Clinical study on the disease characteristics,genotype analysis and ketogenic diet therapy of glucose transporter tape 1 deficiency syndrome

doi:10.19854/j.cnki.1008-2425.2024.04.0004

Abstract

Abstract: Objective To explore the clinical characteristics,gene mutation characteristics and therapeutic effect of ketogenic diet on glucose transporter 1 deficiency syndrome (GLUT1-DS). Methods A retrospective analysis was performed on 8 children with GLUT1-DS admitted to our hospital from January 2019 to December 2023,and the detailed clinical manifestations of these 8 cases were recorded. Results Among the 8 cases,5 were males and 3 females.The age of onset ranged from 3 months to 96 months.Epilepsy was the first onset symptom of 8 cases.Paroxysmal dyskinesia was the first onset symptom of 2 cases.Psychobehavioral abnormalities combined with movement disorders was the first onset symptom of 1 case.6 cases had different degrees of psychomotor retardation.CSF examination was performed in all patients,and CSF sugar in all 8 cases was reduced to varying degrees,ranging from 1.6-2.3mmol/L,and CSF sugar/glucose ratio ranged from 0.28 to 0.48.3 cases showed slow background activity;3 cases were normal EEG;Epileptiform discharge occurred in 2 cases.5 cases were normal MRI and other cases had nonspecific changes.Genetic tests were performed in all 8 cases,among which 4 cases were missense variation,3 were frameshift variation and 1 was exon large fragment deletion mutation.All the children were treated with ketogenic diet,starting with classic KDT (2:1),the course of treatment ranged from 7 months to 41 months,and no one gave up due to ketogenic adverse reactions or intolerance.With the exception of 1 case,others had different degrees of improvement in seizure control,dyskinesia and cognitive function. Conclusion The clinical manifestations of glucose transporter type 1 deficiency syndrome are varied.For patients with refractory seizure,developmental retardation and complex dyskinesia,CSF examination or SLC2A1 gene mutation testing can help in the diagnosis of GLUT1-DS.Early initiation of ketogenic diet therapy may improve the symptom and prognosis of the patients.

Key words: Glucose transporter tape 1 deficiency syndrome, SLC2A1, Epilepsy, Ketogenic diet

摘要： 目的探讨葡萄糖转运体1缺陷综合征(glucose transporter type 1 deficiency syndrome,GLUT1-DS)的临床表型和基因型特点及生酮饮食治疗的疗效。方法回顾性分析了我院2019年1月至2023年12月收治的8例GLUT1-DS患儿,对其临床表现、脑脊液、脑电图、影像学、遗传学检测、治疗与转归进行总结。结果 8例患者中,其中男5例,女3例。发病年龄为3个月至8岁,5例患儿以癫痫发作为首诊症状,2例以发作性运动障碍为首诊症状,1例以精神行为异常合并运动障碍为首诊症状。6例患儿存在不同程度的精神运动发育迟缓。所有患儿进行了脑脊液检查,脑脊液糖水平均有不同程度的降低,范围在1.6至2.3 mmol/L之间,脑脊液糖/血糖比值范围在0.28至0.48之间。3例患儿的脑电图提示背景活动偏慢,3例为正常儿童脑电图,2例有痫样放电。5例患儿磁共振示未见明显异常,其余3例有非特异改变。8例患儿均进行了遗传学检测,其中4例为错义变异,3例为移码变异,1例为外显子大片段缺失变异。患儿均接受了生酮饮食治疗,起始均采用经典KDT,比例为2:1,疗程在7至41个月之间不等,目前未有因生酮不良反应或不耐受放弃者。除1例患儿疗效不显著外,其余患儿在癫痫发作、运动障碍、认识水平均有不同程度改善。结论 GLUT1-DS的临床表现复杂多样。对于难治性癫痫发作、发育迟缓和复杂运动障碍的儿童,脑脊液检查或SLC2A1基因突变检测有助于GLUT1-DS的诊断。早期开始生酮饮食治疗可显著改善GLUT1-DS的症状和预后。

关键词: 葡萄糖转运体1缺陷综合征, SLC2A1, 癫痫, 生酮饮食

CLC Number:

R741

Shen Liwei, Ye Xiaofei, Tian Tian, Yang Bin. Clinical study on the disease characteristics,genotype analysis and ketogenic diet therapy of glucose transporter tape 1 deficiency syndrome[J]. Chinese Journal of Stereotactic and Functional Neurosurgery, 2024, 37(4): 210-216.

沈丽伟, 叶小飞, 田甜, 杨斌. 葡萄糖转运体1缺陷综合征疾病特征、基因型分析及生酮饮食治疗的临床研究[J]. 立体定向和功能性神经外科杂志, 2024, 37(4): 210-216.

References

[1] De Vivo DC,Trifiletti RR,Jacobson RI,et al .Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia,seizures,and developmental delay[J].N Engl J Med,1991,325(10):703~709.
[2] Tang M,Monani UR.Glut1 deficiency syndrome:New and emerging insights into a prototypical brain energy failure disorder[J].Neurosci Insights,2021,28(16):26331055211011507.
[3] Veneruzzo GM,Loos MA,Armeno M,et al .Glucose transporter type 1 deficiency syndrome:clinical aspects,diagnosis,and treatment[J].Arch Argent Pediatr,2023,121(1):e202202677.
[4] Seidner G,Alvarez MG,Yeh JI,et al.GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier[J].Nat Genet,1998,18(2):188~191.
[5] Bélanger M,Allaman I,Magistretti PJ.Brain energy metabolism:focus on astrocyte-neuron metabolic cooperation[J].Cell Metab,2011,14(6):724~738.
[6] Winkler EA,Nishida Y,Sagare AP,et al.GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration[J].Nat Neurosci,2015,18(4):521~530.
[7] Varesio C,De Giorgis V,Veggiotti P,et al.GLUT1-DS Italian registry:past,present,and future:a useful tool for rare disorders[J].Orphanet J Rare Dis,2023,18(1):63.
[8] Ramm-Pettersen A,Nakken KO,Skogseid IM,et al.Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome:results from a retrospective Norwegian study[J].Dev Med Child Neurol,2013,55(5):440~447.
[9] Hu Q,Shen Y,Su T,et al.Clinical and genetic characteristics of Chinese children with GLUT1 deficiency dyndrome:case report and literature review[J].Front Genet,2021,12:734481.
[10] Chugani HT.A critical period of brain development:studies of cerebral glucose utilization with PET[J].Prev Med,1998,27(2):184~188.
[11] Wong HY,Chu TS,Lai JC,et al.Sodium valproate inhibits glucose transport and exacerbates Glut1-deficiency in vitro[J].J Cell Biochem,2005,96(4):775~785.
[12] Pong AW,Geary BR,Engelstad KM,et al.Glucose transporter type I deficiency syndrome:epilepsy phenotypes and outcomes.Epilepsia,2012,53(9):1503~1510.
[13] Leen WG,Taher M,Verbeek MM,et al.GLUT1 deficiency syndrome into adulthood:a follow-up study[J].J Neurol,2014,261(3):589~599.
[14] Leen WG,Wevers RA,Kamsteeg EJ,et al.Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome:a systematic review[J].JAMA Neurol,2013,70(11):1440~1444.
[15] Fukumoto H,Seino S,Imura H,et al.Characterization and expression of human HepG2/erythrocyte glucose-transporter gene[J].Diabetes,1988,37(5):657~661.
[16] Sandvig I,Scheffner T,Sheridan E,et al.Glucose transporter-1 deficiency syndrome:the expanding clinical and genetic spectrum of a treatable disorder[J].Brain,2010,133(Pt 3):655~670.
[17] Yang H,Wang D,Engelstad K,et al.Glut1 deficiency syndrome and erythrocyte glucose uptake assay[J].Ann Neurol,2011,70(6):996~1005.
[18] Harb R,Whiteus C,Freitas C,et al.In vivo imaging of cerebral microvascular plasticity from birth to death[J].J Cereb Blood Flow Metab,2013,33(1):146~156.
[19] Tang M,Gao G,Rueda CB,et al.Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein[J].Nat Commun,2017,8:14152.
[20] Tang M,Park SH,Petri S,et al.An early endothelial cell-specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice[J].JCI Insight,2021,6(3):e145789.