GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study

Abstract

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. 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. 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. Our data suggest a dysfunctional hypometabolic state occurring specifically in paediatric Huntington disease brains. '5×1000' Personal Income Tax donation to LIRH Foundation; Italian Ministry of HealthRC2301MH04 and RF-2016-02364123 to CSS.