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Boukje de Vries, MSc; Hafsa Mamsa, MSc; Anine H. Stam, MD; Jijun Wan, PhD; Stef L. M. Bakker, MD, PhD; Kaate R. J. Vanmolkot, PhD; Joost Haan, MD, PhD; Gisela M. Terwindt, MD, PhD; Elles M. J. Boon, PhD; Bruce D. Howard, MD; Rune R. Frants, PhD; Robert W. Baloh, MD; Michel D. Ferrari, MD, PhD; Joanna C. Jen, MD, PhD; Arn M. J. M. van den Maagdenberg, PhD

Arch Neurol. 2009;66(1):97-101.

Background  Episodic ataxia (EA) is variably associated with additional neurologic symptoms. At least 4 genes have been implicated. Recently, a mutation in the SLC1A3 gene encoding the glutamate transporter EAAT1 was identified in a patient with severe episodic and progressive ataxia, seizures, alternating hemiplegia, and migraine headache. The mutant EAAT1 showed severely reduced uptake of glutamate. The syndrome was designated EA6 and shares overlapping clinical features with EA2, which is caused by mutations in CACNA1A.

Objective  To test the role of the SLC1A3 gene in EA.

Design  Genetic and functional studies. We analyzed the coding region of the SLC1A3 gene by direct sequencing.

Setting  Academic research.

Patients  DNA samples from 20 patients with EA (with or without interictal nystagmus) negative for CACNA1A mutations were analyzed.

Main Outcome Measures  We identified 1 novel EAAT1 mutation in a family with EA and studied the functional consequences of this mutation using glutamate uptake assay.

Results  We identified a missense C186S mutation that segregated with EA in 3 family members. The mutant EAAT1 showed a modest but significant reduction of glutamate uptake.

Conclusions  We broadened the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity of EA6 symptoms appears to be correlated with the extent of glutamate transporter dysfunction.

Author Affiliations: Departments of Human Genetics (Ms de Vries and Drs Vanmolkot, Frants, and van den Maagdenberg), Neurology (Drs Stam, Haan, Terwindt, Ferrari, and van den Maagdenberg), and Clinical Genetics (Dr Boon), Leiden University Medical Centre, Leiden, the Netherlands; Departments of Neurology (Ms Mamsa and Drs Wan, Baloh, and Jen), Biological Chemistry (Dr Howard), and Surgery (Dr Howard), School of Medicine, University of California, Los Angeles; Department of Neurology, St. Franciscus General Hospital, Rotterdam, the Netherlands (Dr Bakker); and Department of Neurology, Rijnland Hospital, Leiderdorp, the Netherlands (Dr Haan).

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