GM1神经节苷脂贮积症患儿临床与遗传学特点及文献复习  

Clinical and genetic characteristics of 3 children with GM1 gangliosidosis and literature review

作　　者：铁晓玲 车凤玉 杨颖[2] 陈小聪[1] Tie Xiaoling;Che Fengyu;Yang Ying;Chen Xiaocong(Department of Rehabilitation,Xi′an Children′s Hospital,Xi′an 710003,China;Shaanxi Institute for Pediatric Diseases,Xi′an Children′s Hospital,Xi′an 710003,China)

机构地区：[1]西安市儿童医院康复医学科,西安710003 [2]西安市儿童医院儿科疾病研究所,西安710003

出　　处：《中华神经科杂志》2024年第10期1136-1143,共8页Chinese Journal of Neurology

摘　　要：目的分析3例GM1神经节苷脂贮积症Ⅰ型患儿的临床、遗传学及生物信息学特征,并进行文献复习。方法对2020年1月至2022年12月于西安市儿童医院就诊的3例分别以“反复抽搐发作”“发育落后”“肢体松软”入院的患儿进行全外显子测序、β-半乳糖苷酶活性检测,利用MutaBind2、PyMOL模拟突变对蛋白理化性质、三维结构的影响。结果3例患儿均在婴儿期出现严重发育迟滞或倒退,继发癫痫,血碱性磷酸酶、谷氨酸氨基转移酶明显增高,β-半乳糖苷酶活性分别为1.59%、3.47%、1.96%,骨骼X线示腰椎前缘鸟嘴样改变,头颅磁共振成像示髓鞘形成不良。全外显子测序结果显示3例患儿均携带GLB1基因复合杂合变异,其中c.148T>C变异未见报道及收录,c.785G>T和c.1438A>G、c.304C>G变异仅收录1例。生信分析结果显示突变后蛋白的结合亲和力降低,分子间氢键破坏或与周围残基形成较强空间位阻,结合文献证据,推测突变可能影响蛋白的整体结构和稳定性,使酶活性下降。结论GM1神经节苷脂贮积症的诊断及分型需综合临床特征、外显子组测序及β-半乳糖苷酶活性检测,生信分析有助于预测突变对蛋白结构和功能的影响。ObjectiveTo analyze the clinical,genetic,and bioinformatic characteristics of 3 children diagnosed with GM1 gangliosidosis typeⅠ,and to conduct a literature review.MethodsFrom January 2020 through December 2022,a detailed examination,encompassing whole-exon sequencing and the evaluation ofβ-galactosidase enzymatic function,was undertaken for 3 pediatric inpatients at Xi′an Children′s Hospital.Each child presented with distinct clinical features:recurrent seizures,developmental delays,and hypotonia.Concurrently,computational tools MutaBind2 and PyMOL were employed to prognosticate the potential impact of identified genetic mutations.ResultsAll 3 children experienced severe developmental delay or regression in infancy,accompanied by epilepsy.Serum alkaline phosphatase and aspartate aminotransferase were significantly increased.Furthermore,the serumβ-galactosidase activity was 1.59%,3.47%,1.96%,respectively.Brain magnetic resonance imaging revealed poor myelination and X-ray examinations demonstrated beak-like changes in the anterior edge of the lumbar spine.All 3 children carried compound heterozygous variants in the GLB1 gene.The c.148T>C variant had not been previously reported,while the c.785G>T,c.1438A>G and c.304C>G variants were only present in 1 case.It was predicted that the mutated protein exhibited reduced binding affinity,with an interrupted hydrogen bond or the formation of a significant steric hindrance with the neighboring residues.Combined with the literature evidence,it was hypothesized that the mutations could potentially impact the overall structure and stability of the GLB protein,leading to a decrease in enzyme activity.ConclusionsThe diagnosis and classification of GM1 ganglioside storage disease need to integrate the clinical features,exome sequencing andβ-galactosidase activity assay.Bioinformatics analysis is helpful to predict the effect of mutations on protein structure and function.

关 键 词：神经节苷脂累积病 GM1型 儿童 β半乳糖苷酶类 突变 误义 GLB1基因 

分 类 号：R748[医药卫生—神经病学与精神病学]