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

Identification and pathogenicity prediction of a novel GLB1 variant c.101T>C (p.Ile34Thr) in an infant with GM1 gangliosidosis

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。

Abstract:

GM1 gangliosidosis is an autosomal recessive disorder caused by galactosidase beta1 (GLB1) gene variants which affect the activity of β-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 GM1 gangliosidosis. 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 diffuse θ wave 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.