葡萄糖转运子1缺乏综合征的临床特点与基因突变分析北大核心CSCD

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。     

葡萄糖转运子1缺陷综合征运动障碍特点和诊疗分析

目的 探讨葡萄糖转运子1缺陷综合征（GLUT1-DS）的临床特征和诊疗方法,分析运动障碍的诊断意义。方法 收集4例GLUT1-DS患儿的临床资料,分析其临床特点和治疗随访情况。结果 4例中男2例、女2例,起病年龄2~15个月。表现为运动障碍、癫癎发作和发育迟缓,均以癫癎发作为首诊原因。4例均有持续性共济失调、肌张力异常和构音障碍,2例有持续性震颤,发作性肢体瘫痪和眼球运动障碍各2例,劳累易诱发发作性症状。4例患儿的脑脊液葡萄糖及其与血糖的比值均降低。4例均检测到SLC2A1基因突变,均接受生酮饮食治疗,生酮比3：1~2：1,发作性症状5周内完全缓解。结论 对于合并多样化运动障碍的智力运动发育迟缓的癫癎患儿需考虑GLUT1-DS,生酮饮食的生酮比维持在3：1~2：1可起效。     

Alpers综合征的临床与病理特点及基因突变分析

目的 探讨难治性癫(癎)患儿的病因及Alpers综合征的特点.方法 对1例Alpers综合征患儿进行临床观察,神经电生理、神经影像学检查,脑脊液检查,外周神经、肌肉及脑组织活检,线粒体DNA、脱氧鸟苷激酶基因与多聚酶r1(POLGI)基因突变分析.结果 Alpers综合征患儿的临床特征为难治性癫(癎),应用丙戊酸钠后发生急性肝衰竭、皮质盲和精神运动倒退.脑脊液蛋白与免疫指标增高.脑电图示背景节律性慢波化及双侧枕区棘慢波、快波及θ节律发放.颅脑MRI示半卵圆中心、小脑白质及枕叶皮层病变,后期有弥散性脑萎缩.腓肠肌病理活检无异常,腓肠神经病理示有髓神经纤维减少伴轴索和髓鞘病变,以轴索病变为主.左枕叶病理活检示皮层胶质细胞增牛,神经元丢失,海绵样变性,白质部分脱髓鞘改变、胶质增生和空泡变性.线粒体DNA、脱氧鸟苷激酶基因未发现突变.POLGI基因发现一对新的复合杂合突变c.248T＞c(p.L83P)和c.2662G＞A(p.G888S),其父携带L83P突变,其母携带G888S突变.结论该例患儿临床、电生理、病理及POLGJ基因突变与Alpers综合征高度一致,其突出的白质病变与脑脊液免疫指标异常为首次报道.对于应用丙戊酸钠后出现严重肝功能异常的难治性癫(癎)患儿应高度怀疑Apers综国合征.     

1型葡萄糖转运体缺陷综合征临床特征并文献复习

目的 探讨1型葡萄糖转运体缺陷综合征(glucose transporter 1 deficiency syndrome,GLUT1-DS)的临床特征并进行文献复习.方法 对1例GLUT1-DS患儿的临床资料、脑脊液葡萄糖、脑电图、MRI和基因突变特点进行分析,并进行文献复习.结果 患儿,男,6岁1个月,9个月起晨起空腹时出现全面强直阵挛发作,共发作7次,头围47.5cm.辅助检查:脑脊液葡萄糖1.87mmol/L,脑脊液葡萄糖/血糖比值0.36,头颅MRI正常,发作间期脑电图示广泛性棘慢波发放.SLC2A1基因检查:第4外显子c.350_385del(编码区第350_385号核苷酸缺失)杂合核苷酸变异,该变异为新发现的突变位点.文献复习共219例GLUT1-DS患儿,其中159例(72％)有癫痫发作,105例(47％)有运动障碍,61例(27％)有智力发育落后.脑脊液葡萄糖(1.92±0.31) mmol/L,脑脊液葡萄糖/血糖比值0.36±0.07.183例(96％)患儿存在SLC2A1基因突变,错义突变最多见.结论 GLUT1-DS临床症状谱广,脑脊液葡萄糖、脑脊液葡萄糖/血糖比值明显降低,且排除脑膜炎者可诊断GLUT1-DS,可行SLC2A1突变检查.     

SCN1A基因突变与相关癫(癎)综合征的研究进展

SCN1A基因编码电压门控钠离子通道a1亚单位,是引起可兴奋细胞如神经细胞动作电位的基本单位.SCN1A基因是与癫(癎)综合征相关的最重要的基因之一.SCN1A基因突变导致癫(癎)表型异质性,临床表现多样化,轻者表现为热性惊厥,重者表现为婴儿严重肌阵挛性癫(癎).通过检索SCN1A基因突变数据库,发现约900多种与癫(癎)综合征相关的基因突变.该文就SCN1A基因突变与相关癫(癎)综合征及SCN1A基因筛查的重要意义作一综述.     

吡哆醇依赖性癫(癎)的临床及乙醛脱氢酶7家庭成员A1基因突变分析

目的 分析1例吡哆醇依赖性癫(癎)(PDE)的临床诊治过程及乙醛脱氢酶7家庭成员A1(ALDH7A1)基因突变特征.方法 对1例以早期癫(癎)起病的PDE患儿行临床诊治观察、神经电生理及神经影像学检查、以及ALDH7A1基因突变分析.结果 患儿出生2个月出现反复癫(癎)发作,多种抗癫(癎)药均不能控制发作,多次住院过程中在抗癫(癎)药治疗基础上给予吡哆醇静脉滴注使发作控制,出院后仅用抗癫(癎)药而未用吡哆醇维持治疗,癫(癎)发作分别在吡哆醇撤药后13 d、14 d及38 d出现复发,减停抗癫(癎)药物后仅单纯口服吡哆醇使发作完全控制.治疗前后多次EEG正常,头颅MRI检查正常.ALDH7A1基因检测发现1对新的复合杂合突变,第5外显子c.410G＞ A(p.G137E)和第11内含子IVS11 +1G＞A剪切位点突变,其父携带G137E突变,其母携带IVS11 +1G＞A突变.结论 本例癫(癎)发作早期起病、经吡哆醇治疗有效、撤药后复发临床提示了PDE的可能,ALDH7A1基因分析最终确诊了国内第1例PDE,本例携带的2个基因突变位点均为国际未报道的新位点.     

红细胞膜表面葡萄糖转运蛋白1水平及红细胞葡萄糖摄取率在葡萄糖转运体1缺陷综合征中的诊断价值

目的:探索及评价协助诊断葡萄糖转运体1缺陷综合征(GLUT1-DS)的新方法。方法:回顾性分析。纳入2019年10月至2020年10月在中国人民解放军总医院第一医学中心儿科及上海德济医院营养科就诊的16例 SLC2A1基因突变并癫痫和/或运动障碍的患儿为研究对象,以临床表型、脑脊液和/或基因检查结果判定是否...     

γ-氨基丁酸转运体与癫(癎)

根据γ-氨基丁酸转运体(γ-amino butyric acid transporter,GAT)5种不同亚型的脑区及亚细胞分布特点,GAT1和GAT3两者与癫(癎)的发生和发展关系最为密切.GAT表达异常或功能受损是癫(癎)发作时神经元高兴奋性的原因之一.γ-氨基丁酸能抑制性回路减少及其表达的GAT下降,原发性GAT...     

葡萄糖转运蛋白1缺陷综合征

葡萄糖转运蛋白1缺陷综合nF(G1ut-1 DS)．亦称De Vivo病，于1991年首先由De Vivo等所描述，这是第一个被发现的影响血脑屏障功能的遗传性疾病。该病发病年龄小，对生长发育影响严重．抗癫痫药物治疗无效，而生酮饮食治疗有效。G1ut-1 DS在国内尚未被认识．漏诊的可能性很大，因而提高对该病的认识，早期诊断、早期治疗．对于及时控制症状，改善预后是非常重要的。     

心源性晕厥误诊癫(癎)临床分析

目的 分析总结心源性晕厥的特点及误诊原因.方法 对6例误诊为癫(癎)的心源性晕厥患儿的临床特点及误诊原因进行分析.结果 5例患儿晕厥前有运动或情绪激动史,有心悸、心跳加速、乏力的先兆,晕厥持续时间数秒至8 min不等;尿失禁3例,肢体强直3例;晕厥后均无意识改变.5例院外脑电图异常,其中2例出现(癎)样放电;Holter见多形室速2例,单形窒速1例,房扑、房颤,多形室速可能1例,QT间期延长伴室速2例.出院诊断示2例长QT间期综合征,2例儿茶酚胺敏感型室速,1例室性心动过速,1例房扑、房颤、多形室速可能.单形室速患儿行射频消融术后,室速消失;其余5例患儿均口服倍他乐克,剂量在1.5～2 mg/(kg·d),复查Holter较前明显好转.除1例24 h脑电图恢复成弥漫异常外,其余均恢复正常.结论 运动或劳累中晕厥、与心悸有关的晕厥、有年幼猝死家族史者,若诊为癫(癎),经抗癫(癎)药物治疗无效者,均应考虑心源性晕厥的可能.Holter、动态脑电图检查是明确心源性晕厥诊断的主要手段,频繁发作的心源性晕厥可引起脑电图异常.     

Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome

AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.     

Questionnaire survey on the current status of ketogenic diet therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) in Japan

Objectives

We conducted a questionnaire survey on the efficacy and side effects of ketogenic diet (KD) therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) as well as issues associated with long-term KD therapy from the viewpoint of patients' families.

Adolescents with clinical type 1 diabetes display reduced red blood cell glucose transporter isoform 1 (GLUT1)

Type 1 diabetic (T1D) adolescent children on insulin therapy suffer episodes of both hyper‐ and hypoglycemic episodes. Glucose transporter isoform GLUT1 expressed in blood–brain barrier (BBB) and red blood cells (RBC) compensates for perturbed circulating glucose toward protecting the supply to brain and RBCs. We hypothesized that RBC‐GLUT1 concentration, as a surrogate for BBB‐GLUT1, is altered in T1D children. To test this hypothesis, we measured RBC‐GLUT1 by enzyme‐linked immunosorbent assay (ELISA) in T1D children (n = 72; mean age 15.3 ± 0.2 yr) and control children (CON; n = 11; mean age 15.6 ± 0.9 yr) after 12 h of euglycemia and during a hyperinsulinemic–hypoglycemic clamp with a nadir blood glucose of ?3.3 mmol/L for 90 min (clamp I) or ?3 mmol/L for 45 min (clamp II). Reduced baseline RBC‐GLUT1 was observed in T1D (2.4 ± 0.17 ng/ng membrane protein); vs. CON (4.2 ± 0.61 ng/ng protein) (p < 0.0001). Additionally, baseline RBC‐GLUT1 in T1D negatively correlated with hemoglobin A1c (HbA1c) (R = ?0.23, p < 0.05) but not in CON (R = 0.06, p < 0.9). Acute decline in serum glucose to 3.3 mmol/L (90 min) or 3 mmol/L (45 min) did not change baseline RBC‐GLUT1 in T1D or CON children. We conclude that reduced RBC‐GLUT1 encountered in T1D, with no ability to compensate by increasing during acute hypoglycemia over the durations examined, may demonstrate a vulnerability of impaired RBC glucose transport (serving as a surrogate for BBB), especially in those with the worst control. We speculate that this may contribute to the perturbed cognition seen in T1D adolescents.     

GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging

Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications.     

Glucose transporter type 1 deficiency: a study of two cases with video-EEG

Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose transport. Clinical manifestations are presumed secondary to reduced glucose transport across the blood brain barrier, and include seizures, abnormal tone, developmental delay and hypoglycorrhachia. A high index of suspicion is important as GLUT1 deficiency is a potentially treatable cause of mental retardation. We studied two affected children by continuous video-EEG in order to better understand the cause of the clinical manifestations and improvement on a ketogenic diet. The EEG was characterized by generalized paroxysmal 2–2.5 Hz spike-wave discharges, although normal EEGs were also obtained. Atypical absence seizures were the most prominent clinical seizure. Epileptiform activity and clinical seizures occurred in both children while acutely ketotic and non-ketotic, but were markedly more frequent in one child when non-ketotic. Discharges were not associated with a reduction in substrate for brain metabolism in the blood at that time. Conclusion Atypical absence seizures are common in glucose transporter type 1 deficiency and should alert the clinician to the possibility of this treatable disorder when present in a young child with developmental delay. Our data suggest that the therapeutic mechanism of the ketogenic diet in this disorder is more complicated than simply delivering ketones as an alternative substrate for brain metabolism. Received: 28 September 1998 / Accepted: 12 May 1999     

Clinical and genetic studies of five fatal cases of Japanese Gaucher disease type 1

Five fatal cases of Japanese patients with type 1 Gaucher disease were studied. The causes of death included hemorrhage secondary to esophageal varices (two cases), respiratory distress (one case), hepatic failure (one case) and postoperative sepsis (one case). All of the patients had previous splenectomies, four patients had bone involvement and hepatic cirrhosis. The identified Gaucher genotypes were 1448C/1213G, 1603T/1603T, 1448C/1390G, ?/? and 1213G/1213G. The prognosis of type 1 Gaucher disease is generally good. We propose that patients with a similar clinical course and genotype to those presented in the present study should receive prompt comprehensive treatment. Patients with the 1213G mutation, pulmonary and liver involvement and a previous splenectomy should be considered as candidates for early vigorous treatment.     

血糖水平对缺氧缺血新生大鼠脑内葡萄糖转运蛋白1合成的影响

目的　探讨血糖水平对缺氧缺血 (HI)新生大鼠脑内葡萄糖转运蛋白 1(GLUT1)合成的影响。方法　在成功建立HI并高、低血糖新生大鼠模型的基础上 ,应用免疫组织化学方法定量检测新生大鼠脑内海马和皮质部位GLUT1的合成情况。结果　正常情况下GLUT1随日龄增加而合成增加 ,HI可引起GLUT1合成在短期内明显增加 ,以HI前重症高血糖对GLUT1合成的影响较明显 ,其合成量在HI后 2、2 4、48h显著高于其他各组。结论　在HI前预先补充足量葡萄糖 ,可改善脑内葡萄糖供应。此与HI时增加的无氧酵解代谢方式相适应。