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    • The EEGs of these six patients

    2021-10-15

    The EEGs of these six patients interestingly showed focal, multi-focal and generalized spikes, which was an exclusion criteria in our study as we selected our cohort to exclusively represent focal epilepsy. Remarkably all of these cases were diagnosed with paroxysmal exercise-induced dyskinesia (PED) at some stage or had a first degree family member with PED, although the possibility of ascertainment bias cannot be excluded (Wolking et al., 2014). The combination of focal epilepsy and PED is an interesting topic of further research as this would represent a milder, under-diganosed phenotype of GLUT1 DS. It would therefore be interesting to study the contribution of SLC2A1 mutations in patients with both NAFE and PED. However, late diagnosis and under recognition of PED would make recruitment of a such a cohort difficult. An equally important feature common to these cases is an early onset of focal seizures (average 5 years), while the age of onset in our cohort was much later (average 17 years). Focal epilepsy due to SLC2A1 mutation may be more common in patients with earlier seizure onset. We therefore suggest similar genetic analysis of a pediatric cohort is warranted.
    Conclusion
    Contributors
    Conflicts of interests
    Acknowledgements We thank the patients and their Famprofazone receptor for participating in our research program. Rebekah Stubbs and Amelia McGlade (University of Melbourne) are acknowledged for performing genomic DNA extractions. This study was supported by a National Health and Medical Research Council (NHMRC) Program Grant (1091593) to SFB and IES, a Practitioner Fellowship (1104831) to IES, a Career Development Fellowship (1063799) to MSH, and a Postdoctoral Training Fellowship to SAM (1072081). We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
    Introduction Cognitive function is known to be affected by macronutrient intakes, with high fat diets and obesity being particularly deleterious [1], [2]. In mice, inflammatory responses in the central nervous system (CNS) to high fat diet (HFD) and subsequent brain insulin resistance appear to occur within days after initiating a high fat diet [3]. Although the pathways involved in central insulin resistance have been investigated in considerable detail, knowledge as to the precise mechanisms which transmit HFD associated signals are only partially understood [1], [2], [4]. The CNS depends on glucose as its energy substrate, and glucose needs to be transported across the blood brain barrier. Brain glucose uptake is mediated by facilitated transport via the glucose transporter GLUT1, and an important role of GLUT1 in cognitive function is becoming increasingly apparent [5], [6]. Disturbances in GLUT1 function due to genetic aberrations of the SLC2A1 gene lead to seizures, motor dysfunction, and encephalopathy in GLUT1-haploinsufficient mice and humans, while complete deletion of GLUT1 is lethal [5], [6]. Very recently, HFD was shown to reduce GLUT1 expression in brain endothelia, leading to cognitive impairment in mice [7]. This reaction was counterbalanced by an increased and delayed production of VEGF in myeloid cells, leading to elevated circulating VEGF levels, which increased GLUT1 expression and thereby compensated for the downregulation by HFD. Deletion of VEGF in myeloid cells, however, prevented this protective response and enhanced the development of dementia in mouse models, which underscores the importance of GLUT1 and VEGF expression for cognitive function. The increase in VEGF was proposed to represent an inflammatory response reducing peripheral but increasing central glucose uptake to maintain CNS glucose supply [7]. These data raise the question as to the HFD-related regulation and association of GLUT1 and VEGF in humans with regard to cognition. Serum levels of VEGF were shown to be determined by several genetic polymorphisms [8], [9]. It is unknown whether dietary intakes alter serum levels of VEGF or the expression of GLUT1 in humans. Moreover, it is unknown whether the levels or the reaction to nutritional intakes is determined genetically.