葡萄糖转运子1缺乏综合征的临床特点与基因突变分析

Clinical and genetic characteristics of glucose transporter type 1 deficiency syndrome

目的探讨葡萄糖转运子1缺乏综合征（GLUTI—DS）的临床与SLC2A1基因突变特点。方法对6例GLUTl一DS患儿的临床表现、脑脊液、脑电图、头颅影像学、治疗与转归等临床资料进行总结；应用聚合酶链式反应与测序、多重连接探针扩增技术对SLC2A1基因进行突变分析。结果本组6例，3例患儿为经典型GLUTl一DS，以早发惊厥为主要临床表现，3例患儿为非经典型GLUTI—DS，表现为发作性精神行为异常、意识障碍、共济失调等。5例患儿伴智力运动发育落后。6例患儿血糖均正常，脑脊液糖在1．10—2．45mmol／L之间，均降低，平均值1．68mmot／L，脑脊液糖与血糖比值为0．16～0．51：1，均降低，平均值0．34。4例患儿脑电图正常，2例有局灶性或弥漫性痴样放电，其中一例同时有大量弥漫性慢波。3例头颅MRI正常，3例呈非特异性改变，其中1例呈轻度脑萎缩，1例双侧脑室饱满，1例左侧额、枕叶白质发育迟缓。6例患儿均存在SLC2A1基因突变，例1于第2外显子存在大片段缺失，例2至例6分别为c．741G〉A（E247K）、599delA、761delA、c．1148C〉A（P383H）、C．1198C〉T（R400C）。2例患儿行生酮饮食治疗，3例予增加饮食次数，疗效显著，1例放弃治疗。结论GLUTl-DS临床症状多样，以癫痫及多种发作性的临床症状为主要表现，饥饿与疲劳可诱发临床症状的m现或加重，此特点为本病重要的临床诊断线索，而脑脊液糖与血糖比值的降低是本病最为重要的临床诊断依据。GLUTl-DS是可治性的神经系统疾病，早诊断、早治疗可显著改善患儿的预后。

Objective To analyze the clinical and SLC2A1 gene mutation characteristics of glucose transporter type 1 deficiency syndrome. Method The detailed clinical manifestations of six cases were recorded. The laboratory tests including EEG, MRI, blood chemistry, and lumbar puncture were performed. SLC2A1 gene mutations were analyzed by PCR, DNA sequencing and multiplex ligation-dependent probe amplification （MLPA）. Result Patient 1,2 and 3 had classical clinical symptoms including infantile onset seizures, development delay. Patient 4, 5 and 6 had non-classical clinical symptoms including paroxysmal behavior disturbance, weakness, ataxia, lethargy, especially after fasting or exercise, without severe seizures. The plasma glucose levels were nomlal. The CSF glucose levels decreased in all the six cases, ranged from 1.10 mmol/L to 2.45 mmol/L, the mean level was 1.68 mmol/L. The CSF glucose/plasma glucose ratios decreased, ranged from 0. 16 to 0. 51, the mean ratio was 0. 34. Four patients had normal EEG. Two patients had focal and diffuse epileptiform discharge, and one of them also had paroxysmal occipital or generalized high-amplitude slow waves during awake and sleep time. MRI abnormalities were found in three patients, patient 1 with mild brain atrophy, patient 3 with bilateral ventricle plump, and patient 4 with high signals in T2 in the frontal and occipital white matter, interpreted as hypomyelination. SLC2A1 gene mutations were found in six cases. Patient I has ｜arge scale deletion in exon 2. In patient 2 to 6, the mutations were c. 741 G 〉 A （E247K）, 599delA, 761delA, c. 1148 C 〉 A （P383H）, c. 1198 C 〉 T （R400C） respectively. Two patients were treated with ketogenic diet. The seizures disappeared and development became normal. Three patients responded to frequent meals with snacks. One patient refused any treatments, the symptoms continued to exist. Conclusion The clinical manifestations of glucose transporter type 1 deficiency syndrome are varied. The common symptoms included infantile onset seizures and various paroxysmal events. These neurologic symptoms generally fluctuated and were influenced by factors such as fasting or fatigue. This feature could be a very important clue for the diagnosis of GLUTI -DS. Lumbar puncture is recommended in patients with episodic CNS symptoms especially ＂after fasting. GLUT1- DS is a treatable neurometabolic disorder, early diagnosis and treatment may improve the prognosis of the