背景：具有高度扩增突变（HE-PHD;>80CAG重复）的小儿亨廷顿病非典型，与成人发作的亨廷顿病（AOHD）相比，神经发育迟缓，癫痫,大脑葡萄糖代谢异常，早期纹状体损伤,减少寿命。由于遗传性GLUT-1缺乏综合征表现出类似于HE-PHD的症状谱，我们调查了两种主要葡萄糖转运蛋白的潜在作用，GLUT-1和GLUT-3，在HE-PHD。
方法：我们比较了HE-PHD中GLUT-1和GLUT-3蛋白的表达，青少年发病（JOHD），和AOHD大脑（n=2；n=3；n=6）和外围（n=3；n=2；n=2）与健康成人对照（n=6；n=6）。我们还研究了线粒体复合物和己糖激酶II蛋白的表达。
结果：HE-PHD额叶皮质中GLUT-1和GLUT-3的表达明显低于对照组（p=0.009,95%[CI13.4,14.7]；p=0.017,95%[CI14.2,14.5]）。在成纤维细胞中，GLUT-1和GLUT-3表达低于对照组(p<0.0001,95%[CI0.91,1.09];p=0.046,95%[CI0.93,1.07])。在额叶皮层,这种情况的发生没有证据表明广泛的神经元变性。HE-PHD患者线粒体复合物表达下调,特别是配合物II-III，与对照组相比,额叶皮质的水平较低(p=0.027,95%[CI17.1,17.6];p=0.002,95%CI[16.6,16.9])和AOHD患者(p=0.052,95%[CI17.0,17.6];p=0.002,95%[CI16.6,16.7])。与对照组相比，HE-PHD额叶皮质和纹状体中的己糖激酶II表达也较低（p=0.010,95%[CI17.8,18.2]；p=0.045,95%[CI18.6,18.7]），与AOHD患者相比，额叶皮质中的己糖激酶II表达也较低（p=0.013,95%[CI17.7,18.1]）。表达JOHD水平始终不同于HE-PHD的水平,但类似于AOHD的水平。
结论：我们的数据表明，儿童亨廷顿病的大脑发生了功能失调的低代谢状态。
背景：\'5×1000\'向LIRH基金会捐赠个人所得税；意大利卫生部RC2301MH04和RF-2016-02364123到CSS。
BACKGROUND: Paediatric Huntington disease with highly expanded mutations (HE-PHD; >80 CAG repeats) presents atypically, compared to adult-onset Huntington disease (AOHD), with neurodevelopmental delay, epilepsy, abnormal brain glucose metabolism, early striatal damage, and reduced lifespan. Since genetic GLUT-1 deficiency syndrome shows a symptom spectrum similar to HE-PHD, we investigated the potential role of the two main glucose transporters, GLUT-1 and GLUT-3, in HE-PHD.
METHODS: We compared GLUT-1 and GLUT-3 protein expression in HE-PHD, juvenile-onset (JOHD), and AOHD brains (n = 2; n = 3; n = 6) and periphery (n = 3; n = 2; n = 2) versus healthy adult controls (n = 6; n = 6). We also investigated mitochondrial complexes and hexokinase-II protein expression.
RESULTS: GLUT-1 and GLUT-3 expression were significantly lower in HE-PHD frontal cortex (p = 0.009, 95% [CI 13.4, 14.7]; p = 0.017, 95% [CI 14.2, 14.5]) versus controls. In fibroblasts, GLUT-1 and GLUT-3 expression were lower compared to controls (p < 0.0001, 95% [CI 0.91, 1.09]; p = 0.046, 95% [CI 0.93, 1.07]). In the frontal cortex, this occurred without evidence of extensive neuronal degeneration. Patients with HE-PHD had deregulated mitochondrial complex expression, particularly complexes II-III, levels of which were lower in frontal cortex versus controls (p = 0.027, 95% [CI 17.1, 17.6]; p = 0.002, 95% CI [16.6, 16.9]) and patients with AOHD (p = 0.052, 95% [CI 17.0, 17.6]; p = 0.002, 95% [CI 16.6, 16.7]). Hexokinase-II expression was also lower in HE-PHD frontal cortex and striatum versus controls (p = 0.010, 95% [CI 17.8, 18.2]; p = 0.045, 95% [CI 18.6, 18.7]) and in frontal cortex versus patients with AOHD (p = 0.013, 95% [CI 17.7, 18.1]). Expression JOHD levels were consistently different to those of HE-PHD but similar to those of AOHD.
CONCLUSIONS: Our data suggest a dysfunctional hypometabolic state occurring specifically in paediatric Huntington disease brains.
BACKGROUND: \'5 × 1000\' Personal Income Tax donation to LIRH Foundation; Italian Ministry of HealthRC2301MH04 and RF-2016-02364123 to CSS.
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