Analysis of diagnosis and treatment of children with glucose transporter 1 deficiency syndrome and literature review

doi:10.3877/cma.j.issn.1673-5250.2020.06.011

Objective

To investigate clinical features of Chinese children with glucose transporter 1 deficiency syndrome (GLUT1-DS).

Methods

By retrospectively analytic method, clinical data of a girl with GLUTl-DS who was diagnosed and treated in Chishui People′s Hospital in June 2018 was selected. The clinical manifestation, diagnosis, treatment measures and sequelae of GLUT1-DS of domestic population were summarized by reviewing Chinese and English literature of GLUT1-DS with basically complete clinical data in domestic and foreign databases. This study was approved by the Ethics Committee of Cishui People′s Hospital (Approval No. 201801). Informed consent was obtained from the guardian of this child for the diagnosis and treatment.

Results

① The girl was diagnosed with GLUTl-DS at 2 years and 4 months old as main clinical manifestations of paroxysmal facial cyanosis, microcephaly, developmental retardation and dyskinesia. Monitoring results of video EEG was abnormal, levels of cerebrospinal fluid glucose, and levels of cerebrospinal fluid glucose to levels of plasma glucose ratio (cerebrospinal fluid glucose/plasma glucose) were both decreased. Gene detection (Sanger method) showed heterozygous missense mutation of exon 5: C. 661G>A (p.E221K) (from her father). The girl was intolerant to ketogenic diet (KD) therapy and response poorly to 6 months of Traditional Chinese Medicine rehabilitation treatment in other hospital. After followed up to 3 years and 11 months old, motor and language development of the girl was obviously behind that of normal children. ② Results of literature review: the clinical data of 18 cases with GLUTl-DS in China including 17 cases from 7 pieces of Chinese or English literature and one case in this study were summarized as follows. The male to female ratio of GLUTl-DS incidence was 10∶8, the median age of onset was 7 months, and the median age at diagnosis was 55 months. Main clinical symptoms were epileptic seizures (94.4%, 17/18), development retardation (88.9%, 16/18) and ataxia (72.2%, 13/18). The cerebrospinal fluid glucose concentration, and cerebrospinal fluid glucose/plasma glucose decreased in all the 18 cases (100.0%). SLC2A1 gene screening were performed in 17 cases, and revealed gene mutation in 15 cases. KD therapy were administered in 11 cases, and symptoms were effectively controlled in 8 cases but another 3 cases discontinued KD therapy due to intolerance. Four cases achieved good treatment results by increase the frequency of meals and high carbohydrate intake.

Conclusions

Typical clinical manifestations, laboratory examination and SLC2A1 gene detection results, can confirm the diagnosis of GLUTl-DS. For suspected or clinically diagnosed patients with GLUTl-DS, early start of KD therapy or increase the frequency of eating or sugar intake evidently can improve their prognosis.

Key words: Glucose transporter type 1, Deficiency diseases, SLC2A1 gene, Seizures, Developmental retardation, Ataxia, Ketogenic diet, Child

图1 本例GLUT1-DS患儿(女性，2岁4个月龄)及其父母SLC2A1基因Sanger法测序图[红色箭头所示为患儿及其父亲均存在第5外显子C.661G>A(p.E221K)杂合错义突变，患儿母亲该位点无突变]

表1 本例及文献纳入研究的17例GLUTl-DS患儿临床病例资料分析

病例(No.)	文献(第1作者，文献发表年)	发病年龄	诊断年龄	性别	痫性发作	智力、运动发育落后	共济失调	踝阵挛	语言障碍	小头畸形
1	刘燕燕^[5]，2013	41 d	3个月	男	有	有	无	无	无	无
2	刘燕燕^[5]，2013	60 d	3个月	男	有	有	无	无	无	无
3	刘燕燕^[5]，2013	33 d	6岁	男	有	有	有	无	无	无
4	刘燕燕^[5]，2013	3岁7个月	7岁	女	无	有	有	无	无	无
5	刘燕燕^[5]，2013	6岁2个月	6岁5个月	男	有	无	有	无	无	无
6	刘燕燕^[5]，2013	2岁10个月	5岁	女	有	有	有	无	无	有
7	李晓华^[6]，2014	6个月	6个月	女	有	有	无	无	无	有
8	李晓华^[6]，2014	73 d	4个月	女	有	有	无	无	无	无
9	余宾^[7]，2015	2个月	2岁6个月	男	有	有	有	无	有	无
10	叶小飞^[8]，2012	2个月	2个月	男	有	有	无	无	无	无
11	段丽芬^[9]，2016	9个月	6岁1个月	男	有	无	有	无	无	有
12	Fung^[10]，2010	18个月	5岁	男	有	有	有	无	有	有
13	Fung^[10]，2010	8个月	17岁	女	有	有	有	无	有	无
14	姬辛娜^[11]，2018	11个月	4岁2个月	女	有	有	有	有	有	无
15	姬辛娜^[11]，2018	15个月	11岁1个月	男	有	有	有	有	有	无
16	姬辛娜^[11]，2018	2个月	3岁4个月	男	有	有	有	有	有	无
17	姬辛娜^[11]，2018	6个月	6岁	女	有	有	有	有	有	无
18	杨贵云，2020	1岁	2岁2个月	女	有	有	有	无	有	有
病例(No.)	其他症状	视频脑电图	头颅CT或MRI	SLC2A1基因检测	脑脊液葡萄糖浓度(mmol/L)	脑脊液葡萄糖/血糖
1	无	多灶痫样放电	轻度脑萎缩	2号外显子大片段缺失	1.10～2.45，平均为1.68^b	0.16～0.51，平均为0.34^b
2	无	正常	正常	5号外显子C.741G>A(E247K)
3	晨起及餐前发作性困倦、无力	正常	双侧脑室饱满	5号外显子C.599delA
4	发作性无力、睡眠增多、意识障碍	正常	脑白质发育迟缓	6号外显子C.761delA
5	发作性精神症状	慢波、全导和局灶痫样放电	正常	9号外显子C.1148C>A(P383H)
6	发作性无力	正常	正常	9号外显子C.1198C>T(R400C)
7	肌张力低下	背景为弥散性2～ 3 Hz低波幅δ波	未作	未发现基因突变点	1.60	0.24
8	左膝腱反射略活跃	双额及中央顶、枕区多灶性棘波、尖波、多棘波散发或簇发	未作	8号外显子C.972＋1G>C	2.30	0.32
9	运动障碍	背景活动慢，以中高幅4～5 Hz θ波为主	正常	C.516 ＋2T>G(杂合突变)^a	1.35	0.32
10	无	δ活动为主	正常	未描述	1.10	0.21
11	晨起头痛，空腹行走不稳	广泛性棘慢波发放	正常	4号外显子C.350_385del	1.87	0.36
12	肌张力障碍	正常	正常	2号外显子240delC	1.80	0.38
13	饥饿时发作性无力	正常	正常	8号外显子杂合突变c.1176 C>T(R333W)	1.90	0.38
14	空腹或玩耍时发作性肢体瘫痪、肌张力异常、震颤	全导阵发性高幅慢波，夹杂癫痫放电	正常	6号外显子c.787_791delTTCCG(p.F263Lfs)	均降低，但是未提供具体数据^c	均降低，但是未提供具体数据^c
15	肌张力异常，发作性眼球运动障碍	右侧大脑半球持续性慢波，右侧大脑半球及左侧额区癫痫放电	双侧额叶皮层下异常信号	4号外显子c.376G>A(p.R126C)
16	震颤、肌张力异常，发作性眼球运动障碍	全导癫痫放电，以额区、枕区显著	双侧额、颞叶脑沟增宽	6号外显子c.377G>A(p.R126H)
17	肌张力异常	双侧额、中央及额中线区偶见不典型尖波	正常	6号外显子c.688_689 insT
18	肌张力升高	醒睡各期大量弥散性快波或快波节律发放，睡眠期多灶性棘波、尖波、棘慢波发放	正常	5号外显子c.661G>A	2.43	0.44

表1 本例及文献纳入研究的17例GLUTl-DS患儿临床病例资料分析

病例(No.)	文献(第1作者，文献发表年)	发病年龄	诊断年龄	性别	痫性发作	智力、运动发育落后	共济失调	踝阵挛	语言障碍	小头畸形
1	刘燕燕^[5]，2013	41 d	3个月	男	有	有	无	无	无	无
2	刘燕燕^[5]，2013	60 d	3个月	男	有	有	无	无	无	无
3	刘燕燕^[5]，2013	33 d	6岁	男	有	有	有	无	无	无
4	刘燕燕^[5]，2013	3岁7个月	7岁	女	无	有	有	无	无	无
5	刘燕燕^[5]，2013	6岁2个月	6岁5个月	男	有	无	有	无	无	无
6	刘燕燕^[5]，2013	2岁10个月	5岁	女	有	有	有	无	无	有
7	李晓华^[6]，2014	6个月	6个月	女	有	有	无	无	无	有
8	李晓华^[6]，2014	73 d	4个月	女	有	有	无	无	无	无
9	余宾^[7]，2015	2个月	2岁6个月	男	有	有	有	无	有	无
10	叶小飞^[8]，2012	2个月	2个月	男	有	有	无	无	无	无
11	段丽芬^[9]，2016	9个月	6岁1个月	男	有	无	有	无	无	有
12	Fung^[10]，2010	18个月	5岁	男	有	有	有	无	有	有
13	Fung^[10]，2010	8个月	17岁	女	有	有	有	无	有	无
14	姬辛娜^[11]，2018	11个月	4岁2个月	女	有	有	有	有	有	无
15	姬辛娜^[11]，2018	15个月	11岁1个月	男	有	有	有	有	有	无
16	姬辛娜^[11]，2018	2个月	3岁4个月	男	有	有	有	有	有	无
17	姬辛娜^[11]，2018	6个月	6岁	女	有	有	有	有	有	无
18	杨贵云，2020	1岁	2岁2个月	女	有	有	有	无	有	有
病例(No.)	其他症状	视频脑电图	头颅CT或MRI	SLC2A1基因检测	脑脊液葡萄糖浓度(mmol/L)	脑脊液葡萄糖/血糖
1	无	多灶痫样放电	轻度脑萎缩	2号外显子大片段缺失	1.10～2.45，平均为1.68^b	0.16～0.51，平均为0.34^b
2	无	正常	正常	5号外显子C.741G>A(E247K)
3	晨起及餐前发作性困倦、无力	正常	双侧脑室饱满	5号外显子C.599delA
4	发作性无力、睡眠增多、意识障碍	正常	脑白质发育迟缓	6号外显子C.761delA
5	发作性精神症状	慢波、全导和局灶痫样放电	正常	9号外显子C.1148C>A(P383H)
6	发作性无力	正常	正常	9号外显子C.1198C>T(R400C)
7	肌张力低下	背景为弥散性2～ 3 Hz低波幅δ波	未作	未发现基因突变点	1.60	0.24
8	左膝腱反射略活跃	双额及中央顶、枕区多灶性棘波、尖波、多棘波散发或簇发	未作	8号外显子C.972＋1G>C	2.30	0.32
9	运动障碍	背景活动慢，以中高幅4～5 Hz θ波为主	正常	C.516 ＋2T>G(杂合突变)^a	1.35	0.32
10	无	δ活动为主	正常	未描述	1.10	0.21
11	晨起头痛，空腹行走不稳	广泛性棘慢波发放	正常	4号外显子C.350_385del	1.87	0.36
12	肌张力障碍	正常	正常	2号外显子240delC	1.80	0.38
13	饥饿时发作性无力	正常	正常	8号外显子杂合突变c.1176 C>T(R333W)	1.90	0.38
14	空腹或玩耍时发作性肢体瘫痪、肌张力异常、震颤	全导阵发性高幅慢波，夹杂癫痫放电	正常	6号外显子c.787_791delTTCCG(p.F263Lfs)	均降低，但是未提供具体数据^c	均降低，但是未提供具体数据^c
15	肌张力异常，发作性眼球运动障碍	右侧大脑半球持续性慢波，右侧大脑半球及左侧额区癫痫放电	双侧额叶皮层下异常信号	4号外显子c.376G>A(p.R126C)
16	震颤、肌张力异常，发作性眼球运动障碍	全导癫痫放电，以额区、枕区显著	双侧额、颞叶脑沟增宽	6号外显子c.377G>A(p.R126H)
17	肌张力异常	双侧额、中央及额中线区偶见不典型尖波	正常	6号外显子c.688_689 insT
18	肌张力升高	醒睡各期大量弥散性快波或快波节律发放，睡眠期多灶性棘波、尖波、棘慢波发放	正常	5号外显子c.661G>A	2.43	0.44

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