GM1神经节苷脂沉积病致病基因GLB1新变异c.101T>C(p.Ile34Thr)的识别和致病性分析
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摘要
单唾液酸四己糖神经节苷脂(GM1)神经节苷脂沉积病是由半乳糖苷酶beta-1(GLB1)基因变异影响GLB活性所致的常染色体隐性遗传病,GLB功能缺陷造成GM1降解障碍而在溶酶体贮积。该文报道1例GM1神经节苷脂沉积病患儿的临床及遗传学特点。患儿,女,2岁5个月,因运动发育倒退1年余就诊。体格检查发现双眼球偏斜伴水平震颤,眼底镜检查无异常,四肢肌张力高,肘、膝、踝关节活动受限,膝腱反射亢进。血生化检查发现AST明显升高。24小时脑电图监测到频繁癫痫发作,弥漫性θ波活动增多,以右半球显著。头颅MRI显示双侧脑室周围白质变薄并见弥漫性T2WI高信号影,边界不清;白质纤维束三维重建(DTI)提示双侧大脑半球白质纤维束细小、稀疏,以右侧为著。遗传学分析发现患儿GLB1基因存在来自于其父母的c.446C>T(p.Ser149Phe)和c.101T>C(p.Ile34Thr)复合杂合突变,其中c.101T>C(p.Ile34Thr)未见文献报道。患儿最终确诊为GM1神经节苷脂沉积病。予抗癫痫和康复训练等对症支持治疗2个月,病情未见好转。
GM1 gangliosidosis is an autosomal recessive disorder caused by galactosidase beta1(GLB1)gene variants which affect the activity ofβ-galactosidase(GLB).GLB dysfunction causes abnormalities in the degradation of GM1 and its accumulation in lysosome.This article reports the clinical and genetic features of a child with GM1gangliosidosis.The girl,aged 2 years and 5 months,was referred to the hospital due to motor developmental regression for more than one year.Physical examination showed binocular deflection and horizontal nystagmus,but no abnormality was found on fundoscopy.The girl had increased muscular tone of the extremities,limitation of motion of the elbow,knee,and ankle joints,and hyperactive patellar tendon reflex.Blood biochemical examination showed a significant increase in aspartate aminotransferase.The 24-hour electroencephalographic monitoring detected frequent seizure attacks and diffuseθwave activity,especially in the right hemisphere.Head magnetic resonance imaging showed thinner white matter in the periventricular region and diffuse high T2WI signal with unclear boundary.Three-dimensional reconstruction of white matter fiber tracts by diffusion tensor imaging showed smaller and thinner white matter fiber tracts,especially in the right hemisphere.Genetic analysis showed that the girl had compound heterozygous mutations of c.446C>T(p.Ser149Phe)and c.101T>C(p.Ile34Thr)in the GLB1 gene from her parents,among which c.101T>C(p.Ile34Thr)had not been reported in the literatures.The girl was finally diagnosed with GM1 gangliosidosis.Her conditions were not improved after antiepileptic treatment and rehabilitation training for 2 months.
GM1 gangliosidosis is an autosomal recessive disorder caused by galactosidase beta1(GLB1)gene variants which affect the activity ofβ-galactosidase(GLB).GLB dysfunction causes abnormalities in the degradation of GM1 and its accumulation in lysosome.This article reports the clinical and genetic features of a child with GM1gangliosidosis.The girl,aged 2 years and 5 months,was referred to the hospital due to motor developmental regression for more than one year.Physical examination showed binocular deflection and horizontal nystagmus,but no abnormality was found on fundoscopy.The girl had increased muscular tone of the extremities,limitation of motion of the elbow,knee,and ankle joints,and hyperactive patellar tendon reflex.Blood biochemical examination showed a significant increase in aspartate aminotransferase.The 24-hour electroencephalographic monitoring detected frequent seizure attacks and diffuseθwave activity,especially in the right hemisphere.Head magnetic resonance imaging showed thinner white matter in the periventricular region and diffuse high T2WI signal with unclear boundary.Three-dimensional reconstruction of white matter fiber tracts by diffusion tensor imaging showed smaller and thinner white matter fiber tracts,especially in the right hemisphere.Genetic analysis showed that the girl had compound heterozygous mutations of c.446C>T(p.Ser149Phe)and c.101T>C(p.Ile34Thr)in the GLB1 gene from her parents,among which c.101T>C(p.Ile34Thr)had not been reported in the literatures.The girl was finally diagnosed with GM1 gangliosidosis.Her conditions were not improved after antiepileptic treatment and rehabilitation training for 2 months.
引文
[1]Brunetti-Pierri N,Scaglia F.GM 1 gangliosidosis:Review of clinical,molecular,and therapeutic aspects[J].Mol Gene Metab,2008,94(4):391-396.
[2]O'Brien JS,Stern MB,Landing BH,et al.Generalized gangliosidosis:Another inborn error of ganglioside metabolism?[J].Am J Dis Child,1965,109:338-346.
[3]Okada S,O’Brien JS.Generalized gangliosidosis:betagalactosidase deficiency[J].Science,1968,160(3831):1002-1004.
[4]冀浩然,肖江喜,李东晓,等.GM1神经节苷脂累积病6例患儿临床及遗传学研究[J].中华实用儿科临床杂志,2016,31(20):1536-1540.
[5]Sinigerska I,Chandler D,Vaghjiani V,et al.Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population[J].Mol Genet Metab,2006,88(1):93-95.
[6]Hofer D,Paul K,Fantur K,et al.GM1 gangliosidosis and Morquio B disease:expression analysis of missense mutations affecting the catalytic site of acidβ-galactosidase[J].Hum Mutat,2009,30(8):1214-1221.
[7]Baiotto C,Sperb F,Matte U,et al.Population analysis of the GLB1 gene in south Brazil[J].Genet Mol Biol,2011,34(1):45-48.
[8]Sperb F,Vairo F,Burin M,et al.Genotypic and phenotypic characterization of Brazilian patientswith GM1 gangliosidosis[J].Gene,2013,512(1):113-116.
[9]Santamaria R,Chabás A,Coll MJ,et al.Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients:possible common origin for the prevalent p.R59H mutation among gypsies[J].Hum Mutat,2006,27(10):1060.
[10]Muthane U,Chickabasaviah Y,Kaneski C,et al.Clinical features of adult GM1 gangliosidosis:report of three Indian patients and review of 40 cases[J].Move Disord,2004,19(11):1334-1341.
[11]Pierson TM,Adams DA,Markello T,et al.Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis[J].Neurology,2012,79(2):123-126.
[12]Nestrasil I,Ahmed A,Utz JM,et al.Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses:Volumetric quantitative MRI study[J].Mol Gene Metab,2018,123(2):97-104.
[13]Deodato F,Procopio E,Rampazzo A,et al.The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression[J].Metab Brain Dis,2017,32(5):1529-1536.
[14]Takenouchi T,Kosaki R,Nakabayashi K,et a1.Paramagnetie signals in the globus pallidus as late radiographic sign of juvenile-onset GMl gangliosidosis[J].Pediatr Neurol,2015,52(2):226-229.
[15]Samorodnitsky E,Datta J,Jewell BM,et al.Comparison of custom capture for targeted next-generation DNA sequencing[J].J Mol Diagn,2015,17(1):64-75.
[16]Xue Y,Ankala A,Wilcox WR,et al.Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing:single-gene,gene panel,or exome/genome sequencing[J].Genet Med,2015,17(6):444-451.
[17]齐朝月,张尧,宋金青,等.婴儿型GM1神经节苷脂沉积病5例临床及影像学分析[J].临床儿科杂志,2006,24(12):966-969.
[18]Lee JS,Choi JM,Lee M,et al.Diagnostic challenge for the rare lysosomal storage disease:Late infantile GM1 gangliosidosis[J].Brain Dev,2018,40(5):383-390.
[19]Jarnes Utz JR,Kim S,King K,et al.Infantile gangliosidoses:Mapping a timeline of clinical changes[J].Mol Gene Metab,2017,121(2):170-179.
[20]Tuteja M,Bidchol AM,Girisha KM,et al.White matter changes in GM1 gangliosidosis[J].Indian Pediatr,2015,52(2):155-156.
[21]Vieira JP,Concei??o C,Scortenschi E.GM1 gangliosidosis,late infantile onset dystonia,and T2 hypointensity in the globuspallidus and substantia Nigra[J].Pediatr Neurol,2013,49(3):195-197.
[22]Gray-Edwards HL,Reqier DS,Shirley JL,et al.Novel biomarkers of human GM1 gangliosidosis reflect the clinical efficacy of gene therapy in a feline model[J].Mol Ther,2017,25(4):892-903.
[23]Ohto U,Usui K,Ochi T,et al.Crystal structure of humanβ-galactosidase:structural basis of GM1 gangliosidosis and morquio B diseases[J].J Biol Chem,2012,287(3):1801-1812.
[24]Reardon D,Farber GK.The structure and evolution of alpha/beta barrel proteins[J].FASEB J,1995,9(7):497-503.
[25]Fantur KM,Wrodnigg TM,Stütz AE,et al.Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1-gangliosidosis and Morquio B disease[J].J Inherit Metab Dis,2012,35(3):495-503.
[26]Hayward C,Patel HC,Manohar SG,et al.Gene therapy for GM1 gangliosidosis:challenges of translational medicine[J].Ann Transl Med,2015,3(Suppl 1):S28.
[27]Regier DS,Proia RL,D’Azzo A,et al.The GM1 and GM2gangliosidoses:natural history and progress toward therapy[J].Pediatr Endocrinol Rev,2016,13(Suppl 1):663-673.
[28]Takaura N,Yagi T,Maeda M,et al.Attenuation of ganglioside GM1 accumulation in the brain of GM1gangliosidosis mice by neonatal intravenous gene transfer[J].Gene Ther,2003,10(17):1487-1493.
[29]Broekman ML,Baek RC,Comer LA,et al.Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by neonatal adeno-associated virusmediated gene delivery[J].Mol Ther,2007,15(1):30-37.
[30]Condori J,Acosta W,Ayala J,et al.Enzyme replacement for GM1 gangliosidosis:uptake,lysosomal activation,and cellular disease correction using a novelβ-galactosidase:RTB lectin fusion[J].Mol Genet Metab,2016,117(2):199-209.
[2]O'Brien JS,Stern MB,Landing BH,et al.Generalized gangliosidosis:Another inborn error of ganglioside metabolism?[J].Am J Dis Child,1965,109:338-346.
[3]Okada S,O’Brien JS.Generalized gangliosidosis:betagalactosidase deficiency[J].Science,1968,160(3831):1002-1004.
[4]冀浩然,肖江喜,李东晓,等.GM1神经节苷脂累积病6例患儿临床及遗传学研究[J].中华实用儿科临床杂志,2016,31(20):1536-1540.
[5]Sinigerska I,Chandler D,Vaghjiani V,et al.Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population[J].Mol Genet Metab,2006,88(1):93-95.
[6]Hofer D,Paul K,Fantur K,et al.GM1 gangliosidosis and Morquio B disease:expression analysis of missense mutations affecting the catalytic site of acidβ-galactosidase[J].Hum Mutat,2009,30(8):1214-1221.
[7]Baiotto C,Sperb F,Matte U,et al.Population analysis of the GLB1 gene in south Brazil[J].Genet Mol Biol,2011,34(1):45-48.
[8]Sperb F,Vairo F,Burin M,et al.Genotypic and phenotypic characterization of Brazilian patientswith GM1 gangliosidosis[J].Gene,2013,512(1):113-116.
[9]Santamaria R,Chabás A,Coll MJ,et al.Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients:possible common origin for the prevalent p.R59H mutation among gypsies[J].Hum Mutat,2006,27(10):1060.
[10]Muthane U,Chickabasaviah Y,Kaneski C,et al.Clinical features of adult GM1 gangliosidosis:report of three Indian patients and review of 40 cases[J].Move Disord,2004,19(11):1334-1341.
[11]Pierson TM,Adams DA,Markello T,et al.Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis[J].Neurology,2012,79(2):123-126.
[12]Nestrasil I,Ahmed A,Utz JM,et al.Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses:Volumetric quantitative MRI study[J].Mol Gene Metab,2018,123(2):97-104.
[13]Deodato F,Procopio E,Rampazzo A,et al.The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression[J].Metab Brain Dis,2017,32(5):1529-1536.
[14]Takenouchi T,Kosaki R,Nakabayashi K,et a1.Paramagnetie signals in the globus pallidus as late radiographic sign of juvenile-onset GMl gangliosidosis[J].Pediatr Neurol,2015,52(2):226-229.
[15]Samorodnitsky E,Datta J,Jewell BM,et al.Comparison of custom capture for targeted next-generation DNA sequencing[J].J Mol Diagn,2015,17(1):64-75.
[16]Xue Y,Ankala A,Wilcox WR,et al.Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing:single-gene,gene panel,or exome/genome sequencing[J].Genet Med,2015,17(6):444-451.
[17]齐朝月,张尧,宋金青,等.婴儿型GM1神经节苷脂沉积病5例临床及影像学分析[J].临床儿科杂志,2006,24(12):966-969.
[18]Lee JS,Choi JM,Lee M,et al.Diagnostic challenge for the rare lysosomal storage disease:Late infantile GM1 gangliosidosis[J].Brain Dev,2018,40(5):383-390.
[19]Jarnes Utz JR,Kim S,King K,et al.Infantile gangliosidoses:Mapping a timeline of clinical changes[J].Mol Gene Metab,2017,121(2):170-179.
[20]Tuteja M,Bidchol AM,Girisha KM,et al.White matter changes in GM1 gangliosidosis[J].Indian Pediatr,2015,52(2):155-156.
[21]Vieira JP,Concei??o C,Scortenschi E.GM1 gangliosidosis,late infantile onset dystonia,and T2 hypointensity in the globuspallidus and substantia Nigra[J].Pediatr Neurol,2013,49(3):195-197.
[22]Gray-Edwards HL,Reqier DS,Shirley JL,et al.Novel biomarkers of human GM1 gangliosidosis reflect the clinical efficacy of gene therapy in a feline model[J].Mol Ther,2017,25(4):892-903.
[23]Ohto U,Usui K,Ochi T,et al.Crystal structure of humanβ-galactosidase:structural basis of GM1 gangliosidosis and morquio B diseases[J].J Biol Chem,2012,287(3):1801-1812.
[24]Reardon D,Farber GK.The structure and evolution of alpha/beta barrel proteins[J].FASEB J,1995,9(7):497-503.
[25]Fantur KM,Wrodnigg TM,Stütz AE,et al.Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1-gangliosidosis and Morquio B disease[J].J Inherit Metab Dis,2012,35(3):495-503.
[26]Hayward C,Patel HC,Manohar SG,et al.Gene therapy for GM1 gangliosidosis:challenges of translational medicine[J].Ann Transl Med,2015,3(Suppl 1):S28.
[27]Regier DS,Proia RL,D’Azzo A,et al.The GM1 and GM2gangliosidoses:natural history and progress toward therapy[J].Pediatr Endocrinol Rev,2016,13(Suppl 1):663-673.
[28]Takaura N,Yagi T,Maeda M,et al.Attenuation of ganglioside GM1 accumulation in the brain of GM1gangliosidosis mice by neonatal intravenous gene transfer[J].Gene Ther,2003,10(17):1487-1493.
[29]Broekman ML,Baek RC,Comer LA,et al.Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by neonatal adeno-associated virusmediated gene delivery[J].Mol Ther,2007,15(1):30-37.
[30]Condori J,Acosta W,Ayala J,et al.Enzyme replacement for GM1 gangliosidosis:uptake,lysosomal activation,and cellular disease correction using a novelβ-galactosidase:RTB lectin fusion[J].Mol Genet Metab,2016,117(2):199-209.