Glucose transporter 1 deficiency in the idiopathic generalized epilepsies
Glucose transporter 1 deficiency in the idiopathic generalized epilepsies
复制标题
DOI：
10.1002/ana.23702
复制
发表时间：
2012-11-01
影响因子：
11.2
通讯作者：
Scheffer, Ingrid E.
中科院分区：
文献类型：
--
作者：
Arsov, Todor;Mullen, Saul A.;Scheffer, Ingrid E.
目的：我们检查葡萄糖转运蛋白 1 (GLUT1) 缺乏是否会导致常见特发性全身性癫痫 (IGE)。方法：IGE 是常见的遗传性癫痫，通常遵循复杂的遗传规律；目前人们对它们的遗传结构知之甚少。由于 SLC2A1 突变，先前被认为罕见的 GLUT1 缺陷会导致葡萄糖穿过血脑屏障转运失败以及大脑代谢所需的葡萄糖不足。 GLUT1 缺陷首先与脑病相关，最近在患有癫痫和阵发性劳力性运动障碍 (PED) 的罕见显性家族中发现。 504 名具有 IGE 的先证者和 470 名对照者接受了 SLC2A1 测序。在非洲爪蟾卵母细胞中表达 SLC2A1 变体后，对葡萄糖转运进行了测定。对所有可用的亲属进行了表型分析，并对 SLC2A1 进行了测序。结果：经功能验证的 SLC2A1 突变存在于 504 名先证者中的 7 名（1.4%）和 470 名对照者中的 0 名。研究前未确诊的 PED 发生在 1 名先证者和 13 名携带突变的亲属中的 3 名身上。先证者和亲属的 IGE 与典型的 IGE 没有区别。 3例（0.6%）存在较大功能效应突变，呈常染色体显性遗传或新发突变。 4例（0.8%）有微妙的功能影响； 2 人表现出可能的显性遗传，2 人则没有。这些导致细微功能损伤的等位基因可能导致 IGE 的复杂多基因遗传。解释：SLC2A1 突变作为复杂遗传中的显性基因和易感等位基因，约占 IGE 的 1%。 GLUT1 缺乏症的诊断具有重要的治疗（生酮饮食）和遗传咨询意义。限制性葡萄糖输送的机制不同于目前将 IGE 作为离子通道障碍的关注点。安神经学 2012；72：807815
Objective: We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs). Methods: The IGEs are common, heritable epilepsies that usually follow complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the bloodbrain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced. Results: Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE. Interpretation: SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders. ANN NEUROL 2012;72:807815