Elsevier

Epilepsy Research

Volume 133, July 2017, Pages 54-57
Epilepsy Research

Evaluation of GLUT1 variation in non-acquired focal epilepsy

https://doi.org/10.1016/j.eplepsyres.2017.04.007Get rights and content

Highlights

  • Genetic analysis of 200 patients suggests that the frequency of GLUT1 mutation in non-acquired focal epilepsy is low.

  • Limitations of this study include the mean age of onset and cohort size.

  • Future research should focus on subpopulations of focal epilepsy with lower age of seizure onset and co-existent movement disorders.

Abstract

Brain glucose transport is dependent on glucose transporter 1 (GLUT1), encoded by the solute carrier family 2 member 1 (SLC2A1) gene. Mutations in SLC2A1 cause GLUT1 deficiency which is characterized by a broad spectrum of neurological phenotypes including generalized epilepsy, motor disorders, developmental delay and microcephaly. Recent case reports suggest SLC2A1 mutations can contribute to non-acquired focal epilepsy (NAFE) but interrogation of a large patient cohort has not been reported. We studied 200 patients with NAFE (126 with temporal lobe epilepsy) comprising 104 females and 96 males with a mean age of onset of 18 years. Polymerase chain reaction (PCR) and Sanger sequencing was performed to detect variants in all 10 coding exons and splice site regions of the SLC2A1 gene. We did not detect any pathogenic mutations in SLC2A1 in this cohort. Our data suggests that the frequency of GLUT1 mutations in NAFE is low. Limitations of this study include the mean age of onset and cohort size. Future research should focus on subpopulations of focal epilepsy with lower age of seizure onset particularly with co-existent movement disorders in which GLUT1 mutations may play a more important role.

Introduction

Glucose is the main fuel of the brain 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.

Section snippets

Clinical Phenotyping

Australian patients (n = 200) with well-documented focal epilepsy without a known acquired cause were recruited over a period of 25 years at first-seizure and epilepsy clinics at Austin Health, private practices of the investigators and by referral for genetics research. Comprehensive clinical phenotyping was performed by review of source data, medical records and family history, including electroencephalography (EEG) and magnetic resonance imaging (MRI) data from most patients. Both 1.5T and 3T

Clinical Syndromes

The patient cohort consisted of 200 individuals with non-acquired focal epilepsy (NAFE) and 10 healthy controls. A total of 104 female and 96 male patients with a mean age of 39 years (range 12–84) were included (Table 1). Their average age of onset was 18 years (range 0.5–48 years). As expected the most common syndrome was temporal lobe epilepsy (126/200 patients), consistent with its well-documented prevalence (Zarrelli et al., 1999). The other patients had less common syndromes including

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

Conclusion

Our data suggests that the frequency of GLUT1 mutations in NAFE is low. Limitations of this study include the mean age of onset and cohort size.

Contributors

S.A.M., and M.S.H. initiated and directed the project. A.P., and J.A.D. performed molecular genetics experiments. S.T.B., I.E.S., S.F.B., and I.E.S. conducted clinical phenotyping. A.P., and S.A.M. completed statistical analysis. A.P., S.F.B., S.A.M., and M.S.H. wrote the paper. All authors discussed the results and commented on the manuscript.

Conflicts of interests

IES discloses payments from UCB Pharma, Eisai, GSK, Athena Diagnostics, and Transgenomics for lectures and educational presentations, and a patent for SCN1A testing held by Bionomics Inc. licensed to various diagnostic companies. SFB discloses payments from UCB Pharma, Novartis Pharmaceuticals, Sanofi-Aventis, and Jansen Cilag for lectures and educational presentations, and a patent for SCN1A testing held by Bionomics Inc. licensed to various diagnostic companies. None of the other authors has

Acknowledgements

We thank the patients and their families 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

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