Departments of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Neurology. 2011 Sep 6;77(10):959-64. doi: 10.1212/WNL.0b013e31822e0479. Epub 2011 Aug 10.
Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as paroxysmal choreoathetosis/spasticity (DYT9) and linked close to but not including the SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1 defects.
The German/Dutch family and an Australian monozygotic twin pair were clinically (re-)investigated, and 139 index cases with dominant or sporadic HSP in which relevant dominant genes were partially excluded were identified from databanks. SLC2A1 was sequenced in all cases in this observational study and the functional effects of identified sequence variations were tested in glucose uptake and protein expression assays.
We identified causative mutations in SLC2A1 in both families, which were absent in 400 control chromosomes, cosegregated with the affection status, and decreased glucose uptake in functional assays. In the 139 index patients with HSP without paroxysmal dyskinesias, we only identified one sequence variation, which, however, neither decreased glucose uptake nor altered protein expression.
This study shows that DYT9 and DYT18 are allelic disorders and enlarges the spectrum of GLUT1 phenotypes, now also including slowly progressive spastic paraparesis combined with PED. SLC2A1 mutations were excluded as a cause of HSP without PED in our cohort.
SLC2A1 基因突变导致广泛的神经发育障碍，包括经典的葡萄糖转运蛋白 1 缺乏症（GLUT1 缺乏症）、阵发性运动诱发运动障碍（PED，DYT18）和失神癫痫。以前曾描述过一个大型的德荷家族为阵发性舞蹈手足徐动症/痉挛（DYT9），与染色体 1p 上的 SLC2A1 基因座紧密相连，但不包括该基因座。我们检测了 1）除 PED 外，是否还有描述的 DYT9 中那样的进行性痉挛性截瘫，以及 2）是否 SLC2A1 缺陷导致不伴 PED 的常染色体显性遗传性痉挛性截瘫（HSP）。
对德国/荷兰家族和澳大利亚的一对同卵双胞胎进行临床（重新）检查，并从数据库中确定了 139 例具有显性或散发性 HSP 的指数病例，其中部分排除了相关显性基因。在这项观察性研究中，对所有病例进行 SLC2A1 测序，并在葡萄糖摄取和蛋白表达测定中测试鉴定出的序列变异的功能影响。
我们在两个家族中均发现了 SLC2A1 的致病突变，在 400 个对照染色体中均不存在，与受累状态共分离，并在功能测定中降低了葡萄糖摄取。在没有阵发性运动障碍的 139 例 HSP 指数患者中，我们仅发现了一个序列变异，但它既没有降低葡萄糖摄取，也没有改变蛋白表达。
本研究表明 DYT9 和 DYT18 是等位基因疾病，并扩大了 GLUT1 表型谱，现在也包括伴有 PED 的缓慢进行性痉挛性截瘫。在我们的队列中，排除了 SLC2A1 突变是不伴 PED 的 HSP 的原因。
