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.
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.
Authors: Dalyir I Pretto; Madhur Kumar; Zhengyu Cao; Christopher L Cunningham; Blythe Durbin-Johnson; Lihong Qi; Robert Berman; Stephen C Noctor; Randi J Hagerman; Isaac N Pessah; Flora Tassone Journal: Neurobiol Aging Date: 2013-11-16 Impact factor: 4.673
Authors: Verneri Anttila; Hreinn Stefansson; Mikko Kallela; Unda Todt; Gisela M Terwindt; M Stella Calafato; Dale R Nyholt; Antigone S Dimas; Tobias Freilinger; Bertram Müller-Myhsok; Ville Artto; Michael Inouye; Kirsi Alakurtti; Mari A Kaunisto; Eija Hämäläinen; Boukje de Vries; Anine H Stam; Claudia M Weller; Axel Heinze; Katja Heinze-Kuhn; Ingrid Goebel; Guntram Borck; Hartmut Göbel; Stacy Steinberg; Christiane Wolf; Asgeir Björnsson; Gretar Gudmundsson; Malene Kirchmann; Anne Hauge; Thomas Werge; Jean Schoenen; Johan G Eriksson; Knut Hagen; Lars Stovner; H-Erich Wichmann; Thomas Meitinger; Michael Alexander; Susanne Moebus; Stefan Schreiber; Yurii S Aulchenko; Monique M B Breteler; Andre G Uitterlinden; Albert Hofman; Cornelia M van Duijn; Päivi Tikka-Kleemola; Salli Vepsäläinen; Susanne Lucae; Federica Tozzi; Pierandrea Muglia; Jeffrey Barrett; Jaakko Kaprio; Markus Färkkilä; Leena Peltonen; Kari Stefansson; John-Anker Zwart; Michel D Ferrari; Jes Olesen; Mark Daly; Maija Wessman; Arn M J M van den Maagdenberg; Martin Dichgans; Christian Kubisch; Emmanouil T Dermitzakis; Rune R Frants; Aarno Palotie Journal: Nat Genet Date: 2010-08-29 Impact factor: 38.330