Glucose transporter 1 deficiency in the idiopathic generalized epilepsies
Article first published online: 27 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 5, pages 807–815, November 2012
How to Cite
Arsov, T., Mullen, S. A., Rogers, S., Phillips, A. M., Lawrence, K. M., Damiano, J. A., Goldberg-Stern, H., Afawi, Z., Kivity, S., Trager, C., Petrou, S., Berkovic, S. F. and Scheffer, I. E. (2012), Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol., 72: 807–815. doi: 10.1002/ana.23702
- Issue published online: 27 DEC 2012
- Article first published online: 27 DEC 2012
- Accepted manuscript online: 26 JUL 2012 10:12AM EST
- Manuscript Accepted: 25 MAY 2012
- Manuscript Revised: 7 MAY 2012
- Manuscript Received: 20 DEC 2011
- National Health and Medical Research Council program. Grant Number: 6289521
We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).
The IGEs are common, heritable epilepsies that usually follow complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood–brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced.
Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE.
SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders. ANN NEUROL 2012;72:807–815