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    • br Acknowledgements This work was supported by the grants

    2021-10-09


    Acknowledgements This work was supported by the grants from National key Basic Research Program of China (2012CB124702), 948 Program (2015-Z33), National Natural Science Foundation of China (31172093, 31301947), the National Science Foundation for Fostering Talents in Basic Research (J1103510), Specialized Research Fund for the Doctoral Program of Higher Education (20110146130002), the Fundamental Research Funds for the Central Universities (2013PY005), the Scientific Research Foundation of Guangxi University (XTZ130719), and Guangxi Natural Science Foundation (2014GXNSFDA118014).
    Introduction Glucose is the main fuel of the Sodium Phenylbutyrate and its diffusion across the blood-brain barrier from the systemic circulation is dependent on specific transporters. Glucose transporter 1 (GLUT1), encoded by the solute carrier family 2 member 1 (SLC2A1) gene, is the key facilitator responsible for the delivery of glucose across the blood-brain barrier (Simpson et al., 2007). Mutations in SLC2A1 impair glucose uptake in the brain leading to a wide variety of symptoms defined as GLUT1 deficiency syndrome (GLUT1 DS). GLUT1 is the only glucose or lactate transporter implicated in epilepsy (Hildebrand et al., 2014). While classic GLUT1 DS is characterized by infantile-onset encephalopathy, milder seizure phenotypes associated with SLC2A1 mutation have been described over the last decade (Arsov et al., 2012a, Suls et al., 2009). Approximately 90% of GLUT1 DS cases present with seizures, although this high prevalence may reflect some ascertainment bias as until recently infantile epilepsy was considered an essential symptom of GLUT1 DS. The majority of cases had genetic generalised epilepsy (GGE) syndromes such as early-onset absence epilepsy (EOAE) and myoclonic astatic epilepsy (MAE) (Arsov et al., 2012b, Mullen et al., 2011, Mullen et al., 2010, Suls et al., 2009). Until recently, focal seizures were only a feature of patients with GLUT1 encephalopathy. However, newer case reports describe SLC2A1 mutations in a small number of individuals with focal epilepsies including multi-focal and temporal lobe epilepsy (Leary et al., 2003, Mullen et al., 2010, Pong et al., 2012, Wolking et al., 2014). This led to our hypothesis that GLUT1 DS might also be a significant contributor to non-acquired focal epilepsy (NAFE). The contribution of SLC2A1 mutation to NAFE has not been systematically determined in a large cohort of cases despite focal epilepsy being the most common type, observed in 60% of all epilepsy patients. It is critical to identify a contribution of GLUT1 DS to NAFE as patients could benefit from the ketogenic diet (KD), a treatment that has achieved seizure reduction in a substantial number of patients with SLC2A1 mutations.
    Materials and Methods
    Results
    Discussion Sequence analysis did not reveal any potentially pathogenic mutations in the SLC2A1 gene in a relatively large cohort of 200 NAFE patients. The hypothesis that GLUT1 DS would make a significant contribution to focal epilepsy is therefore not supported by our data. When the results are compared to generalized epilepsies, we can conclude that there is a significantly lower rate of SLC2A1 mutation in focal epilepsy than in EOAE (Arsov et al., 2012a, Suls et al., 2009): 11/100 cases vs 0/200 cases (P<0.005) (Team., 2014). The rate of SLC2A1 mutation shows a non-significant trend to be lower than the reported rate in GGE (Arsov et al., 2012b): 7/504 vs. 0/200. Despite the data described here, SLC2A1 mutations have been previously reported in a small number of patients with focal seizures. It is questionable, however, whether all reported cases would be classified as having a focal epilepsy syndrome or rather that a number of cases had focal seizures as an early feature of epileptic encephalopathy (EE) (Leary et al., 2003). Wolking et al. described two patients with SLC2A1 mutations that could be phenotyped as exclusively NAFE, leading to a total number of six published NAFE patients with SLC2A1 mutations (Leary et al., 2003, Mullen et al., 2010, Pong et al., 2012, Wolking et al., 2014).