病机制及诊治研究进展
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摘要
随着中国二孩政策的全面放开,高危妊娠日益增多,出生缺陷发生率也随之升高。除环境因素外,遗传因素是导致出生缺陷的另一常见原因,尤其是染色体异常。脆性X综合征是一种X染色体连锁不完全显性遗传疾病,发病率仅次于唐氏综合征,常表现为遗传性智力障碍和自闭症等多系统疾病。作为导致智力障碍的第二大原因,其主要由脆性X染色体智力低下基因1中三核苷酸重复序列(CGG)n结构扩展的动态突变,导致其编码的脆性X智能低下蛋白表达缺失或严重减少引起。脆性X综合征的诊断主要依靠临床表现和基因检测,目前尚无有效治疗方法,未来应进一步研究其靶向治疗。
With the implementation of universal two-child policy in China,the high risk pregnancy is increasing by day,and the incidence of birth defect has also increased. Besides the environmental factor,the genetic factor is another common cause of the birth defect,especially the chromosome abnormality. Fragile X syndrome is a X chromosome linked incomplete dominant inherited disease,the incidence of which is second only to Down syndrome,often characterized by multi-systemic diseases including inherited intellectual disability and autism spectrum disorder. As the second reason of intellectual disability,it is mainly caused by the dynamic mutation of trinucleotide repeat sequence( CGG) n expansion in the fragile X mental retardation gene 1,which induces the absent or decreasing expression of fragile X mental retardation protein. The diagnosis of fragile X syndrome is according to the clinical manifestation and genetic test. There is no effective treatment at present. Further research on targeted therapy should be carried out in the future.
With the implementation of universal two-child policy in China,the high risk pregnancy is increasing by day,and the incidence of birth defect has also increased. Besides the environmental factor,the genetic factor is another common cause of the birth defect,especially the chromosome abnormality. Fragile X syndrome is a X chromosome linked incomplete dominant inherited disease,the incidence of which is second only to Down syndrome,often characterized by multi-systemic diseases including inherited intellectual disability and autism spectrum disorder. As the second reason of intellectual disability,it is mainly caused by the dynamic mutation of trinucleotide repeat sequence( CGG) n expansion in the fragile X mental retardation gene 1,which induces the absent or decreasing expression of fragile X mental retardation protein. The diagnosis of fragile X syndrome is according to the clinical manifestation and genetic test. There is no effective treatment at present. Further research on targeted therapy should be carried out in the future.
引文
[1]Lozano R,Rosero CA,Hagerman RJ.Fragile X spectrum disorders[J].Intractable Rare Dis Res,2014,3(4):134-146.
[2]韩冰,李红,杨伟文.脆性X染色体综合征的产前诊断[J].国外医学(计划生育分册),2001,20(4):203-207.
[3]Ciaccio C,Fontana L,Milani D,et al.Fragile X syndrome:A review of clinical and molecular diagnoses[J].Ital J Pediatr,2017,43(1):39.
[4]Lee M,Martin GE,Berry-Kravis E,et al.A developmental,longitudinal investigation of autism phenotypic profiles in fragile X syndrome[J].J Neurodev Disord,2016,8:47.
[5]Martin JP,Bell J.A pedigree of mental defect showing sexlinkage[J].J Neurol Psychiatry,1943,6(3/4):154-157.
[6]Lubs HA.A marker X chromosome[J].Am J Hum Genet,1969,21(3):231-244.
[7]Verkerk AJ,Pieretti M,Sutcliffe JS,et al.Identification of a gene(FMR-1)containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome[J].Cell,1991,65(5):905-914.
[8]Basuta K,Schneider A,Gane L,et al.High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome[J].Am J Med Genet A,2015,167A(9):2154-2161.
[9]史旭刚,赵志鹏,康龙丽.脆性X染色体综合征的生殖遗传研究进展[J].国外医学(医学地理分册),2015,36(2):155-158.
[10]Saldarriaga W,Tassone F,González-Teshima LY,et al.Fragile X syndrome[J].Colomb Med,2014,45(4):190-198.
[11]Pretto DI,Mendoza-Morales G,Lo J,et al.CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles[J].J Med Genet,2014,51(5):309-318.
[12]Hayward BE,Kumari D,Usdin K.Hum Recent advances in assays for the fragile X-related disorders[J].Hum Genet,2017,136(10):1313-1327.
[13]Bonaccorso CM,Spatuzza M,Di Marco B,et al.Fragile X mental retardation protein(FMRP)interacting proteins exhibit different expression patterns during development[J].Int J Dev Neurosci,2015,42:15-23.
[14]Peyser A,Singer T,Mullin C,et al.Reduction in the number of CGG repeats on the FMR1 gene in carriers of genetic disorders versus noncarriers[J].JBRA Assist Reprod,2017,21(4):327-329.
[15]Niu M,Han Y,Dy ABC,et al.Autism symptoms in fragile X syndrome[J].J Child Neurol,2017,32(10):903-909.
[16]Cheng YK,Lin CS,Kwok YK,et al.Identification of fragile X premutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay:Implications for screening and prenatal diagnosis[J].Hong Kong Med J,2017,23(2):110-116.
[17]Lisik MZ.Health problems in females carriers of premutation in the FMR1 gene[J].Psychiatr Pol,2017,51(5):899-907.
[18]Mila M,Alvarez-Mora MI,Madrigal I,et al.Fragile X syndrome:An overview and update of the FMR1 gene[J].Clin Genet,2018,93(2):197-205.
[19]Robertson EE,Hall DA,Mc Asey AR,et al.Fragile X-associated tremor/ataxia syndrome:Phenotypic comparisons with other movement disorders[J].Clin Neuropsychol,2016,30(6):849-900.
[20]Rovozzo R,Korza G,Baker MW,et al.CGG Repeats in the 5'UTR of FMR1 RNA regulate translation of other RNAs localized in the same RNA granules[J].PLo S One,2016,11(12):e0168204.
[21]Grigsby J.The fragile X mental retardation 1 gene(FMR1):Historical perspective,phenotypes,mechanism,pathology,and epidemiology[J].Clin Neuropsychol,2016,30(6):815-833.
[22]Hessl D,Grigsby J.Fragile X-associated tremor/ataxia syndrome:another phenotype of the fragile X gene[J].Clin Neuropsychol,2016,30(6):810-814.
[23]Lozano R,Azarang A,Wilaisakditipakorn T,et al.Fragile X syndrome:A review of clinical management[J].Intractable Rare Dis Res,2016,5(3):145-157.
[24]Hadd AG,Filipovic-Sadic S,Zhou L,et al.A methylation PCR method determines FMR1 activation ratios and differentiates permutation allele mosaicism in carrier siblings[J].Clin Epigenetics,2016,8:130.
[25]Tassone F.Advanced technologies for the molecular diagnosis of fragile X syndrome[J].Expert Rev Mol Diagn,2015,15(11):1465-1473.
[26]Jacquemont S,Pacini L,Jnch AE,et al.Protein synthesis levels are increased in a subset of individuals with fragile X syndrome[J].Hum Mol Genet,2018,27(12):2039-2051.
[27]Gabis LV,Hochberg O,Leon Attia O,et al.Prolonged time lag to final diagnosis of fragile X syndrome[J].J Pediatr,2018,193(2):217-221.
[28]Stark Z,Francis D,Gaffney L,et al.Prenatal diagnosis of fragile X syndrome complicated by full mutation retraction[J].Am J Med Genet A,2015,167A(10):2485-2487.
[29]Miao Z,Liu X,Li W,et al.Assessment of efficacy of prenatal genetic diagnosis for fragile X syndrome using nested PCR[J].Exp Ther Med,2018,15(6):5107-5112.
[30]Bilousova TV,Dansie L,Ngo M,et al.Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model[J].J Med Genet,2009,46(2):94-102.
[31]Leigh MJ,Nguyen DV,Mu Y,et al.A randomized double-blind,placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome[J].J Dev Behav Pediatr,2013,34(3):147-155.
[32]Lee M,Won J,Lee S,et al.Benefits of physical exercise for individuals with fragile X syndrome in humans[J].J Lifestyle Med,2015,5(2):35-38.
[33]Davenport MH,Schaefer TL,Friedmann KJ,et al.Pharmacotherapy for fragile X syndrome:Progress to date[J].Drugs,2016,76(4):431-445.
[34]Liu XS,Wu H,Krzisch M,et al.Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene[J].Cell,2018,172(5):979-992.e6.
[35]Dwivedi RS.A new diagnostic algorithm for an early diagnosis of patients with fragile X syndrome[J].Neurol India,2016,64(6):1136-1137.
[36]Bhattacharyya A,Zhao X.Human pluripotent stem cell models of fragile X syndrome[J].Mol Cell Neurosci,2016,73:43-51.
[2]韩冰,李红,杨伟文.脆性X染色体综合征的产前诊断[J].国外医学(计划生育分册),2001,20(4):203-207.
[3]Ciaccio C,Fontana L,Milani D,et al.Fragile X syndrome:A review of clinical and molecular diagnoses[J].Ital J Pediatr,2017,43(1):39.
[4]Lee M,Martin GE,Berry-Kravis E,et al.A developmental,longitudinal investigation of autism phenotypic profiles in fragile X syndrome[J].J Neurodev Disord,2016,8:47.
[5]Martin JP,Bell J.A pedigree of mental defect showing sexlinkage[J].J Neurol Psychiatry,1943,6(3/4):154-157.
[6]Lubs HA.A marker X chromosome[J].Am J Hum Genet,1969,21(3):231-244.
[7]Verkerk AJ,Pieretti M,Sutcliffe JS,et al.Identification of a gene(FMR-1)containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome[J].Cell,1991,65(5):905-914.
[8]Basuta K,Schneider A,Gane L,et al.High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome[J].Am J Med Genet A,2015,167A(9):2154-2161.
[9]史旭刚,赵志鹏,康龙丽.脆性X染色体综合征的生殖遗传研究进展[J].国外医学(医学地理分册),2015,36(2):155-158.
[10]Saldarriaga W,Tassone F,González-Teshima LY,et al.Fragile X syndrome[J].Colomb Med,2014,45(4):190-198.
[11]Pretto DI,Mendoza-Morales G,Lo J,et al.CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles[J].J Med Genet,2014,51(5):309-318.
[12]Hayward BE,Kumari D,Usdin K.Hum Recent advances in assays for the fragile X-related disorders[J].Hum Genet,2017,136(10):1313-1327.
[13]Bonaccorso CM,Spatuzza M,Di Marco B,et al.Fragile X mental retardation protein(FMRP)interacting proteins exhibit different expression patterns during development[J].Int J Dev Neurosci,2015,42:15-23.
[14]Peyser A,Singer T,Mullin C,et al.Reduction in the number of CGG repeats on the FMR1 gene in carriers of genetic disorders versus noncarriers[J].JBRA Assist Reprod,2017,21(4):327-329.
[15]Niu M,Han Y,Dy ABC,et al.Autism symptoms in fragile X syndrome[J].J Child Neurol,2017,32(10):903-909.
[16]Cheng YK,Lin CS,Kwok YK,et al.Identification of fragile X premutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay:Implications for screening and prenatal diagnosis[J].Hong Kong Med J,2017,23(2):110-116.
[17]Lisik MZ.Health problems in females carriers of premutation in the FMR1 gene[J].Psychiatr Pol,2017,51(5):899-907.
[18]Mila M,Alvarez-Mora MI,Madrigal I,et al.Fragile X syndrome:An overview and update of the FMR1 gene[J].Clin Genet,2018,93(2):197-205.
[19]Robertson EE,Hall DA,Mc Asey AR,et al.Fragile X-associated tremor/ataxia syndrome:Phenotypic comparisons with other movement disorders[J].Clin Neuropsychol,2016,30(6):849-900.
[20]Rovozzo R,Korza G,Baker MW,et al.CGG Repeats in the 5'UTR of FMR1 RNA regulate translation of other RNAs localized in the same RNA granules[J].PLo S One,2016,11(12):e0168204.
[21]Grigsby J.The fragile X mental retardation 1 gene(FMR1):Historical perspective,phenotypes,mechanism,pathology,and epidemiology[J].Clin Neuropsychol,2016,30(6):815-833.
[22]Hessl D,Grigsby J.Fragile X-associated tremor/ataxia syndrome:another phenotype of the fragile X gene[J].Clin Neuropsychol,2016,30(6):810-814.
[23]Lozano R,Azarang A,Wilaisakditipakorn T,et al.Fragile X syndrome:A review of clinical management[J].Intractable Rare Dis Res,2016,5(3):145-157.
[24]Hadd AG,Filipovic-Sadic S,Zhou L,et al.A methylation PCR method determines FMR1 activation ratios and differentiates permutation allele mosaicism in carrier siblings[J].Clin Epigenetics,2016,8:130.
[25]Tassone F.Advanced technologies for the molecular diagnosis of fragile X syndrome[J].Expert Rev Mol Diagn,2015,15(11):1465-1473.
[26]Jacquemont S,Pacini L,Jnch AE,et al.Protein synthesis levels are increased in a subset of individuals with fragile X syndrome[J].Hum Mol Genet,2018,27(12):2039-2051.
[27]Gabis LV,Hochberg O,Leon Attia O,et al.Prolonged time lag to final diagnosis of fragile X syndrome[J].J Pediatr,2018,193(2):217-221.
[28]Stark Z,Francis D,Gaffney L,et al.Prenatal diagnosis of fragile X syndrome complicated by full mutation retraction[J].Am J Med Genet A,2015,167A(10):2485-2487.
[29]Miao Z,Liu X,Li W,et al.Assessment of efficacy of prenatal genetic diagnosis for fragile X syndrome using nested PCR[J].Exp Ther Med,2018,15(6):5107-5112.
[30]Bilousova TV,Dansie L,Ngo M,et al.Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model[J].J Med Genet,2009,46(2):94-102.
[31]Leigh MJ,Nguyen DV,Mu Y,et al.A randomized double-blind,placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome[J].J Dev Behav Pediatr,2013,34(3):147-155.
[32]Lee M,Won J,Lee S,et al.Benefits of physical exercise for individuals with fragile X syndrome in humans[J].J Lifestyle Med,2015,5(2):35-38.
[33]Davenport MH,Schaefer TL,Friedmann KJ,et al.Pharmacotherapy for fragile X syndrome:Progress to date[J].Drugs,2016,76(4):431-445.
[34]Liu XS,Wu H,Krzisch M,et al.Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene[J].Cell,2018,172(5):979-992.e6.
[35]Dwivedi RS.A new diagnostic algorithm for an early diagnosis of patients with fragile X syndrome[J].Neurol India,2016,64(6):1136-1137.
[36]Bhattacharyya A,Zhao X.Human pluripotent stem cell models of fragile X syndrome[J].Mol Cell Neurosci,2016,73:43-51.