疑似儿童神经元蜡样脂褐质沉积症5例诊断分析
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摘要
目的探讨儿童神经元蜡样脂褐质沉积症(NCL)的诊断方式,特别是基因诊断的意义。方法回顾性分析2013年1月至2017年1月在首都医科大学宣武医院就诊的5例临床疑诊NCL的患儿资料,其中男3例、女2例,有2例为兄妹关系。患儿发病年龄3岁4个月至8岁11个月,来院首诊年龄3岁6个月至14岁。对脑影像表现异常的4例患儿及其父母、兄弟提取外周血DNA,检测相关基因。结果 4例确诊为NCL,1例为儿童癔症。基因检测:例1 TPP1基因c.887-17A>G为剪切变异;c.646G>A为错义变异。例2 TPP1基因c.1015_1016 del为移码变异;c.640C>T为无义变异。例3 CLN6基因核苷酸改变为c.158T>C(p.L53P)及c.889C>T(p.P297S)。3例父母均只携带其中1个杂合变异,例3受检者哥哥未携带突变。例4 CLN3基因c.1160_1169 delCAGCCTACGTinsGC杂合突变,母亲未检测到该突变,缺失父亲样本;CLN3基因外显子E3-E8杂合缺失,为真实缺失,母源。随访15～60个月,无死亡病例。结论对于怀疑NCL的患儿应及时检查头颅磁共振成像、脑电图及基因检测,导致NCL的基因突变TPP1(c.887-17A>G,c.1015_1016 del),CLN3(c.1160_1169 delCAGCCTACGTinsGC),CLN6[(c.158T>C(p.L53P),c.889C>T(p.P297S)]位点均为首次报告,基因型对于NCL的分型、判断预后十分重要。
Objective To investigate diagnosis of children's neuronal ceroid lipofuscinosis(NCL),especially the significance of gene diagnosis. Methods The clinical data of 5 cases of suspected NCL in our hospital from January 2013 to January 2017 were retrospectively analyzed. There were 3 boys and 2 girls,2 of whom were sister and brother. The age of onset ranged from 3 years and 4 months to 8 years and 1 month,averaged 5 years and 9 months. The first visit to our hospital ranged from 3 years and 6 months to 14 years,with an average of 8 years and 1 month. DNA of peripheral blood was extracted from 4 children with abnormal imaging and their parents and brothers,and the related genes were detected.Results Four cases of children were diagnosed with NCL,and 1 case was diagnosed with hysteria;gene detection showed:case 1:TPP1 gene c.887-17 A>G was a shearing variant,and c.646 G>A was a missense mutation;case 2:TPP1 gene c.1015_1016 del was frameshift mutation,and c.640 C>T was nonsense mutation;the nucleotide of case 3:CLN6 gene changed to c.158 T>C(p.L53 P)and c.889 C>T(p.P297 S). The parents of the 3 cases only carried one of the heterozygous variants,and the brother of case 3 had no mutation. Heterozygous mutation existed in case 4:CLN3 gene,c.1160_1169 delCAGCCTACGTinsGC,which was not detected in the mother,and there was the deletion of the paternal sample;there was loss of heterozygosity in the exon E3-E8 of the CLN3 gene,which was the true missing from mother.Five cases were followed up for 15-60 months and there was no death. Conclusion Suspected NCL patients should be checked head MRI,electroencephalogram and gene. The gene mutation leads to NCL,such as TPP1(c.887-17 A>G,c.1015_1016 del),CLN3(c.1160_1169 delCAGCCTACGTinsGC),CLN6[(c.158 T>C(p.L53 P) and c.889 C>T(p.P297 S)],are reported for the first time. Genotype is very important for NCL classification and prognosis.
Objective To investigate diagnosis of children's neuronal ceroid lipofuscinosis(NCL),especially the significance of gene diagnosis. Methods The clinical data of 5 cases of suspected NCL in our hospital from January 2013 to January 2017 were retrospectively analyzed. There were 3 boys and 2 girls,2 of whom were sister and brother. The age of onset ranged from 3 years and 4 months to 8 years and 1 month,averaged 5 years and 9 months. The first visit to our hospital ranged from 3 years and 6 months to 14 years,with an average of 8 years and 1 month. DNA of peripheral blood was extracted from 4 children with abnormal imaging and their parents and brothers,and the related genes were detected.Results Four cases of children were diagnosed with NCL,and 1 case was diagnosed with hysteria;gene detection showed:case 1:TPP1 gene c.887-17 A>G was a shearing variant,and c.646 G>A was a missense mutation;case 2:TPP1 gene c.1015_1016 del was frameshift mutation,and c.640 C>T was nonsense mutation;the nucleotide of case 3:CLN6 gene changed to c.158 T>C(p.L53 P)and c.889 C>T(p.P297 S). The parents of the 3 cases only carried one of the heterozygous variants,and the brother of case 3 had no mutation. Heterozygous mutation existed in case 4:CLN3 gene,c.1160_1169 delCAGCCTACGTinsGC,which was not detected in the mother,and there was the deletion of the paternal sample;there was loss of heterozygosity in the exon E3-E8 of the CLN3 gene,which was the true missing from mother.Five cases were followed up for 15-60 months and there was no death. Conclusion Suspected NCL patients should be checked head MRI,electroencephalogram and gene. The gene mutation leads to NCL,such as TPP1(c.887-17 A>G,c.1015_1016 del),CLN3(c.1160_1169 delCAGCCTACGTinsGC),CLN6[(c.158 T>C(p.L53 P) and c.889 C>T(p.P297 S)],are reported for the first time. Genotype is very important for NCL classification and prognosis.
引文
[1]Groh J,Berve K,Martini R.Fingolimod and teriflunomide attenuate neurodegeneration in mouse models of neuronal ceroid lipofuscinosis[J].Mol Ther,2017,25(8):1889-1899.
[2]Mink JW,Augustine EF,Adams HR,et al.Classification and natural history of the neuronal ceroid lipofuscinoses[J].J Child Neurol,2013,28(9):1101-1105.
[3]任守臣,高宝勤,王雅洁,等.神经元蜡样脂褐质沉积病五例的临床表现、基因与超微病理特点[J].中华医学杂志,2016,96(43):3504-3507.
[4]莫志强,王大勇,李小松,等.脾切除及保留副脾治疗儿童戈谢病的疗效观察[J].中华小儿外科杂志,2016,37(7):537-540.
[5]Benitez BA,Sands MS.Primary fibroblasts from CSPαmutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis[J].Sci Rep,2017,7(1):6332.
[6]Savchenko E,Singh Y,Konttinen H,et al.Loss of CLN5 causes altered neurogenesis in a childhood neurodegenerative disorder[J].Dis Model Mech,2017,10(9):1089-1100.
[7]Kim K,Kleinman HK,Lee HJ,et al.Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders[J].Orphanet J Rare Dis,2017,12(1):113.
[8]Schulz A,MousaUem T,Venkataramani M,et al.The CLN9 protein,a regulator of dihydroceramide synthase[J].J Biol Chem,2006,281(5):12784-2794.
[9]Ren SC,Gao BQ,Wang YJ,et al.Clinical,genetic and pathological features of neuronal ceroid lipofuscinosis in 5 Chinese patients[J].Zhonghua Yi Xue Za Zhi,2016,96(43):3504-3507.
[10]Jadav RH,Sinha S,Yasha TC,et al.Clinical,eleetrophysiological,imaging,and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes[J].Pediatr Neurol,2014,50(1):85-95.
[11]Khan KN,El-Asrag ME,Ku CA,et al.Specific alleles of CLN7/MFSD8,a protein that localizes to photoreceptor synaptic terminals,cause a spectrum of nonsyndromic retinal dystrophy[J].Invest Ophthalmol Vis Sci,2017,58(7):2906-2914.
[12]Ku CA,Hull S,Arno G,et al.Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration[J].JAMA Ophthalmol,2017,135(7):749-760.
[13]Petkau TL,Blanco J,Leavitt BR.Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice[J].Neurobiol Dis,2017,106:14-22.
[14]宋红梅.提高对单基因遗传自身炎症性疾病的认识[J].中国实用儿科杂志,2018,33(1):8-10.
[15]Yao X,Liu X,Zhang Y,et al.Gene Therapy of adult neuronal ceroid lipofuscinoses with CRISPR/Cas9 in zebrafish[J].Hum Gene Ther.2017,28(7):588-597.
[16]Ju W,Wronska A,Moroziewicz DN,et al.Genotype-phenotype analyses of classic neuronal ceroid lipofuscinosis(NCLs):genetic predictions from clinical and pathological findings.[J].J Peking University,2006,38(38):41-48.
[17]赵玉英,盖红,温冰,等.经典青少年型神经元蜡样质脂褐质沉积症一例[J].中华神经科杂志,2016,49(8):647-649.
[18]Kousi M,Lehesjoki AE,Mole SE.Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses[J].Hum Mutat,2012,33(1):42-63.
[19]张静,张月华.神经元腊样脂褐质沉积症分型和诊断[J].中国实用儿科杂志,2018,33(4):257-281.
[20]任晓敏,封志纯.神经元蜡样脂褐质沉积症诊断策略和治疗进展[J].中国实用儿科杂志,2012,27(2):153-156.
[2]Mink JW,Augustine EF,Adams HR,et al.Classification and natural history of the neuronal ceroid lipofuscinoses[J].J Child Neurol,2013,28(9):1101-1105.
[3]任守臣,高宝勤,王雅洁,等.神经元蜡样脂褐质沉积病五例的临床表现、基因与超微病理特点[J].中华医学杂志,2016,96(43):3504-3507.
[4]莫志强,王大勇,李小松,等.脾切除及保留副脾治疗儿童戈谢病的疗效观察[J].中华小儿外科杂志,2016,37(7):537-540.
[5]Benitez BA,Sands MS.Primary fibroblasts from CSPαmutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis[J].Sci Rep,2017,7(1):6332.
[6]Savchenko E,Singh Y,Konttinen H,et al.Loss of CLN5 causes altered neurogenesis in a childhood neurodegenerative disorder[J].Dis Model Mech,2017,10(9):1089-1100.
[7]Kim K,Kleinman HK,Lee HJ,et al.Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders[J].Orphanet J Rare Dis,2017,12(1):113.
[8]Schulz A,MousaUem T,Venkataramani M,et al.The CLN9 protein,a regulator of dihydroceramide synthase[J].J Biol Chem,2006,281(5):12784-2794.
[9]Ren SC,Gao BQ,Wang YJ,et al.Clinical,genetic and pathological features of neuronal ceroid lipofuscinosis in 5 Chinese patients[J].Zhonghua Yi Xue Za Zhi,2016,96(43):3504-3507.
[10]Jadav RH,Sinha S,Yasha TC,et al.Clinical,eleetrophysiological,imaging,and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes[J].Pediatr Neurol,2014,50(1):85-95.
[11]Khan KN,El-Asrag ME,Ku CA,et al.Specific alleles of CLN7/MFSD8,a protein that localizes to photoreceptor synaptic terminals,cause a spectrum of nonsyndromic retinal dystrophy[J].Invest Ophthalmol Vis Sci,2017,58(7):2906-2914.
[12]Ku CA,Hull S,Arno G,et al.Detailed clinical phenotype and molecular genetic findings in CLN3-associated isolated retinal degeneration[J].JAMA Ophthalmol,2017,135(7):749-760.
[13]Petkau TL,Blanco J,Leavitt BR.Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice[J].Neurobiol Dis,2017,106:14-22.
[14]宋红梅.提高对单基因遗传自身炎症性疾病的认识[J].中国实用儿科杂志,2018,33(1):8-10.
[15]Yao X,Liu X,Zhang Y,et al.Gene Therapy of adult neuronal ceroid lipofuscinoses with CRISPR/Cas9 in zebrafish[J].Hum Gene Ther.2017,28(7):588-597.
[16]Ju W,Wronska A,Moroziewicz DN,et al.Genotype-phenotype analyses of classic neuronal ceroid lipofuscinosis(NCLs):genetic predictions from clinical and pathological findings.[J].J Peking University,2006,38(38):41-48.
[17]赵玉英,盖红,温冰,等.经典青少年型神经元蜡样质脂褐质沉积症一例[J].中华神经科杂志,2016,49(8):647-649.
[18]Kousi M,Lehesjoki AE,Mole SE.Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses[J].Hum Mutat,2012,33(1):42-63.
[19]张静,张月华.神经元腊样脂褐质沉积症分型和诊断[J].中国实用儿科杂志,2018,33(4):257-281.
[20]任晓敏,封志纯.神经元蜡样脂褐质沉积症诊断策略和治疗进展[J].中国实用儿科杂志,2012,27(2):153-156.