Episodic Ataxia Associated With EAAT1 Mutation C186S Affecting Glutamate Reuptake

Abstract

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.

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

“…19 Glutamate and aspartate are excitatory neurotransmitters involved in various CNS diseases. Heterozygous mutations in the SLC1A3 gene have been reported in one sporadic case and in three members of a family affected by type 6 episodic ataxia, 20,21 and SLCA3 was included in the duplication of one of the five patients with intellectual disability, developmental delay and severe behavioural abnormalities described by Yan et al 16 We hypothesise that SLC1A3 may contribute to the neurological impairment of our patient 1 (which is extreme even among CdLS patients), and minimise the role of the other genes. Interpreting the effect of the loss of a single gene mapping to a deleted region is very difficult, especially when the deletion is too large to identify the specific contribution of each gene to the phenotype.…”

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments

“…However, a mutation in the glutamate transporter GLAST, which is mainly expressed in the cerebellum, has been reported to decrease glutamate uptake and cause episodic ataxia in human subjects. 31,32 In addition, GLAST mutant mice exhibited mild motor discoordination. 33 In light of such findings, the elevated extracellular glutamate concentrations observed in our hyponatremic rat model may therefore play an important role in hyponatremia-induced gait disturbances.…”

DrosophilaGlial Glutamate Transporter Eaat1 Is Regulated by Fringe-Mediated Notch Signaling and Is Essential for Larval Locomotion

“…Certain astrocyte populations take up and recycle extracellular glutamate by expressing high-affinity, sodiumdependent excitatory amino acid transporters (EAATs) known as GLAST (alternate name EAAT1) and GLT-1 (alternate name EAAT2), the primary transporters for glutamate in the mammalian CNS (Matthias et al, 2003). GLAST mutations are found in patients with type 6 episodic ataxia (EA6), a rare form of the disease that variably involves seizures, migraine, cerebellar atrophy, and hemiplegia (Jen et al, 2005;de Vries et al, 2009). Furthermore, expression of EAATs is dysregulated in amyotrophic lateral sclerosis, stroke, epilepsy, schizophrenia, and Alzheimer's and Huntington's diseases, among others (Beart and O'Shea, 2007).…”