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Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures

From the Departments of Neurology (Drs. Jen, Wan, Palos, and Baloh), Biological Chemistry (Dr. Howard), and Head & Neck Surgery (Dr. Baloh), School of Medicine, University of California, Los Angeles.

Address correspondence and reprint requests to Dr. Robert W. Baloh, Departments of Neurology and Head &Neck Surgery, School of Medicine, University of California, Los Angeles, CA 90095; e-mail: rwbaloh{at}ucla.edu

Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter.

Methods: We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3, which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft.

Results: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect.

Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the August 23 issue to find the title link for this article.

This article was previously published in electronic format as an Expedited E-Pub on June 29, 2005, at www.neurology.org.

Supported by National Institutes of Health Grant DC05524 (R.W.B.).

Received April 18, 2005. Accepted in final form May 18, 2005.

This article has been cited by other articles:

				J.C. Jen, T.D. Graves, E.J. Hess, M.G. Hanna, R.C. Griggs, R.W. Baloh, and the CINCH investigators Primary episodic ataxias: diagnosis, pathogenesis and treatment Brain, October 1, 2007; 130(10): 2484 - 2493. [Abstract] [Full Text] [PDF]

				R. C. G. van de Ven, S. Kaja, J. J. Plomp, R. R. Frants, A. M. J. M. van den Maagdenberg, and M. D. Ferrari Genetic Models of Migraine Arch Neurol, May 1, 2007; 64(5): 643 - 646. [Abstract] [Full Text] [PDF]

				K. A. Kerber, J. C. Jen, H. Lee, S. F. Nelson, and R. W. Baloh A New Episodic Ataxia Syndrome With Linkage to Chromosome 19q13 Arch Neurol, May 1, 2007; 64(5): 749 - 752. [Abstract] [Full Text] [PDF]

				T.D. Graves Ion channels and epilepsy QJM, April 1, 2006; 99(4): 201 - 217. [Full Text] [PDF]